The invention relates to a method for industrially producing highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide (crystal) or (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol. The method for producing N-carbamate-protected xcex2-aminoepoxide crystal, includes one or more of the following steps (a) to (d):

The present invention relates to a method for producing and purifying N-carbamate-protected xcex2-aminoepoxide with a specific steric configuration {(2R, 3S) or (2S, 3R)} and a method for producing the crystal. The invention also relates to a method for producing and purifying N-carbamate-protected xcex2-aminoalcohol with a specific steric configuration {(2R, 3S) or (2S, 3R)}.
The N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2) is a useful compound as a pharmaceutical intermediate:
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing a hetero atom in these carbon backbones; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)}.
It is known for example that (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide is useful as an intermediate of HIV protease inhibitors and renin inhibitors (see for example Raddatz et al., Journal of Medicinal Chemistry, 1991, 34, 11,3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update).
It has been known that N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2) can be synthesized according to the following pathway.
{in the formula, R and A represent the same meanings described above; X represents halogen atom}.
When (3S)-N-carbamate-protected xcex1-halomethylketone as the compound represented by the general formula (4) is used as a starting material, for example, the starting material is reduced to afford (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol, followed by treatment with a base, to afford (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide.
Similarly, when (3R)-N-carbamate-protected xcex1-halomethylketone is used as a starting material, the starting material is reduced to afford (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol, followed by treatment with a base, to afford (2S, 3R)-N-carbamate-protected aminoepoxide.
Herein, the reduction of N-carbamate-protected xcex1-halomethylketone with an appropriate reducing agent involves the generation of the diastereomer as a byproduct.
For example, the reduction of (3S)-N-carbamate-protected xcex1-halomethylketone represented by the general formula (13) involves the generation of the diastereomer (2S, 3S)-N-carbamate-protected xcex2-aminoalcohol (7) as a byproduct.
Upon treatment with a base, the byproduct is converted to as (2S, 3S)-N-carbamate-protected xcex2-aminoepoxide (11) as the diastereomer of the objective compound (see the following scheme).
{in the formulas, R, A, X represent the same meanings as described above.}
More specifically, for example, it is reported that the reduction of, e.g., (3S)-3-tert-butoxycarbonylamino-1-halo-4-phenyl-2-butane in ether with lithium aluminum tri-tert-butoxyhydride involves the generation of the diastereomer (2S, 3S)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4phenylbutane at a ratio of about 1 mol equivalent to 5 to 8 mol equivalents of the objective (2R, 3S) compound (see P. Raddatz et al., J. Med. Chem., 1991, 34, 11, 3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update). (2R, 3S)-3-tert-butoxycarbonylamino 1,2-epoxy-4-phenylbutane afforded by an additional treatment with a base also contains the diastereomer at about the same ratio.
The above references disclose methods for separating (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol or (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide by silica gel chromatography or high-performance liquid chromatography, but the methods require the use of vast amounts of expensive carriers and solvents and take a long time due to the complex procedures. Accordingly, these methods are not industrially appropriate.
Of the references above, the latter reference discloses on page 3 that because (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol or (2R, 3S)N-carbamate-protected xcex2-aminoepoxide is at a lower melting point and a higher solubility than those of the diastereomer, the ratio of the diastereomer to the objective compound can be reduced to 94:6, at most, by purification with crystallization and that no more purification thereof by recrystallization is possible.
Further, the technique for removing other impurities is not necessarily satisfactory. Hence, the development of an industrial method for producing highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide has been desired.
It is an object of the present invention to provide an industrial method for producing (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide (including the crystal) and N-carbamate-protected xcex2-aminoalcohol.
The present inventors have made investigations so as to solve the problem. The following findings have been found.
1) By dissolving (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity or an optical isomer thereof in a solvent including at least one or more selected from aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, thereby removing insoluble matters, the diastereomer as an impurity is highly separated and removed.
2) By treating (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide containing at least the diastereomer as an impurity or an optical isomer thereof with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative, and separating and removing the resulting derivative in water or an aqueous mixture solvent, the diastereomer as an impurity is highly separated and removed.
3) By crystallizing (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide or an optical isomer thereof in an aqueous mixture solvent, a more highly pure crystal of the epoxide can be obtained.
Accordingly, the object of the present invention, and others, may be accomplished with a method for producing N-carbamate-protected xcex2-aminoepoxide crystal including:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity and being represented by the general formula (1), in a solvent including at least one or more selected from aromatic hydrocarbon solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble matters:
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in these carbon backbones; X represents halogen atom; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(b) treating the N-carbamate-protected xcex2-aminoalcohol represented by the general formula (1) with a base, thereby converting the N-carbamate-protected xcex2-aminoalcohol to N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2):
{in the formula, R, A and * represent the same meanings as described above; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(c) treating the N-carbamate-protected xcex2-aminoepoxide containing at least the diastereomer as an impurity and being represented by the general formula (2) with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative represented by the general formula (3):
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in these carbon backbones; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)
{in the formula, A and * represent the same meaning as described above; the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S)}, and, if necessary, separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and
(d) crystallizing the N-carbamate-protected aminoepoxide represented by the general formula (2) in an aqueous mixture solvent.
Another embodiment of the invention provides a crystal of N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the invention provides a method for producing an N-carbamate-protected xcex2-aminoalcohol, which includes:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol including at least a diastereomer thereof as an impurity and represented by the formula (1) in at least one solvent selected from the group including aromatic hydrocarbon, aryl halide, saturated hydrocarbon, aqueous mixture, acetone and 2-propanol, to remove insoluble materials:
wherein in formula (1):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone;
X represents halogen atom; and
* represents asymmetric carbon atom;
wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide, which includes:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol including at least a diastereomer thereof as an impurity and represented by the formula (1), in at least one solvent selected from the group including aromatic hydrocarbon, aryl halide, saturated hydrocarbon, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble materials:
wherein in formula (1):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone;
X represents halogen atom; and
* represents asymmetric carbon atom;
wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R);
(b) treating the N-carbamate-protected xcex2-aminoalcohol represented by the formula (1) with a base, thereby converting the N-carbamate-protected xcex2-aminoalcohol to N-carbamate-protected xcex2-aminoepoxide represented by the formula (2):
wherein in formula (2), R, A and * have the same meanings as recited above; and wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide crystal, which includes:
(c) treating the N-carbamate-protected xcex2-aminoepoxide including at least a diastereomer thereof as an impurity and represented by the formula (2) with an acid, thereby converting the diastereomer to oxazolidin-2-one derivative represented by the formula (3):
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; and wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R);
wherein in formula (3), A and * have the same meaning as recited above; and wherein the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S), and optionally separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and
(d) crystallizing the N-carbamate-protected aminoepoxide represented by the formula (2) in an aqueous mixture solvent.
Another embodiment of the present invention provides a crystal of the N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide crystal, which includes:
(d) crystallizing the N-carbamate-protected xcex2-aminoepoxide represented by the formula (2) in an aqueous mixture solvent:
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a crystal of N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the present invention provides a method for producing an N-carbamate-protected aminoepoxide, which includes:
(c) treating the N-carbamate-protected aminoepoxide including at least a diastereomer thereof as an impurity and being represented by the formula (2) with a solid acid insoluble in solvents, thereby converting the diastereomer to oxazolidin-2-one derivative represented by the formula (3):
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R);
wherein in formula (3), A and * have the same meaning as recited above; and wherein the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S); and
separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent.
By the methods of the present invention, highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide or (2R, 3S) or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol can be efficiently produced.
Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood from the following detailed description of the preferred embodiments of the invention.
In the present specification, (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol is sometimes abbreviated as (2R, 3S) alcohol; and the diastereomer as an impurity is sometimes abbreviated as (2S, 3S) alcohol.
Additionally, (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol is sometimes abbreviated as (2S, 3R) alcohol; and the diastereomer as an impurity is sometimes abbreviated as (2R, 3R) alcohol.
Still additionally, (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide is sometimes abbreviated as (2R, 3S) epoxide; and the diastereomer as an impurity is sometimes abbreviated as (2S, 3S) epoxide.
Furthermore, (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide is sometimes abbreviated as (2S, 3R) epoxide; and the diastereomer as an impurity is sometimes abbreviated as (2R, 3R) epoxide.
In the formulas in accordance with the invention, X represents halogen atom. As the halogen atom, chlorine atom and bromine atom are preferable; and chlorine atom is particularly preferable.
In the formulas in accordance with the invention, R represents a lower alkyl group, benzyl group or fluorenylmethyl group. As the R, a lower alkyl group is preferable. The lower alkyl group includes an alkyl group with 1 to 8 carbon atoms, preferably an alkyl group with 1 to 4 carbon atoms. Methyl group, ethyl group and tert-butyl group are particularly preferred.
As the R, tert-butyl group is most particularly preferable.
In the formulas in accordance with the invention, A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing a hetero atom in these carbon backbones. Preferably, A represents an unsubstituted or substituted alkyl group with 1 to 8 carbon atoms, an unsubstituted or substituted aryl group with 6 to 13 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 18 carbon atoms, or a group containing a hetero atom in these carbon backbones. When A is substituted one or more groups as above-mentioned, the substituent is not particularly limited unless it especially affect the reaction of the invention. The substituent includes, for example, alkoxyl group (preferably with 1 to 7 carbon atoms), nitro group, alkyl group (preferably with 1 to 6 carbon atoms), and halogen atom.
The group containing one or more hetero atoms in these carbon backbones includes, for example, methylthioethyl group, t-butylthiomethyl group, tritylthiomethyl group, (p-methylbenzyl)thiomethyl group, (p-methoxybenzyl)thiomethyl group, t-butoxymethyl group, benzyloxymethyl group, t-butoxyethyl group, benzyloxyethyl group, 4-(t-butoxy)phenylmethyl group, 4-benzyloxyphenylmethyl group and phenylthiomethyl group.
Such groups can be introduced by using for example amino acid as a raw material. In case that A is methyl group, for example, alanine is used as a raw material; in case that A is isopropyl group, valine is used as a raw material; in case that A is 2-methylpropyl group, leucine is used as a raw material; in case that A is 1-methylpropyl group, isoleucine is used as a raw material; in case that A is benzyl group, phenylalanine is used as a raw material; in case that A is methylthioethyl group, methionine is used as a raw material.
Additionally, A may satisfactorily be a group introduced from a raw material amino acid with a functional group in the side chain of the amino acid under protection, for example S-t-butylcysteine, S-tritylcysteine, S-(p-methylbenzyl)cysteine, S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine, O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine and O-benzyltyrosine.
Furthermore, A is not limited to groups introduced from raw materials derived from natural amino acid, but may satisfactorily be groups (for example, phenyl group and phenylthiomethyl group) introduced from raw materials derived from non-natural amino acid.
In accordance with the invention, preference is given to compounds wherein A is an aryl group with 6 to 15 carbon atoms, an aralkyl group with 7 to 20 carbon atoms or a group containing a hetero-atom in these carbon backbones; furthermore, preference is given to compounds wherein A is an aralkyl group with 7 to 20 carbon atoms or a group containing a hetero-atom in these carbon backbones. More specifically, preference is given to compounds wherein A is benzyl group, phenylthiomethyl group, 4-benzyloxyphenylmethyl group, isopropyl group, 2-methylpropyl group and 1-methylpropyl group; still furthermore, preference is given to compounds wherein A is benzyl group, phenylthiomethyl group and 4-benzyloxyphenylmethyl group. Compounds wherein A is benzyl group are particularly preferable.
The preferable process (a) is described below.
N-Carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity and being represented by the general formula (1), namely the (2R, 3S) alcohol or (2S, 3R) alcohol, may be obtained by reducing (3S)-N-carbamate protected xcex1-aminohalomethylketone represented by the general formula (13) or (3R)-N-carbamate-protected aminohalomethylketone represented by the general formula (14)
{in the formula, R, A and X represent the same meanings as described above}
{in the formula, R, A and X represent the same meanings as described above}.
It has been known that the ratio of the generated (2R, 3S) alcohol and (2S, 3S) alcohol through reduction varies depending on the type of a reducing agent. By selecting an appropriate reducing agent, the ratio of the diastereomer as an impurity can be suppressed at some extent (see T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update). This is the same for the ratio of the (2S, 3R) alcohol and the (2R, 3R) alcohol in the case of the reduction of (3R)-N-carbamate-protected xcex1-aminohalomethylketone.
Preferable reducing agents include for example lithium aluminum tri-tert-butoxyhydride, (+)-B-chlorodiisopinocamphenylborane, and boron potassium trisec-butylhydride; particularly, lithium aluminum tri-tert butoxyhydride is preferable.
Herein, (3S)-N-protected xcex1-aminohalomethylketone and (3R)-N-protected xcex1-aminohalomethylketone can be produced by known methods, for example, such as the method including allowing amino acid ester with the amino group under protection, to react with a metal enolate prepared from xcex1-haloacetic acid, thereby eliminating carbonate (see International Patent Publication WO 96/23756).
When the reaction mixture recovered by the method is subjected for example to the process (a) of the invention, the ratio of the objective (2R, 3S) alcohol or (2S, 3R) alcohol is preferably high. Even when the ratio of each of these diastereomers to the (2R, 3S) alcohol or (2S, 3R) alcohol is high, the method of the invention is applicable.
The method of the invention is applicable to a mixture at a molar ratio of (2S, 3S) alcohol/(2S, 3R) alcohol or (2R, 3R) alcohol/(2S, 3R) alcohol, below 100, preferably below 1, more preferably below xc2xd, particularly preferably below ⅓.
The aromatic hydrocarbon solvent to be used at the process (a) includes for example benzene, xylene, toluene and an appropriate mixture solvent of these solvents Particularly, xylene, toluene and an appropriate mixture solvent of these solvents are preferable; toluene is particularly preferable.
The aryl halide solvent to be used at the process (a) includes for example chlorobenzene, bromobenzene and appropriate mixture solvents of these solvents. Particularly, chlorobenzene is preferable.
The saturated hydrocarbon solvent to be used at the process (a) includes for example n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, isohexane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, petroleum ether, and appropriate mixture solvents of these solvents.
Particularly preferable solvents include n-hexane, n-heptane, cyclohexane, methylcyclohexane and appropriate mixtures of these solvents. Particularly, n-heptane is preferable.
The aqueous mixture solvent at the process (a) means a mixture solvent of a water-miscible organic solvent with water; the organic solvent miscible with water includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran. Methanol, ethanol, 2-propanol, acetone and appropriate mixture solvents of these solvents are preferable; furthermore, methanol, ethanol, 2-propanol and appropriate mixture solvents of these solvents are more preferable; and particularly, 2-propanol is preferable. Acetone and 2-propanol can be used singly, but preferably, they are used in the form of mixture solvents with water.
The composition ratio of water and an organic solvent is not particularly limited, but the ratio is preferably 5 to 95%, more preferably 25 to 90% (% is expressed as the volume ratio of an organic solvent in a mixture solvent).
More preferable are aromatic hydrocarbon solvents and aqueous mixture solvents among the solvents for use at the process (a). Particularly, aromatic hydrocarbon solvents are preferable. Among them, more preferable are toluene, xylene and a mixture solvent of 2-propanol with water; particularly, toluene is preferable.
As far as the advantages of the invention are not adversely influenced, other solvents may be added to the solvent for use as the solvent at the process (a).
At the process (a) of the invention, the (2R, 3S) alcohol or (2S, 3R) alcohol at least containing the diastereomer as an impurity is dissolved in aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, acetone, 2-propanol or aqueous mixture solvent, to remove insoluble matters. More specifically, a state such that the objective (2R, 3S) alcohol or (2S, 3R) alcohol is dissolved in these solvents while the diastereomer is present as insoluble matters, is to be realized, despite any procedure adopted.
For example, a solvent including at least one or more selected from aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol is added to the (2R, 3S) alcohol or (2S, 3R) alcohol at least containing the diastereomer as an impurity, for agitation. Then, the (2R, 3S) alcohol or (2S, 3R) alcohol is relatively readily dissolved in these solvents, while the diastereomer thereof is slightly soluble and turns insoluble matters to be generally prepared as a form of slurry, although the form depends on the content of impurities, the solvent volume and the temperature. For example, at a high temperature above ambient temperature, the slurry form is modified into a solution state, which is then cooled down to an appropriate temperature to deposit the diastereomer as an impurity.
For example, for subjecting the reaction mixture obtained by reduction to the process (a) of the present invention, the reaction solvent is preferably concentrated or more preferably sufficiently evaporated after the reduction is terminated; and subsequently, the aforementioned solvent is added to the resulting residue, from the respect of purification efficiency.
The quantity of solvent to be added is not particularly limited, but is preferably at a weight 1- to 50-fold the weight of a mixture to be subjected to the process (a). The temperature for agitation is not particularly limited and is for example a temperature at xe2x88x9220xc2x0 C. to a temperature below the boiling point of the solvent to be used. The temperature preferably varies, depending on the type and quantity of the solvent to be used. So as to decrease the loss of the objective compound, for example, wherein a saturated hydrocarbon solvent is used, the solvent is heated to an appropriate temperature above ambient temperature and below the boiling point of the solvent (preferably, 35xc2x0 C. to 70xc2x0 C.), preferably, while insoluble matters are filtered under heating as they are. In case that an aromatic hydrocarbon solvent or aryl halide solvent is used, for example, the temperature of the solvent is controlled to below ambient temperature down to an appropriate temperature (for example, about xe2x88x9220xc2x0 C.), preferably, while insoluble matters are filtered. In case that an aqueous mixture solvent is used, for example, insoluble matters are satisfactorily filtered within a range of about 0xc2x0 C. to 50xc2x0 C., which varies depending on the mixing ratio of water and a solvent. The agitation time is not particularly limited but is preferably 10 minutes to 6 hours; more preferably 30 minutes to 5 hours, and most preferably, 1 hour to 4 hours.
A person with an ordinary skill in the art can readily determine preferable conditions depending on the solvent to be used, on the basis of the description of the specification.
Then, insoluble matters are preferably removed, e.g., by filtration. The (2S, 3S) alcohol or (2R, 3R) alcohol as an impurity is then removed as solid. By evaporation of the solvent in the filtrate, the (2R, 3S) alcohol or (2S, 3R) alcohol can be obtained. By cooling the filtrate, the objective compound can satisfactorily be isolated by crystallization. If necessary, the solvent of the filtrate is removed by azeotropic distillation for the following reaction process. And if necessary, the filtrate is used at the following reaction process after the filtrate is concentrated or as it is.
The purification procedures described above can satisfactorily be repeated at plural times, if necessary, in case that mixtures at a high impurity content are purified. Additionally, and optionally, the purification procedures may satisfactorily be effected in combination with other purification procedures known to a person with an ordinary skill in the art. For the synthesis of the objective compound for example through reduction, as described above, the ratio of the diastereomer as an impurity can be suppressed at a certain degree by selecting an appropriate reducing agent, so that single purification procedure may afford highly purified objective compound.
According to the process (a) of the invention, the (2R, 3S) alcohol or (2S, 3R) alcohol as the objective compound can be efficiently purified and isolated by simple procedures; the content of the diastereomer as an impurity can be reduced below 6%, which is described as impossible in the above reference.
More specifically, the solid separated as insoluble matters is a solid containing the (2S, 3S) alcohol or (2R, 3R) alcohol as the principal component, although the solid generally contains a certain content of the (2R, 3S) alcohol or (2S, 3R) alcohol. The solid is purified by using known purification methods such as Soxhlet extraction, the process (a) of the invention or a combination of these methods if necessary; otherwise, these purification methods can be repeated, if necessary, to thereby afford highly purified (2S, 3S) alcohol or (2R, 3R) alcohol.
The preferable process (b) is described below.
By treating the N-carbamate-protected xcex2-aminoalcohol represented by the general formula (1) with a base, the N-carbamate-protected xcex2-aminoalcohol can be converted to N-carbamate-protected xcex2-aminoepoxide as an intermediate at a progressed stage, which is represented by the general formula (2) (see the references described above).
The base preferably includes potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride; sodium hydroxide and potassium carbonate are particularly preferable.
The reaction solvent preferably includes protonic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1,2-dimethylpropanol and water or non-protonic solvents such as acetone, tetrahydrofuran and acetonitrile, singly or in mixture; ethanol, a mixture solvent of ethanol and water, a mixture solvent of 2-propanol and water, and a mixture solvent of acetone and water are particularly preferable.
The amount of the base to be used varies depending on the type of the base to be used and the combination of solvents, but the amount is generally 1 to 10 equivalents, preferably 1 to 5 equivalents. The reaction temperature varies depending on the type of the base and the combination of solvents, but the temperature is generally xe2x88x9210 to 80xc2x0 C., preferably 0 to 60xc2x0 C. The reaction time is not particularly limited, but the reaction time is preferably about 10 minutes to about 50 hours, more preferably about 30 minutes to about 40 hours, and most preferably about 1 hour to about 30 hours.
The reaction is preferably performed under agitation; after termination of the reaction, acid is satisfactorily added to quench the reaction. The acid, preferably, includes hydrochloric acid, sulfuric acid, acetic acid, citric acid and aqueous potassium hydrogen sulfate solution.
The (2R, 3S) epoxide or (2S, 3R) epoxide may be isolated from the reaction solvent by methods such as extraction, but preferably by the crystallization method at the process (d) described below. Further, so as to further remove the impurity diastereomer, the process (c) described below is preferably effected.
Preferably, for performing the process (c) or process (d) subsequent to the process (b), the reaction solvent is concentrated or substituted with an appropriate solvent, if necessary, without extraction, for use at the following process. Additionally, crystallization may be performed by the method of the process (d) after the process (b), followed by the process (c), to obtain N-carbamate-protected xcex2-aminoepoxide crystal, again at the process (d). In such manner, the same processes can be performed at plural times, if necessary.
The preferable process (c) is described below.
N-Carbamate-protected xcex2-aminoepoxide containing the diastereomer as an impurity, as represented by the general formula (2), is treated with an acid, to convert the impurity diastereomer to oxazolidin-2-one represented by the general formula (3), if necessary, which is then separated and removed in water or an aqueous mixture solvent.
When N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2), namely the (2R, 3S) epoxide or (2S, 3R) epoxide, is treated with an acid, the diastereomer (2S, 3S) epoxide or (2R, 3R) epoxide is relatively rapidly converted to oxazolidin-2-one derivative represented by the general formula (3) (see Reference Examples 4 and 5 described below). Because the reaction velocity of the (2R, 3S) epoxide or (2S, 3R) epoxide is slow, the diastereomer as an impurity can be removed, preferentially, by removing the resulting oxazolidin-2-one derivative from the system (Tetrahedron Letters, Vol. 35, No. 28, pp. 4939-4942, 1994).
As the acid, for example, preference is given to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acidic ion exchange resin (ion exchange resin acid catalyst), acid alumina (alumina acid catalyst), acid zeolite (zeolite acid catalyst) and acid china clay; solid acids insoluble in solvents such as p-toluenesulfonic acid, acid ion exchange resin, acid zeolite, and acid china clay, are preferable. Solid acids insoluble in solvents suitable for the reaction, such as acid ion exchange resin, acid alumina, acid zeolite and acid china clay are readily removed, while byproducts generated via the reaction of the epoxide with acids can be removed under filtration, simultaneously. Thus, these solid acids are particularly preferable.
The preferable reaction solvent includes methanol, ethanol, 2-propanol, 1,2-dimethylpropanol, water, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, dichloroethane, diethyl ether, benzene, toluene, hexane and heptane, singly or in mixture; non-protonic solvents such as dichloromethane, toluene, acetone and acetonitrile are particularly preferable.
The quantity of acid varies, depending on the type of the acid used, and is not particularly limited. With respect to the quality (purity) and yield of the objective (2R, 3S) or (2S, 3R) epoxide, a person with an ordinary skill in the art can easily determine an appropriate amount without undue experimentation.
When p-toluenesulfonic acid is used, for example, about 1 to 5 equivalents of the acid to the (2S, 3S) or (2R, 3R) epoxide contained as an impurity is preferably used. In case that strong acid ion exchange resins and acid zeolite are used, additionally, 1 to 200% by weight of the acids is preferably used to the (2R, 3S) or (2S, 3R) epoxide to be treated.
The reaction temperature varies, depending on a combination of acids and solvents, but the reaction temperature is generally xe2x88x9210 to 120xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is preferably about 10 minutes to 50 hours, more preferably about 30 minutes to about 40 hours, and most preferably about 1 hour to about 30 hours, with no specific limitation. The objective (2R, 3S) or (2S, 3R) epoxide reacts just slowly with such acid and is converted to oxazolidin-2-one, so the reaction for a period more than necessary is not preferable. Like the quantity of the acid to be used, an appropriate reaction time can readily be determined by a person with an ordinary skill in the art, by monitoring the concentration of the diastereomer in the reaction solution, with respect to the desired quality (purity) and yield of the objective compound.
Through the acid treatment described above, the diastereomer contained as an impurity is preferentially converted to oxazolidin-2-one derivative.
Because the oxazolidin-2-one derivative is soluble in water, the oxazolidin-2-one derivative can be readily separated and removed by dissolving the oxazolidin-2-one derivative in water or an aqueous mixture solvent. The aqueous mixture solvent means a mixture solvent of a water-miscible organic solvent with water; the organic solvent includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran.
The method for separating and removing the oxazolidin-2-one derivative in water or an aqueous mixture solvent includes extraction or crystallization, but with no specific limitation. Wherein the process (d) is performed after the process (c), crystallization is performed in an aqueous mixture solvent, so the oxazolidin-2-one derivative is separated and removed in the mother liquor. Therefore, generally, it is not necessary to preliminarily remove the oxazolidin-2-one derivative by extraction and the like, prior to the process (d).
The preferable extraction case is described herein below. In this case, water is particularly preferable as the solvent for dissolving the oxazolidin-2-one derivative.
When solvent-soluble acids, such as p-toluenesulfonic acid, are used in the acid treatment process, for example, aqueous basic solutions such as sodium hydrogen carbonate are added under agitation, if necessary, after an appropriate reaction time, to terminate the reaction.
Thereafter, the organic layer is optionally evaporated, so as to substitute the organic layer with a solvent preferable for extraction. The extraction solvent preferably includes toluene, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and dichloromethane; with respect to the separation and removal efficacy of the oxazolidin-2-one into an aqueous phase, toluene is particularly preferable. For extraction, preferably, insoluble matters in the organic layer or in the aqueous phase are preliminarily filtered off. After extraction, the organic layer is separated and preferably rinsed further in water, to efficiently remove (4S, 5R) or (4R, 5S) oxazolidin-2-one.
When solvent-insoluble acids, such as ion exchange resin and acid zeolite, are used, these acids can be removed under filtration to terminate the reaction. Thereafter, the organic solvent is optionally evaporated, so as to substitute the organic solvent with a solvent preferable for extraction. The extraction solvent preferably includes toluene, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and dichloromethane; with respect to the separation and removal efficacy of the oxazolidin-2-one into the aqueous phase, toluene is particularly preferable. Then, water or aqueous mixture solvents are added for extraction; then, preferably, insoluble matters in the organic layer or in the aqueous layer are preliminarily filtered off. After extraction, the organic layer is separated and preferably rinsed further in water, to efficiently remove (4S, 5R) or (4R, 5S) oxazolidin-2-one.
By the method of the process (c) described above, the diastereomer as an impurity can be removed at a high efficiency. After the method of the process (a) of preliminarily removing the diastereomer, (2R, 3S) or (2S, 3R) epoxide, from which the diastereomer has been greatly removed, can be obtained by the process (c). Through the processes (a) and (c) of the invention or via the process (d) after these processes, the (2R, 3S) or (2S, 3R) epoxide can be obtained with a content of the diastereomer as an impurity below 3%, preferably below 2% and more preferably below 1%. The (2R, 3S) or (2S, 3R) epoxide thus afforded can be obtained as solid by evaporating the organic layer under reduced pressure. If necessary, further, the resulting solid can be purified with adsorption resins and the like. By the process (d) described below, the crystal of the (2R, 3S) or (2S, 3R) epoxide at a high purity can be recovered by such industrially advantageous method.
The preferable process (d) is described below.
Through crystallization of the (2R, 3S) or (2S, 3R) epoxide in an aqueous mixture solvent, the crystal at high purity can be obtained.
Firstly, an aqueous mixture solvent is added to the (2R, 3S) or (2S, 3R) epoxide. The aqueous mixture solvent means a mixture solvent of a water-miscible organic solvent with water; and the organic solvent includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran. Particular preference is given to methanol, ethanol, 2-propanol, acetonitrile and acetone. The composition ratio of water and the organic solvent is not particularly limited but is preferably at 5 to 95%, more preferably at 25 to 85% (% is expressed as the ratio of the organic solvent in the mixture solvent).
The volume of the aqueous mixture solvent to be used is not particularly limited, but for example, the solvent of a volume of 2 to 20 ml to 1 g of for example the (2R, 3S) or (2S, 3R) epoxide can be used.
By subsequently cooling of the mixture, the (2R, 3S) or (2S, 3R) epoxide is crystallized.
The temperature for crystallization is preferably xe2x88x9240xc2x0 C. to 25xc2x0 C., particularly preferably xe2x88x9220xc2x0 C. to 10xc2x0 C. The crystallization then is performed, satisfactorily, under agitation or while left to stand alone. The crystallization is preferably performed under agitation, however. Generally, the (2R, 3S) or (2S, 3R) epoxide is not easily crystallized even in the aqueous mixture solvent which is comparatively good solvent for crystallizing (2R, 3S) or (2S, 3R) epoxide in comparison with other solvents. However, the crystallization may be easily performed by adding the seed crystal under the aqueous mixture solvent.
Optionally, to enhance the purification effect, the resulting crystal is heated to about 10xc2x0 C. to about 40xc2x0 C. to partially dissolve the crystal, which is again cooled to xe2x88x9220xc2x0 C. to 10xc2x0 C., for crystallization. The resulting crystal is preferably washed with water and the like. The process (d) enables efficient removal of the highly polar impurity into the mother liquor. Thus, highly pure (2R, 3S) or (2S, 3R) epoxide can be obtained.
Because the diastereomer (2S, 3S) or (2R, 3R) epoxide is hardly removed even by crystallization, as described above, more highly pure (2R, 3S) or (2S, 3R) epoxide can be recovered by performing the processes (a) and (b), or the process (c), or a combination of the processes (a), (b) and (c). If necessary, additionally, the process (d) may satisfactorily be carried out at plural times.

Abstract: (a) dissolving (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity in a solvent including at least one or more selected from aromatic hydrocarbon solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble matters;

Abstract: (b) treating the (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol with a base, thereby converting the N-carbamate-protected xcex2-aminoalcohol to (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide;

Abstract: (c) treating the (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide containing at least the diastereomer as an impurity with an acid, thereby converting the diastereomer as an impurity to (4S, 5R) or (4R, 5S) oxazolidin-2-one derivative, and optionally separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and

Abstract: (d) crystallizing the (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide in a mixture solvent of water and water-miscible organic solvent. By the methods of the present invention, highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide or (2R, 3S) or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol can be efficiently produced.


An ice-making tray according to the concept of the present invention is capable of making ice at high speed and improving the transparency of ice by providing a second tray having ice cells for storing ice-making water to be coupled, in an overlapping manner, to the upper surface of a first tray which is in contact with a refrigerant pipe. The first tray may be formed of an aluminum material, the second tray may be formed of a plastic material, and the first tray formed of an aluminum material can efficiently function as a heat exchanger of an ice-making space due to having high thermal-conductivity. In the second tray, a fixing part for fixing the ice-making tray inside the ice-making space, a shaft accommodating part for accommodating the rotation shaft of an ejector, a temperature sensor accommodating part for accommodating a temperature sensor, and an air insulating part for insulating the ice-making tray and an ice separating motor may be formed integrally.

In general, a refrigerator is an appliance which includes storage compartments and cooling air supply units which supply cooling air to the storage compartments and thus maintains the freshness of stored food. The refrigerator may further include an ice-making chamber and an ice-making unit for generating ice.
An automatic ice-making unit includes an ice-making tray which stores ice-making water, an ejector which separates ice made by the ice-making tray, an ice-separating heater which heats the ice-making tray when the ice is separated from the ice-making tray, and an ice bucket which stores the ice separated from the ice-making tray.
Among ice-making methods for cooling ice-making water, a direct cooling method has a refrigerant pipe provided to extend into an ice-making chamber for cooling ice-making water and to be in contact with an ice-making tray. In such a direct cooling method, the ice-making tray receives cooling energy from the refrigerant pipe by thermal conduction. Accordingly, the direct cooling method has a merit in that a cooling speed of ice-making water is fast. However, when the cooling speed of ice-making water is excessively fast, ice which is not transparent and is turbid is generated.

This patent is subject to a terminal disclaimer.

Ice-making tray and refrigerator comprising same


An improved coupler body having an area of increased material in the upper lock chamber.

The coupler assemblies on railcars sometimes do not operate properly in lock set. When the coupler is in the lock set position, the couplers are still engaged, but pulling forces between the railcars allows them to be pulled apart. The knuckle of the coupler may jam against the lock, preventing proper knuckle rotation. In some cases, may be as much as 50% of the time, knuckle and lock interference occurs in lock set, requiring the user to lift and hold the uncoupling lever in its most raised position to facilitate uncoupling. The traditional focus when addressing lock set jamming concerns between the knuckle and lock was on the lock and its interface with the thrower.
The options for addressing these problems are limited if the focus is only on the locations addressed in previous patents, such as U.S. Pat. Nos. 2,350,470; 2,709,007; 3,850,312; 4,084,705 and 4,363,414, all of which are herein incorporated by reference in their entirety. The options are also limiting when the focus is only on the mating parts of the system.
Other complications when attempting to solve this problem include the inability to completely measure (scan) to a very accurate level (+/−0.001″) all the surfaces of each component (either theoretically or from actual production parts), create a very accurate CAD model (+/−0.001″) of each part, and then create a working assembly of the system. Furthermore, the designer may not have the ability to use that model to investigate the issues, and to model and then simulate the proposed design changes to the model. In the past, the companies with the design engineering talents were either not interested in, or unable to undertake the time, provide the necessary engineering resources and/or spend the money necessary to investigate the concerns to the detail necessary to identify the concern, and then design a fix to these concerns. Modern day computer software and hardware is now available (at an attainable cost) and provide the tools necessary so that those that are experts in the field can use these tools to solve the problems that were here-to-for unsolvable.
There is a need to improve knuckle rotation to eliminate such jamming without delineating significantly from the accepted coupler assembly.

Railway coupler body improvements to improve knuckle rotation


Provided herein, in some embodiments, are artificial secretion peptides capable of directing secretion from Lactobacillus for use, for example, in producing heterologous proteins, including therapeutic proteins.

Most secretory proteins have an N-terminal signal peptide that directs translocation across membranes in the secretory pathway. These peptides are usually 15-60 amino acids long and may be characterized by an N-terminal region that typically comprises positively charged amino acids, a central hydrophobic region, and a short C-terminal region. In prokaryotes, including bacteria, secretion signal peptides often direct cellular export through the Sec translocase. In nature, every protein exported via the Sec pathway is conjoined to its own unique secretion signal.

Artificial secretion peptides for heterologous protein production

President and Fellows of Harvard College


Incorporating water-based polymer breakers, such as oxidizers, enzymes and/or acids, into a mixture of an oil and oil-soluble surfactants creates an emulsion that can then perform as a dual-functional breaker for reducing the viscosity of hybrid fluids gelled with both a viscoelastic surfactant (VES) and a polymer. The outer phase of the dual-functional breaker emulsion is oil, e.g. a mineral oil, containing an oil-soluble surfactant that will, over time and with heat, break the VES portion of the gel. As it does so, the polymer breaker in the internal aqueous phase will be released to then break the polymer portion of the gel. The polymer breaker will not start to break the polymer gel before the oil-soluble surfactant starts to break the VES gel. The overall breaking using the emulsion is slower as compared to introducing the polymer breaker and the oil-soluble surfactant in a non-emulsified form.

Hydrocarbons such as oil, natural gas, etc., may be obtained from a subterranean geologic formation, e.g., a reservoir, by drilling a well that penetrates the hydrocarbon-bearing formation. This provides a partial flowpath for the hydrocarbons to reach the surface. In order for oil to be produced, that is travel from the formation to the well bore (and ultimately to the surface), there must be a sufficiently unimpeded flowpath from the formation to the well bore. Unobstructed flow through the formation rock (e.g., sandstone, carbonates) is possible when rock pores of sufficient size and number are present for the oil to move through the formation.
However, as is becoming more generally known, greater effort and more varied approaches must be undertaken to produce hydrocarbons since the relatively easier to produce subterranean formations have generally been found. Thus, the oil and gas industry is looking at producing hydrocarbons from subterranean formations where recovering the hydrocarbons is more difficult and requires many steps, including the introduction and placement of various components, additives and agents at relatively precise locations downhole.
One such more complicated process involves hydraulically fracturing the subterranean formation—literally breaking or fracturing a portion of the strata surrounding the wellbore. The development of suitable fracturing fluids to provide the necessary hydraulic force is a complex art because the fluids must simultaneously meet a number of conditions. For example, they must be stable at high temperatures and/or high pump rates and high shear rates which can cause the fluids to degrade and prematurely settle out the proppant before the fracturing operation is complete. Various fluids have been developed, but most commercially used fracturing fluids are aqueous based liquids which have either been gelled or foamed. When the fluids are gelled, typically a polymeric gelling agent, such as a solvatable polysaccharide is used, which may or may not be crosslinked. The thickened or gelled fluid helps keep the proppants within the fluid during the fracturing operation.
Aqueous fluids gelled with viscoelastic surfactants (VESs) are also known in the art. VES-gelled fluids have been widely used as gravel-packing, frac-packing and fracturing fluids because they exhibit excellent rheological properties. VES fluids are non-filter cake-building fluids.
In some cases aqueous fluids are gelled with both a VES and a hydratable polymer to gain some of the advantages of both gelled fluid types. While such hybrid fluids may be "broken" or have their viscosities reduced by a separate conventional VES-gel breaker and a separate polymer gel breaker, it would be desirable if one breaker system could be devised for such hybrid fluids.

Dual-functional breaker for hybrid fluids of viscoelastic surfactant and polymer


A system for suppressing fires generated within air ducts. The system can include a duct with an aperture, a reservoir containing fire retardant material adjacent to the aperture, and a temperature-sensitive sidewall. The aperture can be sealed with the temperature-sensitive sidewall creating a temporary barrier to fluid communication with the interior of the duct and the reservoir. When a source of heat exists within the duct, the temperature-sensitive sidewall melts or ruptures, expelling fire retardant material. The temperature-sensitive sidewall can be a fusible plug or a frangible tube positioned within the duct in a non-obstructive fashion. The fire retardant material stored in the attached reservoir can be expelled into the interior of the duct, suppressing or retarding the source of heat in response to a temperature in excess to a predetermined value.

Several systems have attempted to deal with the issue of fires in air ducts. U.S. Pat. No. 6,105,678 discloses a heat responsive fire extinguishing assembly for a ventilating duct. The system includes a nozzle head that is mounted inside the duct. The nozzle head is in fluid communication with a reservoir containing the fire suppressant material via the valve. When the temperature inside the duct reaches a certain level, the valve is opened and the fire extinguishing material is dispensed through the nozzle in the duct. This automatic fire suppression system provides a nozzle head protruding into the duct undesirably blocking airflow through the duct.
U.S. Pat. No. 6,095,252 is a means for fighting fire in at least one cable or line run. A frangible tube is mounted inside a cable run. The tube is filled with fire extinguishing material under pressure. When the temperature inside the duct reaches a predetermined value, the tube ruptures releasing the fire extinguishing material into the cable. This reference depicts an automatic fire suppression system with a frangible tube adapted for suppressing fires in electrical cable runs.
U.S. Pat. No. 5,575,312 is a fire retarding heating and cooling duct. Heat meltable plastic is inserted into the duct at six foot intervals. When a fire occurs in the duct, the plastic melts almost immediately, sealing off the fire from the rest of the duct system. This type of duct stops the duct fire spreading to the rest of the ducting system.
U.S. Pat. No. 5,493,820 describes a fire preventing duct system. In this system a narrow tube containing cold water is inserted into the duct system. When a fire occurs, the heat is absorbed by the cold water, which impedes the progress of the fire. Once the temperature inside the duct reaches a predetermined value, the now hot water is flushed and replaced with cold water to absorb more heat, further impeding the progress of the fire. This system discloses a cooling system that removes heat from a duct system to delay the spread and growth of a potential duct fire.
U.S. Pat. No. 4,143,670 describes another system to impede the progress of a fire. The ducting fire protection system is created by placing a thermoplastic sleeve inside a duct. When a fire occurs, elevated temperatures inside the duct causes the sleeve to collapse, sealing off the fire from the rest of the duct system. This provides a device that seals off the duct fire from the rest of the ducting system.
U.S. Pat. No. 3,720,153 is another ducting fire protection system similar to the previous patent. In this system, a valve device is placed inside the duct. When a fire occurs, the elevated temperatures cause the value to close, stopping the fire from spreading to the rest of the duct system.


Disclosed is a new and distinct variety of pistachio rootstock called ‘UCB1-D90’ characterized in that, when compared to the industry standard ‘UCB1-Dl’ rootstock, it has greater growth and tolerance to the soil salts of calcium chloride, sodium sulfate, sodium carbonate and sodium bicarbonate; greater growth and tolerance to high levels of dissolved salts in irrigation water; earlier vegetative bud break; and greater graft compatibility with commercial pistachio clones.

The present invention comprises a new and distinct cultivar of hybrid pistachio (Pistacia atlantica (not patented)×Pistacia integerrima (not patented) used as a rootstock known by the varietal name 'UCB1-D90.' The variety 'UCB1-D90,' is an in vitro, single selection of the segregating controlled cross of (P. atlantica×P. integerrima) made at Davis, Calif. The purpose of the selection program was to develop rootstocks with superior tolerance to soil salts. Seedlings were tested in salt trials in the laboratory and compared to the 'UCB1-D1' rootstock (not patented). Those seedlings that exhibited high tolerance to various soil salts were selected. The new variety exhibits high tolerance to numerous, common salts found in the soil and irrigation water. The present variety has higher resistance to Verticillium disease than the female parent, Pistacia atlantica; and has higher cold tolerance than the male parent, Pistacia integerrima.
The following characteristics distinguish clone 'UCB1-D90' from the industry standard, 'UCB1-D1' rootstock:                1. Greater growth and tolerance to the soil salts, calcium chloride, sodium sulfate, sodium carbonate and sodium bicarbonate.        2. Greater growth and tolerance to high levels of dissolved salts in irrigation water.        3. Earlier vegetative bud break.        4. Greater graft compatibility with commercial pistachio clones.        5. The present variety differs from rootstocks UCB1-D71, UCB1-D110, and UCB1-D154 in that the present variety is more tolerant than the industry standard rootstock, UCB1-D1, to the soil salts tested, sodium sulfate, sodium carbonate and sodium bicarbonate; but it is the least tolerant of these rootstock to these same soil salts.


In a control apparatus, an acquisition unit acquires the coordinates of a detection starting position and detection ending position detected by a radar, for each of a plurality of moving vehicles moving along a road. A calculation unit calculates an average value of the coordinates of the detection starting positions and an average value of the coordinates of the detection ending positions, and stores information of radar detection including the calculated average values in a radar detection storage unit. A comparison unit compares the average values of the coordinates of the detection starting positions and detection ending positions with respective determined reference values. An abnormality determination unit determines based on the comparison results whether or not an abnormality has occurred in the radar, and outputs, if determining that an abnormality has occurred, information indicative of the occurrence of the abnormality.

In order to detect conditions under which vehicles are moving along a road, the technique of an infrastructure-mounted radar or the like has traditionally been used. For example, a radar, such as a milliwave radar, is mounted at a position which overlooks a road for detecting moving vehicles.
For example, the use of such a technique makes it possible to detect traffic conditions on a road, such as vehicles moving along the road, traffic congestion caused due to temporary stopping of a vehicle or long stopping of a vehicle due to an accident or the like, and measured traffic volume, in order to manage road conditions. In addition, it is possible to inform succeeding vehicles and the like of the road conditions by the use of a display unit or the like mounted beside the road, in order to prevent an accident.
Furthermore, a technique for detecting a variation of radar mounting by the use of two radars is known as a technique for detecting a positional variation of vehicle-mounted radar mounting. In this case, one radar performs detection in an upper area and the other radar performs detection in a lower area. These areas overlap and the overlap area is parallel to a road surface (see, for example, Japanese Laid-open Patent Publication No. 11-14747). With this technique a moving object such as another vehicle is to be detected in the overlap area if the radars are mounted in normal positions. On the other hand, if a radar changes its angle upward or downward, a moving object is also detected outside the overlap area, which means a variation of radar mounting.
An infrastructure-mounted radar, for example, may be used for a decade or even longer. Therefore, it is desirable that radar maintenance be unneeded. From this point of view, a scannerless radar in which an angle between a transmission antenna plane and a receiving antenna plane is fixed and does not need changing at vehicle detection time is preferable to a mechanical scan type radar in which an angle between a transmission antenna plane and a receiving antenna plane is physically changed at vehicle detection time. Furthermore, in scannerless radars, radars using an antenna beam of narrow width (narrow beam radars) are preferable because they have higher receiving power than wide beam radars and are capable of sharply detecting the position of an object.
Such a narrow beam radar, however, may fail to cover a desired detection area due to a variation of angle of the radar. Therefore, the angle of radar mounting needs to be checked if it is always correct.
The technique disclosed in the above Japanese Laid-open Patent Publication No. 11-14747 uses two radars for detecting a positional variation although one radar is sufficient for the original purpose, which is not economical.
In addition, it is desirable from the viewpoint of easy maintenance that the occurrence of an abnormality of a radar, such as a variation of an mounting angle, is detected only based on data outputted therefrom without actually inspecting the radar.

Control apparatus, radar detection system, and radar detection method


A vehicle seat is provided with a linkage that may be used to raise and lower a front portion of the seat base. A track assembly is provided in combination with the linkage that moves the seat in a fore-and-aft direction with the seat back in either an upright or fold flat position. The linkage for adjusting the position of the front of the seat base may be actuated by pivoting the seat back between the upright and fold flat position.

Vehicle seats are designed to provide comfortable seating for vehicle occupants. Vehicle seats may be designed to fold or pivot to provide flexibility in the way that a vehicle may be arranged to provide added storage space for hauling cargo. The following patents and published patent applications were reviewed in the course of preparing this application: U.S. Pat. Nos. 4,767,157; 4,778,138; 5,979,985; 7,631,939; and U.S. Published Application 2008/0048477.

Stowable rear seat with fore and aft adjustment


A composition unit generates a composite image by compositing a frame image of interest and a processed image obtained by applying minimum value filtering processing to the frame image of interest. An LPF processor generates a low frequency component image by applying low-pass filtering processing to the composite image. A difference detector generates a difference image between the frame image of interest and the low frequency component image, and an adder generates a high frequency component image by adding the difference image to the frame image of interest. The composition unit executes composition processing using a minimum composite ratio a so that all pixel values which configure a region in the high frequency component image corresponding to a steep edge region in the composite image are equal to or larger than zero.

1. Field of the Invention
The present invention relates to moving image processing for frame rate conversion and, more particularly, to a conversion process for performing convertion to a higher frame rate, for example, converting a 60 Hz image into a 120 Hz image.
2. Description of the Related Art
As a movie display device represented by a television receiver, a display device using a liquid crystal device (hold type) and a field emission type display device (impulse type) are known.
As a driving method of these display devices, a method of distributing a frame image into two sub-frames based on frequency components to take a motion blur measure for a hold type display device or a flicker measure for an impulse type display device is known.
As an example of a method of realizing double-speed driving of the hold type display device, a technique disclosed in patent reference 1 (Japanese Patent Laid-Open No. 2006-184896) is known. FIG. 10 shows a part of the circuit arrangement disclosed by patent reference 1. An LPF (low-pass filter) processor 104 generates a sub-frame image including only low frequency components based on an input frame image.
A difference detector 105 extracts, as high frequency components, a difference between the input frame image and the sub-frame image, which is generated by the LPF processor 104 and includes only low frequency components. A subsequent adder 199 adds the high frequency component image extracted by the difference detector 105 and the input frame image, thus obtaining a sub-frame image, high frequency components of which are emphasized.
A switching circuit 107 switches the sub-frame image including only low frequency components and that whose high frequency components are emphasized at cycles of 120 Hz, and outputs the selected image to the subsequent stage. Alternate displaying of the sub-frame image from which high frequency components are excluded and that whose high frequency components are emphasized is equivalent to reproduction of an original frame image when viewed at a time cycle of 60 Hz.
However, a frame image, which is observed as if two images were composited by alternately displaying the two sub-frame images, does not often become the same as the original frame image. This point will be described below with reference to FIGS. 11A to 11F.
FIG. 11A shows a waveform example of an input frame image. FIG. 11B shows a waveform as a result of processing of this input frame image by the LPF processor 104. FIG. 11C shows a waveform of a frame image output from the difference detector 105 when the input frame image having the waveform shown in FIG. 11A and the frame image having the waveform shown in FIG. 11B are input to the difference detector 105. Since this frame image is an image of high frequency components, its waveform assumes positive and negative values. FIG. 11D shows a waveform of a frame image output from the adder 199 when the frame image having the waveform shown in FIG. 11C and that having the waveform shown in FIG. 11A are input to the adder 199.
Theoretically, by alternately displaying the waveforms shown in FIGS. 11B and 11C at cycles of 120 Hz, an apparent waveform becomes the same as that shown in FIG. 11A. However, when a low luminance level portion in the waveform shown in FIG. 11A assumes a value equal to or close to zero, the waveform shown in FIG. 11D assumes a negative value. Since an image of the negative value cannot be displayed, the negative value is displayed as zero in practice, as shown in FIG. 11E. Then, an apparent composite waveform becomes a waveform shown in FIG. 11F, since the frame image having the waveform shown in FIG. 11B and that having the waveform shown in FIG. 11E are alternately displayed. When the frame image having such waveform is, for example, an image on which white characters are laid out on a black background, that image is perceived as an image on which the edges of these characters are blurred. In this manner, depending on the waveform of an input frame image, an image after the distribution processing cannot be seen as the same image as an original image, and is perceived as a degraded image, thus posing a problem.
In order to solve this problem caused by negative values generated upon division of sub-frame images, in patent reference 2 (Japanese Patent Application No. 2008-119059), a minimum value filtering unit 101 is arranged in front of the LPF processor 104 to apply minimum value filtering processing to the interior of a region to be processed by the LPF processor 104, as shown in FIG. 12. FIGS. 13A to 13F show waveforms of frame images obtained in respective stages by the apparatus having the arrangement shown in FIG. 12.
FIG. 13A shows a waveform of an input frame image. When the minimum value filtering unit 101 applies minimum value filtering processing to this input frame image, a frame image having a waveform shown in FIG. 13B is generated. When the LPF processor 104 applies low-pass filtering processing to the frame image having the waveform shown in FIG. 13B, a frame image having a waveform shown in FIG. 13C is generated. The frame image having this waveform is characterized in that gradient start points match the edges of the frame image having the waveform shown in FIG. 13A, since gradient regions due to the edges are shifted by a half interval length to the high signal value region side by the minimum value filtering processing.
The difference detector 105 generates a frame image having a waveform shown in FIG. 13D by subtracting the frame image having the waveform shown in FIG. 13C from that having the waveform shown in FIG. 13A. Since the frame image having the waveform shown in FIG. 13C assumes values lower than that having the waveform shown in FIG. 13A in every signal regions due to the minimum value filtering processing, the frame image having the waveform shown in FIG. 13D always assumes positive values.
The adder 199 generates a frame image having a waveform shown in FIG. 13E by adding the frame image having the waveform shown in FIG. 13D to that having the waveform shown in FIG. 13A.
Upon display, the frame image having the waveform shown in FIG. 13E and that having the waveform shown in FIG. 13C are temporally alternately displayed as sub-frame images. As a result, a frame image having a waveform shown in FIG. 13F (apparent frame image) can match that having the waveform shown in FIG. 13A (input frame image). In this way, the minimum value filtering processing has a negative value generation suppression function at the time of sub-frame division, thereby improving image quality.
However, this negative value generation suppression function of the minimum value filtering processing suffers a performance issue. That is, since this function depends on a picture on an image and pixel values selected by the minimum value filtering processing are too low, gradient regions of pixel values in edge regions are unwantedly extended by the low-pass filtering processing.
This issue will be explained below with reference to FIGS. 6A and 6B. FIGS. 6A and 6B are graphs both showing image information as linear signal waveforms, the abscissa plots image coordinates, and the ordinate plots pixel values. FIG. 6A shows image information when minimum value filtering processing is used, and FIG. 6B shows image information when no minimum value filtering processing is used. Both the pieces of image information shown in FIGS. 6A and 6B include edges near an image coordinate=10.
As shown in FIGS. 6A and 6B, as for a signal (SL) including only low frequency components, the gradient regions of pixel values obtained using the minimum value filtering processing are broader than those without using the minimum value filtering processing. When a picture remains unchanged temporally, since an apparent frame image obtained by compositing the two sub-frame images becomes the same as an original frame image, this phenomenon does not pose any problem in term of image quality. However, when a picture changes temporally, the above phenomenon imposes an adverse effect in terms of image quality, and a viewer perceives the gradient regions of the pixel values of the signal SL as a ghost in a direction opposite to a motion of an edge area. However, since this adverse effect is a tradeoff from the negative value generation problem at the time of sub-frame image division, it is permitted for negative value generation suppression.
A problem is that a minimum value of a signal including high frequency components (SH) assumes a value larger than zero when sub-frame image division is made using the minimum value filtering processing. Since the broader gradient regions of pixel values of the signal SL are a tradeoff from the negative value generation problem, the minimum value of the signal SH need not be larger than zero, and is most desirably set to be zero to minimize the gradient regions of pixel values of the signal SL if it is possible. However, it is difficult for the method and arrangement disclosed by patent reference 2 to implement it since patent reference 2 discloses only a function of selecting a minimum value of pixels in an interval.

Image processing apparatus and image processing method


An I/O pin is connected to a DUT via a transmission line. A driver generates a test signal to be supplied to the DUT. A driver-side switch and an output resistor are arranged in series between the driver and the I/O pin. A comparator is arranged such that the input terminal thereof is connected to the I/O pin, and configured to judge the level of a signal output from the DUT. A short-circuit switch is arranged between the I/O pin and the ground terminal.

1. Field of the Invention
The present invention relates to a pin electronics circuit.
2. Description of the Related Art
In order to test semiconductor devices (which will also be referred to as "devices under test" or "DUTs" hereafter), a test apparatus is used. In order to measure a large number of DUTs at the same time, such a test apparatus includes several hundred to several thousand channels of pin electronics circuits. FIG. 1 is a block diagram which shows a configuration of a typical test apparatus. A test apparatus 1002 includes a pin electronics board 1012 and an unshown performance board. The pin electronics board 1012 and the performance board are connected to each other via a connector 16 and a cable 18. The performance board includes a socket via which the DUT is to be mounted.
The pin electronics board 1012 includes a driver DR configured to output a test signal to the DUT, and a comparator CP configured to receive a signal output from the DUT, and to judge the level of the signal thus received. The driver DR and the comparator CMP are integrated on a pin electronics IC (Integrated Circuit) 1010. A path that connects an I/O pin PI/O of the pin electronics IC 1010 and a given terminal A on the performance board side will be referred to as the "transmission line 20".
Such a configuration in which the driver DR and the comparator CP are connected to such a shared I/O pin PI/O will also be referred to as a "shared I/O configuration". Such an architecture having such a shared I/O configuration is capable of switching states between a state in which a test signal is output from the driver DR to the DUT, and a state in which the comparator CP receives a signal output from the DUT. Accordingly, a driver-side switch 22 is arranged between the output terminal of the driver DR and the I/O pin PI/O. When the driver-side switch 22 is turned off, the driver DR is cut off from the DUT and the comparator CP.
A programmable load 30 is arranged in order to change the input impedance of the test apparatus 1002 as viewed from the test apparatus 1002. A load-side switch 24 is arranged in order to allow the programmable load 30 to be connected to and to be cut off from the transmission line 20.
The test apparatus 1002 includes a DC test unit (which will also be referred to as a "Parametric Measurement Unit" or "PMU") 32, in addition to the pin electronics board 1012. The DC test unit 32 performs a DC test operation for measuring the DC characteristics of the DUT, e.g., leak current.
The pin electronics IC 1010 and the connector 16 are connected to each other via transmission lines (strip lines or microstrip lines) 14a and 14b and an output relay 26. The DC test unit 32 is connected to the connector 16 via a DC relay 28 and the transmission line 14b. The output relay 26 and the DC relay 28 are arranged in order to switch test modes between an AC test mode and a DC test mode. When the output relay 26 is on and the DC relay 28 is off, the DUT is connected to the pin electronics IC 1010, thereby providing an AC test operation. Conversely, when the output relay 26 is off and the DC relay 28 is on, the DUT is connected to the DC test unit 32, thereby providing a DC test operation.
The above is the configuration of the test apparatus 1002. In order to predict a signal waveform output from the pin electronics IC 1010 or a signal waveform input to the pin electronics IC 1010 from the DUT, in the design of such a test apparatus 1002, the following two factors are required to be known.
(1) The device model of the transmission line 20 between the pin electronics IC 1010 and the terminal A (simulation model).
(2) The terminal impedance of the pin electronics IC 1010 side as viewed from the terminal B.


Improved systems, methods, and apparatus for calibrating a laser ablation system by measuring the optical power and shape of a test surface that has been ablated by energy delivered from a laser. The quality of the ablated test surface can be monitored to minimize undesirable laser system performance, such as might result from flawed internal optics, misalignment, poor laser fluence and the like. Calibration accuracy is generally enhanced by analyzing distortions of a geometrical pattern superimposed with the ablation test surface. The interaction of the pattern and the lens can be analyzed using a microscope, video camera connector, and other existing components of the laser ablation system, and can also provide quantitative test surface characteristics which may be used to accurately adjust the laser system.

The present invention is directed to systems, methods, and apparatus for calibrating laser ablation systems. In particular, the invention relates to methods and apparatus for measuring the refractive power, shape and quality of a laser test ablation on a test surface. The present invention is particularly useful for calibrating excimer lasers used during laser ablation procedures of the eye, such as photorefractive keratotomy (PRK), phototherapeutic keratectomy (PTK), laser in situ keratomileusis (LASIK), or the like.
Ultraviolet and infrared laser based systems and methods are known for enabling ophthalmological surgery on the external surface of the cornea in order to correct vision defects. These procedures generally employ an ultraviolet or infrared laser to remove a microscopic layer of an anterior stromal tissue from the cornea to alter its refractive power. In ultraviolet laser ablation procedures, the radiation ablates corneal tissue in a photodecomposition that does not cause thermal damage to adjacent and underlying tissue. Molecules at the irradiated surface are broken into smaller volatile fragments without substantially heating the remaining substrate; the mechanism of the ablation is photochemical, i.e. the direct breaking of intermolecular bonds. The ablation penetrates into the stroma of the cornea to change its contour for various purposes, such as correcting myopia, hyperopia, and astigmatism.
In such laser based systems and methods, the irradiated flux density and exposure time of the cornea to the laser radiation are controlled so as to provide a surface sculpting of the cornea to achieve a desired ultimate surface change in the cornea. To that end, ablation algorithms have been developed that determine the approximate energy density that must be applied to remove a certain depth of tissue from the cornea. At ultraviolet wavelengths, for example, a cumulative energy density of about 1 joule/cm2 will typically ablate corneal tissue to a depth of about one micron when applied in a series of pulses of about 100 to 400 millijoules/cm2. Accordingly, the ablation algorithms are tailored for each procedure depending on the amount and the shape of corneal tissue which will be removed to correct a particular individual's refractive error.
In order to properly use these laser ablation algorithms, the laser ablation system typically should be calibrated. Calibration of the laser system helps ensure removal of the intended shape and quantity of the corneal tissue so as to provide the desired shape and refractive power modification to the patient's cornea. In addition, it is usually desirable to test for acceptable levels of system performance. For example, such tests can help ensure that internal optics are aligned, that laser fluence is accurate, etc.
Ablations of plastic test materials are often performed prior to excimer laser surgery to calibrate the energy density and ablation shape of the laser. During these tests, a lens is ablated into the test plastic, and the refractive power of the test lens is read by a standard lensometer. The reading from the lensometer is then entered back into the laser system so that the system can make appropriate calibration adjustments. The test lens may also be visually evaluated under a magnifying glass or with the microscope of the laser system, and test samples are sometimes sent to a laboratory for accurate evaluation to help determine beam homogeneity and quality.
Although known laser ablation calibration techniques are fairly effective, these methods still suffer from certain disadvantages. For example, delaying each surgery while obtaining accurate laboratory evaluations of a test lens may be impractical. On the other hand, requiring specialized test lens evaluation equipment at each site could add significantly to equipment costs and overall system complexity. Nonetheless, some information beyond refractive power and a visual evaluation of the test lens would be helpful to improve the accuracy of regular calibrations, whether they are performed monthly, daily, or before each ablation procedure.
In light of the above, it would be desirable to provide improved systems, methods, and apparatus for calibrating laser ablation procedures. It would be particularly desirable if such improvements enhanced calibration accuracy without significantly increasing the overall system costs and complexity. It would further be desirable if such improvements could provide quantifiable data which might be used in an automated calibration feedback and adjustment system.

Systems and methods for calibrating laser ablations


Provided is a method for manufacturing a three-dimensional body. This method includes placing around an in-process three-dimensional body a support configured to hold up the in-process three-dimensional body and producing the three-dimensional body while holding up the in-process three-dimensional body with the support. This method is characterized in that the support is made from a support material including multiple materials with different melting points, and that the support is placed in such a manner that a first material, the material with the lowest melting point, flows with the others remaining solid.

There have been some known additive methods for fabricating a three-dimensional body, such as optical fabrication. In these methods, as suggested by their name, a three-dimensional body is produced by additively stacking cross-sectional patterns. With no mold or similar equipment required, the three-dimensional body can be fabricated directly from its 3D (design) data. Additive fabrication is thus commonly used in product prototyping, in which it is needed to make a small number of three-dimensional bodies in a short period of time. A typical limitation to additive fabrication is the need for a support. By additive fabrication, in which patterns are built up in layers, it is theoretically impossible to produce a structure that has any portion that would be isolated during the process of fabrication just like, for example, the tip of a drooping branch of a tree. To make such a portion by additive fabrication, it is necessary to provide a support that will not be left in the finished three-dimensional body, or "a prop," under the portion that would be isolated, and to remove the support after the completion of fabrication.
The removal of the support is basically manual work. As a natural consequence of its purpose, additive fabrication is not often used to mass-produce a single three-dimensional body. There has been no easy and automated way to remove the supports of three-dimensional bodies with different shapes.
As a solution to this, PTL 1 proposes placing a support made from a heat-melting and heat-removable material around a structural body and removing this support through heating after the completion of fabrication. This seems to be a relatively easy way of removing the support.

Method and apparatus for manufacturing three-dimensional body


A method and an apparatus are provided for mounting and removing electronic components using solder bumps while constraining thermal stresses to a substrate. The method and apparatus for mounting and removing an electronic component (bear chip 32) to be soldered onto the substrate with solder bumps 114 is configured to move the electronic component to detect contact of the solder bumps with the substrate or contact of a tool (chuck unit 38) with the electronic component, to define the contact as an original point for raising a heating temperature of the electronic component and the substrate from the heating temperature to a maximum heating temperature HTm as well as move the electronic component in conformity with the temperature rising, and to move the electronic component from a position where the maximum heating temperature is achieved to a mounting height of the substrate.

1. Field of the Invention
The present invention relates generally to a method and an apparatus for mounting and removing semiconductor devices such as bear chips, flip chip components and other various electronic components connected to a substrate with solder bumps and, more particularly, to a method and an apparatus for mounting and removing electronic components suitable for various processing such as reworking, replacing and repairing bear chips mounted on a resin substrate with the use of solder bumps.
As a mounting technology for bear chips, the C4 (Controlled Collapse Chip Connection) flip chip wiring technology is used and, in this C4 flip chip wiring technology, connecting protruding terminals (micro bumps) are formed with narrowed connection pitches on a LSI (Large Scale Integration) chip or a flip chip component which is mounted on a module substrate with these micro bumps. For bear chips, various processing can be performed, such as mounting, removing, replacing, remounting and the like. The present invention relates to a method and an apparatus for mounting and removing electronic components, which are preferred for mounting electronic components such as the bear chips onto a resin substrate and for various processing such as rework processing, replace processing, repair processing and the like thereof.
2. Description of the Related Art
Conventionally, in rework of a bear chip, a bonding head of a reflow apparatus is positioned to the bear chip mounted on a substrate and the bear chip is detached from the substrate by heating and melting solder with the bonding head. On the substrate after the bear chip is removed, residual solder is heated and removed and the substrate is processed to be in a state equivalent to the state before mounting by performing cleaning processing with a solvent. Then, the bear chip is positioned and fixed at a bear-chip mounting position on the substrate and the bear chip is remounted by heating the entire package (PKG) with a reflow oven for reflow processing.
For this conventional rework, for example, referring to FIGS. 1A to 1C and FIGS. 2A to 2C, FIGS. 1A to 1C show processing for removing a bear chip from a substrate, and FIGS. 2A to 2C show remount processing after the bear chip is removed. As indicated by an arrow a of FIG. 1A, a tool head 8 is positioned and lowered to a bear chip 6 mounted on a substrate 2 with C4 bumps, for example, solder bumps 4 and, as indicated by an arrow b of FIG. 1B, a top surface of the bear chip 6 is contacted with an under surface of the tool head 8, and the solder bumps 4 is heated and melted by the tool head 8 and the like while controlling the pressure thereof. While maintaining this melting state, as indicated by an arrow c of FIG. 1C, the bear head is supported by the tool head 8 and, when the tool head 8 is raised, the bear chip 6 is detached from the substrate and the solder bumps 4 are melted and collapsed on the substrate to become residual solder 10. The residual solder 10 is in a short-circuit state. Therefore, after the residual solder 10 is removed with the use of a jig 12 as shown in FIG. 2A, preliminary solder bumps 14 is formed on the substrate 2 at a mounting position of the bear chip 6 as shown in FIG. 2B, and the bear chip 6 is positioned at the mounting position to be reconnected.
Regarding to such rework of bear chips and mounting technologies using solder bumps, prior patent documents exist, which are Japanese Patent Application Laid-Open Publication Nos. H06(1994)-21147, H10(1998)-294558, H11(1999)-112131, 2001-7157, 2002-57453, 2002-110740 and others.
Japanese Patent Application Laid-Open Publication No. H06(1994)-21147 discloses mounting, removing and remounting of flip chip IC with the use of solder bumps; Japanese Patent Application Laid-Open Publication No. H10(1998)-294558 discloses a rework apparatus for removing semiconductor devices by heating a semiconductor apparatus with the semiconductor devices mounted on a substrate; Japanese Patent Application Laid-Open Publication No. H11(1999)-112131 discloses a method for removing a semiconductor apparatus wherein the semiconductor apparatus is removed by heating and melting solder from a substrate where the semiconductor apparatus has been mounted, and a method for repairing a semiconductor apparatus wherein a semiconductor apparatus is positioned and remounted onto a substrate where the semiconductor apparatus has been removed; Japanese Patent Application Laid-Open Publication No. 2001-7157 discloses repair processing of flip chip mounting; Japanese Patent Application Laid-Open Publication No. 2002-57453 discloses a method for repairing a semiconductor apparatus wherein after a semiconductor apparatus is removed from a substrate by heating the semiconductor apparatus mounted onto the substrate, the semiconductor apparatus is remounted by supplying solder paste for forming preliminary solder, by affixing the semiconductor apparatus onto the preliminary solder and by heating and melting the solder for bonding; and Japanese Patent Application Laid-Open Publication No. 2002-110740 discloses a method and an apparatus for mounting wherein, in a mounting method for lowering a semiconductor apparatus with solder bumps formed on a under surface of a semiconductor device for flip chip bonding on a substrate, a gap between the semiconductor device and the substrate is controlled depending on the height of the semiconductor apparatus.
By the way, in removal of an electronic component in conventional rework processing of various electronic components such as bear chips, pressure control is used for position control of a head unit equipped on a tool. If a bonding portion of a bear chip has narrow gaps, when an error occurs in the position control of the tool, solder may be short-circuited and the residual solder in the short-circuit state must be removed by sufficient cleaning processing before replacing the bear chip. If a bonding portion of a bear chip has narrow gaps, sufficient accuracy is required for the position control of a substrate and the bear chip at the time of mounting in order to enhance reliability of connection.
Although the preliminary-solder processing is used for ensuring connectivity between the substrate and bear chip, thermal stresses are accumulated in the substrate due to the preliminary-solder processing and the reliability of the connection may be reduced.
Also, since the reflow processing of the entire package gives great thermal stresses to the substrate, if a member with limited heat resistance is mounted on the package, reprocessing is difficult and inspection costs are increased for such as the failure analysis of the bear chips at the time of mounting.
These problems cannot be solved by technologies disclosed in the prior patent documents described above.

Method and apparatus for mounting and removing an electronic component