The invention relates to a process for the preparation of bipyridyls by converting at least one pyridine of the formula (III)

This application is a 371 of PCT /EP99/02788 filed Apr. 24, 1988.
The present invention relates to an improved process for the catalytic preparation of substituted bipyridyl derivatives by converting substituted halopyridine derivatives with a base and a reducing agent in the presence of a palladium catalyst.
Such a process, which for bipyridyls follows the reaction equation
has been described in the publications listed below, the reaction with chloropyridines frequently resulting in low yields, and the use of bromopyridines and iodopyridines, which are significantly more expensive and therefore of lesser interest industrially, resulting in higher yields. The processes known hitherto have cost and/or ecological disadvantages.
Bipyridyls, which are also frequently referred to in the literature as bipyridines, including their derivatives are, for example, important as industrial and medicinal intermediates, as analytical reagents or as ligands for the synthesis of metal complexes having catalytic activity. The use of bipyridyl metal complexes, particularly of ruthenium complexes, is of particular importance due to the use as photosensitizers for sensitizing semiconductor surfaces, as photocatalysts for solar cells, in particular for photovoltaic cells or photoelectrochemical cells, as described, for example, in WO 91/16719 or EP-A-0 333 641, and for photo-induced electrolysis.
The synthesis of substituted bipyridyls from halopyridines usually only takes place with good yields in accordance with the prior art if stoichiometric amounts of a metal compound are used. If catalytic amounts of these metal compounds are used, the yield is, by contrast, low in most cases, and the bromopyridines or iodopyridines are used as initiator materials.
Tiecco and Testaferri describe, in Synthesis 1984, 736 et seq., the synthesis of bipyridyl derivatives using stoichiometric amounts of elemental zinc and nickel chloride and four equivalents of triphenylphosphine in dimethylformamide as solvent at 50xc2x0 C. Using this process, it is possible, for example, to convert 3-bromo-2-methoxypyridine in a yield of 75% with one equivalent of zinc(II) chloride and one equivalent of nickel(II) chloride as byproduct. In two comparative experiments, in which palladium on activated carbon is used as catalyst, or copper, the product 3,3xe2x80x2-dimethoxy-2,2xe2x80x2-bipyridyl can only be obtained in a yield of 18% or 23%; the experimental conditions are described in Synthesis 1978, 537 et seq. If catalytic amounts of nickel(II) chloride are used, as published by Zembayashi et al. in Tetrahedron Lett. 1977, 4089 et seq., the dehalogenated initiator material is primarily obtained, and the desired product is obtained only in a low yield.
Using the process described by Tiecco and Testaferri it is also possible to convert chloropyridines, although large amounts of heavy metal salts are also produced at the same time, making this process neither ecologically nor economically attractive. For example, 2-chloro-5-methoxypyridine is converted in a yield of 88% to 5,5xe2x80x2-dimethoxy-3,3xe2x80x2-bipyridyl with one equivalent of zinc(II) chloride and one equivalent of nickel(II) chloride as byproduct.
In DE-A-39 21 025, Langhals discloses that the reaction described by Tiecco and Testaferri can also be carried out in the presence of free phenolic hydroxyl groups. At the same time Langhals discloses that the zinc hydroxide produced in the reaction as a byproduct can only be separated off with difficulty in the examples for the synthesis of 3,3xe2x80x2-dihydroxy-2,2xe2x80x2-bipyridyl and 3,3xe2x80x2-dihydroxy-2,2xe2x80x2-biquinoline.
Newcame discloses, in J. Inorg. Nucl. Chem. 1981, Vol. 43, 1529 et seq., the conversion of methyl-substituted bromopicoline to the corresponding bipyridyl with catalysis by palladium on activated carbon and a phase-transfer reagent in the presence of sodium formate as reducing agent in a two-phase system. Using this process, for example, 2-bromo-6-methylpyridine (=2-bromo-6-picoline) can be converted in a yield of 59% to 3,3xe2x80x2-dimethyl-2,2xe2x80x2-bipyridyl. The disadvantage of this method is that it is absolutely obligatory to use a phase-transfer reagent as cocatalyst in addition to palladium. Likewise, only bromopyridines which are usually substituted by alkyl groups are usually used as initiator materials for this method.
The classical Ullmann reaction, as described by Fanta in Synthesis 1974, 9 et seq., requires extremely drastic reaction conditions and the use of stoichiometric amounts of copper as reducing agent. In most cases, it produces only low yields of the desired bipyridyls or of derivatives thereof.
According to Fanta, the Ullmann reaction cannot be used for the synthesis of bipyridyls which are substituted by amino, hydroxyl and/or free carboxyl groups.
The synthesis of carboxy-substituted bipyridyls of the formula (IIa)
currently represents a particular problem. This class of substance is usually obtained by oxidation of the readily accessible dimethyl-substituted bipyridyls with potassium permanganate, as is described, for example, by Bruce in Liquid Crystals, 1996, Vol. 20, pages 183-193.
In DE-A-24 50 100, Shaw discloses that bipyridyls and bipyridyls substituted by alkyl, amino, cyano and/or carboxyl groups can also be made accessible from the corresponding pyridines in yields of only 50% by an electrochemical process. The large number of byproducts prevents an industrial and ecologically and economically attractive realization. Shaw discloses at the same time that in the case of the other known processes for the preparation of bipyridyls, metal derivatives of pyridine, especially sodium derivatives, frequently have to be prepared as intermediates, meaning that the preparation of bipyridyls by such processes is hazardous and relatively expensive.
In J. Chem. Soc. 1956, 616 et seq., Badger and Sasse describe the conversion of 50 g of nicotinic acid with activated nickel prepared from 125 g of nickel alloy to only 1 g of the coupled product. The low yield of this process renders the process uninteresting for the synthesis of this class of substance.
U.S. Pat. No. 3,767,652 teaches that 2,2xe2x80x2-bis(3-pyridinols) can be prepared in low yields up to 35% by oxidative coupling of the corresponding pyridinols with stoichiometric amounts of lead dioxide as oxidizing agent. The use of stoichiometric amounts of lead salts renders this process ecologically unacceptable.
The synthesis of bipyridyls without substituents takes place, according to DE-A-22 30 562, with yields up to 65% by converting chloro- or bromopyridine in methanol in the presence of water, an additive which has a reducing action, such as, for example, hydroxylamine or hydrazine, a base, such as, for example, potassium hydroxide, and supported palladium. The synthesis of bipyridyls containing alkyl groups as substituents, which are referred to in the laid-open specification as inert substituents, was possible, however, only in yields of up to 26% in accordance with the process described. The great disadvantage of the process is the high conversion to dehalogenated pyridines, which can amount to 68%. The dehalogenation appears to be favored by large amounts of water in the reaction medium.
EP-A-0 206 543 discloses the synthesis of bipyridyl by converting a halopyridine in the presence of 0.2 to 3 MPa of carbon monoxide, an alkaline medium and a supported palladium catalyst. The use of carbon monoxide is, however, uneconomical for industrial realization in view of the high safety requirements for handling this highly toxic gas.
Since the processes for the synthesis of substituted bipyridyls hitherto described can only be carried out in good yields with a high ecological impact, there was a great need for a process which makes accessible substituted bipyridyls and, in particular, carboxy-substituted bipyridyls in a high yield and purity in a manner which is ecological and simple to carry out on an industrial scale. The object was to develop such a process.
This object is achieved by a process for the preparation of bipyridyls by converting at least one pyridine of the formula (III)
in which
Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3, independently of one another, are identical or different and are hydrogen, (C1-C18)-alkyl, alkoxy-(C1-C18), acyloxy-(C1-C18), aryloxy-(C1-C18), perfluoroacyloxy-(C1-C8), NO2, (C1-C18)-aryl, (C1-C18)-heteroaryl, halogen, hydroxyl, nitro, nitroso, CN, COOH, CHO, PO3H2, SO3H, SO2R, SOR, NH2, NH-alkyl-(C1-C18), N-alkyl2-(C1-C18), protected amine, CF3, NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C18), CONH2, CO-alkyl-(C1-C18), NHCOH, NHCOO-alkyl-(C1-C4), CO-(C1-C18)-aryl, COO-(C1-C18)-aryl, CHCH-CO2-alkyl-(C1-C18), CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+,(SO3+)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+, where the cation is an alkali metal (Li, Na, K, Rb, Cs), an alkaline earth metal (Be, Mg, Ca, Sr, Ba), NR2H2, NR3H, NRH3, NR4, NH4, PR2H2, PR3H, PRH3, PR4 and/or PH4 and
where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl, and where at least one of the substituents of Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3 is chloride, bromide or iodide, where optionally Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 among one another together form one or more aliphatic and/or aromatic rings
and/or in which optionally Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 forms a bridge to at least one further pyridine of the formula (III)
and/or in which optionally the radicals Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 have the meanings given above and are substituted by at least one radical which has the meaning given above for Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3
in water in the presence of an alcohol, a base, a palladium catalyst and optionally one or more further solvents at a temperature of 0-200xc2x0 C.
Particularly preferably Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3, independently of one another, are identical or different and are hydrogen, methyl, ethyl, isopropyl, methoxy, acetoxy, trifluoroacetoxy, trifluoromethyl, O-phenyl, phenyl, fluorine, OH, nitro, nitroso, NO2, CN, COOH, CHO, PO3H2, SO3H, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), CONH2, CO-alkyl-(C1-C8), NHCOH, CO-phenyl, CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+, where the cation is Na, K, NR4 and/or PR4 and
where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl
and where at least one of the substituents of Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3 is a non-inert substituent such as OH, COOH, PO3H2 or SO3H, (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, K, NR4 and/or PR4 and
where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl,
and where at least one of the substituents of Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3 is chlorine, bromine or iodine,
where optionally Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 among one another together form one or more aliphatic and/or aromatic rings
and/or in which optionally Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 forms a bridge to at least one further pyridine of the formula (III)
and/or in which optionally the radicals Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3 have the meanings given above and are substituted by at least one radical which has the meaning given above for Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3.
The process is highly suitable for the preparation of symmetrical 2,2xe2x80x2-bipyridyls of the formula (IV), symmetrical 3,3xe2x80x2-bipyridyls of the formula (V) or symmetrical 4,4xe2x80x2-bipyridyls of the formula (VI),
in which
R1 to R4, independently of one another, are hydrogen, (C1-C18)-alkyl, alkoxy-(C1-C18), acyloxy-(C1-C18), aryloxy-(C1-C18), (C1-C18)-aryl, (C1-C18)-heteroaryl, fluorine, hydroxyl, nitro, nitroso, CN, COOH, CHO, PO3H2, SO3H, SO2R, SOR, NH2, NH-alkyl-(C1-C18), N-alkyl2-(C1-C18), protected amine, CF3, NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C18), CONH2, CO-alkyl-(C1-C18), NHCOH, NHCOO-alkyl-(C1-C4), CO-(C1-C18)-aryl, COO-(C1-C18)-aryl, CHCH-CO2-alkyl-(C1-C18), CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is an alkaline earth metal, alkali metal, NR2H2, NR3H, NRH3, NR4, NH4, PR2H2, PR3H, PRH3, PR4 and/or PH4 and where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl,
where optionally R1 to R4 among one another together form one or more aliphatic and/or aromatic rings
and/or in which optionally R1, R2, R3 or R4 of one ring forms a bridge to R1, R2, R3 or R4 of the second ring
and/or in which optionally the radicals R1 to R4 have the meanings given above and are substituted by at least one radical which has the meaning given above for R1 to R4,
by converting 2-halopyridines of the formula (VII), 3-halopyridines of the formula (VIII) or 4-halopyridines of the formula (IX)
in which Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 have the meanings given above for R1 to R4 and in which Hal means chlorine, bromine or iodine, in water in the presence of an alcohol, a base, a palladium catalyst and optionally one or more further solvents at a temperature of 0-200xc2x0 C.
xe2x80x9cProtected aminexe2x80x9d means amines with protective groups, as described, for example, in Greene, Theodora W.; Wuts, Peter G. M. Protective Groups in Organic Synthesis, 2nd Ed. 1991, Publisher: John Wiley and Sons, Inc., New York, N.Y. Reference is made expressly to this publication; by virtue of being cited, it forms part of the description.
In the preparation of these symmetrical bipyridyls, a halopyridine of the formula (VII) produces the symmetrical 2,2xe2x80x2-bipyridyls of the formula (IV), the halopyridine of the formula (VIII) produces the symmetrical 3,3xe2x80x2-bipyridyls of the formula (V), and the halopyridine of the formula (IX) produces the symmetrical 4,4xe2x80x2-bipyridyls of the formula (VI).
Preferably:
R1 to R4, independently of one another, are hydrogen, C1-C8-alkyl, alkoxy-(C1-C8), acyloxy-(C1-C8), aryloxy-(C1-C18), (C1-C18)-aryl, (C1-C18)-heteroaryl, fluorine, hydroxyl, nitro, nitroso, CN, COOH, CHO, PO3H2, SO3H, SO2R, SOR, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), protected amine, CF3, NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C8), CONH2, CO-alkyl-(C1-C8), NHCOH, NHCOO-alkyl-(C1-C4), CO-(C1-C18)-aryl, COO-(C1-C18)-aryl, CHCH-CO2-alkyl-(C1-C8), CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, Li, K, Ca, Mg, NR3H, NR4, NH4, PR3H, PR4 and/or PH4 and where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl
and where at least one of the substituents of R1 to R4 is a non-inert substituent such as acyloxy-(C1-C8), hydroxyl, COOH, PO3H2, SO3H, SO2R, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), protected non-inert amine, NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C8), CONH2, CO-alkyl-(C1-C8), NHCOH, NHCOO-alkyl-(C1-C4), COO-(C1-C18)-aryl, CHCH-CO2-alkyl-(C1-C8), CHCHCO2H, (COOxe2x88x92)n(cation)n+. (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or
(Oxe2x88x92)n(cation)n+,
where the cation is Na, Li, K, Ca, Mg, NR3H, NR4, NH4, PR3H, PR4 and/or PH4 and where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl,
where optionally R1 to R4 among one another together form one or more aliphatic and/or aromatic rings,
and/or in which optionally R1, R2, R3 or R4 of one ring forms a bridge to R1, R2, R3 or R4 of the second ring
and/or in which optionally the radicals R1 to R4 have the meanings given above and are substituted by at least one radical which has the meaning given above for R1 to R4.
Non-inert substituents are regarded as those which react with at least one compound in the reaction medium, so that stable adducts or else the substituent as such can be changed. Thus, for example, a COOH group is to be regarded as non-inert since it spontaneously enters, in the reaction medium, into an acid-base reaction, and also a COONa group since, being a basic compound, it can react with the acid which forms, which is usually scavenged by additions of base.
Particularly preferably:
R1 to R4, independently of one another, are hydrogen, methyl, ethyl, tert-butyl, isopropyl, methoxy, acetoxy, trifluoroacetoxy, trifluoromethyl, O-phenyl, phenyl, fluorine, OH, nitroso, NO2, CN, COOH, CHO, PO3H2, SO3H, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C8), CONH2, CO-alkyl-(C1-C8), NHCOH, NHCOO-alkyl-(C1-C4), CO-phenyl, COO-phenyl, CHCHxe2x80x94CO2-alkyl-(C1-C8), CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, Li, K, NR3H, NR4, PR3H and/or PR4 and where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl
and where at least one of the substituents of R1 to R4 is a non-inert substituent such as acetoxy, trifluoroacetoxy, OH, COOH, PO3H2, SO3H, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C8), CONH2, CO-alkyl-(C1-C8), NHCOH, NHCOO-alkyl-(C1-C4), COO-phenyl, CHCH-CO2-alkyl-(C1-C8), CHCHCO2H, (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, Li, K, NR3H, NR4, PR3H and/or PR4 and where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl,
where optionally R1 to R4 among one another together form one or more aliphatic and/or aromatic rings
and/or in which optionally R1, R2, R3 or R4 of one ring forms a bridge to R1, R2, R3 or R4 of the second ring
and/or in which optionally the radicals R1 to R4 have the meanings given above and are substituted by at least one radical which has the meaning given above for R1 to R4.
Very particularly preferably:
R1 to R4, independently of one another, are hydrogen, methyl, ethyl, isopropyl, methoxy, acetoxy, trifluoroacetoxy, trifluoromethyl, trichloromethyl, O-phenyl, phenyl, fluorine, OH, nitroso, NO2, CN, COOH, CHO, PO3H2, SO3H, NH2, NH-alkyl-(C1-C8), N-alkyl2-(C1-C8), NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), CONH2, CO-alkyl-(C1-C8), NHCOH, CO-phenyl, CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, K, NR4 and/or PR4 and
where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl
and where at least one of the substituents of R1 to R4 is a non-inert substituent such as OH, COOH, PO3H2 or SO3H, (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,
where the cation is Na, K, NR4 and/or PR4 and
where R, independently of one another, are identical or different and are (C1-C18)-aryl and/or (C1-C18)-alkyl,
where optionally R1 to R4 among one another together form one or more aliphatic and/or aromatic rings
and/or in which optionally R1, R2, R3 or R4 of one ring forms a bridge to R1, R2, R3 or R4 of the second ring and/or in which optionally the radicals R1 to R4 have the meanings given above and are substituted by at least one radical which has the meaning given above for R1 to R4.
It is also possible to use the salts of the halopyridines for the conversion. Thus, in particular an alkali metal salt, e.g. the sodium salt, of a halopyridinecarboxylic acid or a hydrochloride of a halopyridine can be used.
The radicals Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 and/or Rxe2x80x3xe2x80x3 can optionally be substituted. Suitable substituents are the radicals R1 to R4 themselves, in particular the non-inert substituents, such as OH, COOH, PO3H2 and/or SO3H.
If two or more different monohalopyridines are used, unsymmetrically coupled bipyridyls are also produced in addition to the symmetrical bipyridyls.
Surprisingly and in contrast to the results to be expected in accordance with the prior art, it has been found that halopyridines containing non-inert substituents can be converted particularly well in water in the presence of an alcohol, such as, for example, methanol, a base, such as, for example, sodium hydroxide, a palladium catalyst and optionally at least one further water-miscible or water-immiscible solvent, but also without further additives, such as, for example, reducing compounds, such as hydrazine or hydroxylamine, at temperatures of 0-200xc2x0 C.
In the case of the particularly preferred halopyridyls, a high water content in the reaction medium ( greater than 35%) favors the formation of the bipyridyl, which was not to be expected according to the prior art. Preference is given to using a water content in the reaction medium of at least 40%, in particular of at least 50%, for the formation of the bipyridyls.
As palladium catalyst, the use of unsupported and, preferably, of supported palladium has proven successful. Suitable supports are the supports customarily used for palladium, in particular activated carbon, metal oxides and/or metal salts, such as, for example, sulfates and/or carbonates of the metals of main groups 2 to 3 and/or of subgroups 1 to 3, such as, for example, aluminum oxide, barium sulfate, calcium carbonate and/or silicon dioxide and, particularly preferably, activated carbon. The supports can also be used in the process according to the invention in mixed form. Suitable as palladium catalysts are both metallic palladium, and also a palladium compound, optionally in combination with one another.
Surprisingly, it has been found that the loading of the palladium on the support, for the same total amount of palladium used, is of considerable importance for the reaction rate. For example, it has been found that 30% by weight of palladium on activated carbon reacts many times more quickly than the same amount of palladium as 5% by weight of palladium on activated carbon. In particular, the loading of the palladium on the support is at least 5% by weight, preferably at least 10% by weight, particularly preferably at least 20% by weight.
The process of the invention is preferably notable for the fact that the palladium catalyst, in each case calculated on the basis of palladium metal, is used in an amount of from 0.0001 to 10 mol %, preferably in an amount of from 0.1 to 5 mol %, based on halopyridine. If more palladium is used, the reaction rate increases accordingly, giving a higher space-time yield.
Particularly in a process in which the palladium catalyst is recovered by simple separation and re-used, the use of large amounts of palladium is therefore advantageous.
The alcohol serves primarily as reducing agent in the reaction and can be further oxidized to give the secondary products aldehyde or ketone, carboxylic acid and/or carbon dioxide or carbonic acid. The aldehydes or ketones which arise in the reaction can further react in the alkaline reaction medium in the sense of an aldol reaction. The alcohols used are therefore preferably alcohols which, following oxidation to the aldehyde or ketone, are unable or are able only with difficulty to participate in an aldol reaction. Methanol and/or ethylene glycol have proven particularly suitable for the process according to the invention.
Bases which can be used are, for example, salts of weak and strong acids. In particular, it is possible to use alkali metal salts and/or alkaline earth metal salts, preferably alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydrogencarbonates, alkali metal acetates and/or alkaline earth metal acetates, particularly preferably sodium hydroxide and/or potassium hydroxide.
The reaction is carried out at a temperature of from 0 to 200xc2x0 C., in particular 10 to 180xc2x0 C, preferably 20 to 150xc2x0 C. and particularly preferably 50 to 120xc2x0 C. The reaction according to the invention is preferably carried out at 0.1 to 2 MPa, in particular at 0.1 to 0.5 MPa. The increased pressure essentially serves to increase the boiling point of the solvent used in order to enable the optimum reaction temperature to be set. The reaction product preferably comprises 2,2xe2x80x2-bipyridyl-4,4xe2x80x2-dicarboxylic acid.
If dihalopyridines, such as, for example, 2,6-dichloroisonicotinic acid are used, as well as the bipyridyls, oligo- and polypyridyls also form, which usually precipitate out of the solution as solid. During the reaction, the dehalogenated products also usually form as byproducts. The chain length of the oligo- and polypyridyls is determined by the ratio of the reaction rates of the reductive dimerization to the dehalogenation. Transference of the process according to the invention to dihalopyridyls, which for the example 2,6-dichloroisonicotinic acid, follows the reaction equation
can therefore be used for the synthesis of mixtures of bi-, oligo- and polypyridyls.
The reaction product of the process according to the invention is preferably reacted with at least one transition metal from subgroup 7 and/or 8, preferably manganese, and/or a noble metal, in particular ruthenium, and/or compounds thereof to give at least one bipyridyl metal complex. These transition metal complexes are highly suitable as sensitizing dyes for dye-sensitized solar cells. Ruthenium complexes in particular, because of their light-absorption and electron-injection properties, have proven particularly suitable in semiconductors such as TiO2. Particularly suitable examples which may be mentioned are the compounds cis-X2bis(2,2xe2x80x2-bipyridyl-4,4xe2x80x2-dicarboxylate)ruthenium(II) where X =Cl, Br, I, CN or SCN. Such compounds can, for example, be obtained from the conversion of water- or methanol-soluble bipyridyl compounds or their salts with metal salts.
Such a reaction product is therefore highly suitable for use in photovoltaic or photoelectrochemical cells, in particular in solar cells, or for photo-induced electrolysis.
The examples below serve to illustrate the process without limiting it thereto.

Method for the catalytic production of substituted bipyridyl derivatives

Abstract: in which

Abstract: Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and Sxe2x80x2xe2x80x3xe2x80x3, independently of one another, are identical or different and are hydrogen, (C1-C18)-alkyl, alkoxy-(C1-C18), acyloxy-(C1-C18), aryloxy-(C1-C18), perfluoroacyloxy-(C1-C8), NO2, (C1-C18)-aryl, (C1-C18)-heteroaryl, halogen, hydroxyl, nitro, nitroso, CN, COOH, CHO, PO3H2, SO3H, SO2R, SOR, NH2, NH-alkyl-(C1-C18), N-alkyl2-(C1-C18), protected amine, CF3, NHCO-alkyl-(C1-C4), N-alkyl-(C1-C4)-CO-alkyl-(C1-C4), COO-alkyl-(C1-C18), CONH2, CO-alkyl-(C1-C18), NHCOH, NHCOO-alkyl-(C1-C4), CO-(C1-C18)-aryl, COO-(C1-C18)-aryl, CHCH-CO2-alkyl-(C1-C18), CHCHCO2H, PO-phenyl2, PO-alkyl2-(C1-C4), (COOxe2x88x92)n(cation)n+, (PO32xe2x88x92)n(cation)2n+, (SO3xe2x88x92)n(cation)n+ and/or (Oxe2x88x92)n(cation)n+,

Abstract: and/or in which optionally Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3and/or Sxe2x80x2xe2x80x3xe2x80x3forms a bridge to at least one further pyridine of the formula (III)

Abstract: and/or in which optionally the radicals Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3, and/or Sxe2x80x2xe2x80x3xe2x80x3 have the meanings given above and are substituted by at least one radical which has the meaning given above for Sxe2x80x2, Sxe2x80x3, Sxe2x80x2xe2x80x3, Sxe2x80x3xe2x80x3 and/or Sxe2x80x2xe2x80x3xe2x80x3


This patent teaches a low cost imager. The imager has an refractive objective lens 10 having a surface with a color correcting diffractive pattern 16 and an infrared transmitting polymeric field lens 18 having a substantially flat surface with a first field-correcting diffractive pattern. In this imager, the first field-correcting diffractive pattern operates to reduce aberrations of an image. In some embodiments, the imager further has a second field-correcting diffractive pattern on the field lens, where the first and second field-correcting diffractive pattern cooperating to reduce aberrations of the image. Additionally, this patent teaches a refractive/diffractive achromatic lens group 30. This achromat 30 can be used in the disclosed imager or in other optical devices. The achromatic group 30 has a refractive lens 10 and a lens 28 having a substantially flat surface with a surface diffractive pattern 16, the surface diffractive pattern cooperating with the refractive lens to reduce chromatic aberrations. Preferably, the second lens is formed from a polymeric sheet. These optics of the present invention can be used in infrared or visible optical devices.

It is known that different frequencies of light do not focus at the same location after passing through a lens. For this reason, color correction has been built into prior art lens systems. This is true not only for lens systems that focus visible light, but also for infrared lens systems. A typical infrared (IR) system operates over a moderate waveband, such as approximately.times.3-5 microns or 8-12 microns. Additionally, most lenses, particularly lenses with spherical surfaces, introduce field aberrations including astigmatism and coma.
FIG. 1 shows a conventional single field-of-view (FOV) imager. It includes 3 refractive elements, the objective 10, color corrector lens 12, and a field lens 14. The objective lens 10 is the primary focusing element which has the most power and is a converging lens. The objective lens collects the light from the desired object to be imaged and focuses this energy onto the detector. The objective lens is commonly made from germanium, due to germanium's high refractive index and low dispersion. Dispersion is the variation of refractive index with wavelength causing each wavelength to focus at a slightly different location. For an 8-12 micron waveband, these multiple foci would cause a blurring of the image. Thus, a color correcting lens is needed. The color corrector lens 12 is a negatively powered highly dispersive material used to bring all desired wavelengths of light to a common focus. The color corrector lens is typically made from zinc selenide. The field lens 14 is a positively powered lens used to correct field or image aberrations such as astigmatism and/or coma. The field lens is typically made from germanium.

Refractive/diffractive infrared imager and optics


To obtain a reinforcing frame capable of securing sufficient reinforcing strength and adhesive strength while suppressing a manufacturing cost by omitting a rim-like frame. A reinforcing frame is adhered to a rear surface, which is a non-light receiving surface of a solar battery panel, and includes a cylindrical portion that has a cylindrical shape along a longitudinal direction of the reinforcing frame and on which an adhesive surface for adhering to the solar battery panel is formed, and protruding portions that protrude from end portions along a longitudinal direction of the adhesive surface and that are substantially parallel to the adhesive surface.

A conventional solar battery module has a solar battery panel in which power generation elements referred to as "cells" are arranged on a translucent panel such as glass. An outer edge portion of the solar battery panel is supported by a rectangular rim-like frame that surrounds the entire circumference. Furthermore, the solar battery panel is fixed via the rim-like frame on a solar battery rack installed on the ground or a roof. Further, a reinforcing frame for supporting a rear surface of the solar battery panel at the time when the solar battery panel is warped is provided inside the rim-like frame (see, for example, Patent Literature 1).
In recent years, a method for configuring a solar battery module without using a rim-like frame has been studied. A solar battery panel not using a rim-like frame has an advantage of excellent productivity and the like because a process of engaging the solar battery panel with the rim-like frame can be omitted. For example, a solar battery panel can be manufactured by applying silicone resin or the like as a contact stopper having excellent heat resistance to an exposed glass end portion of the solar battery panel (see, for example, Patent Literature 2).
Furthermore, there is proposed a solar battery module and the like in which a relatively heavy reinforcing plate such as a glass plate or a metal plate on a rear surface of a solar battery panel is omitted, an outer edge portion of the solar battery panel having flexibility is surrounded by a rim-like frame, and a rib both ends of which are engaged with the rim-like frame is provided as a reinforcing material on the rear surface of the solar battery panel (see, for example, Patent Literature 3).
Further, there is proposed, as a module in which a solar battery panel is fixed on a solar battery rack without using a rim-like frame, a solar battery module in which a tension bar being a reinforcing frame is fixed on a rear surface of the solar battery panel, and both end portions of the tension bar are spanned across bars of the solar battery rack and are supported (for example, see Patent Literature 4).

Reinforcing frame and solar battery module


This application discloses a novel process for the preparation of phosphonate esters useful as intermediates in the preparation of himbacine analogs, themselves useful as thrombin receptor antagonists. The chemistry taught herein can be exemplified by the following scheme:

As described in copending U.S. patent application Ser. No. 11/331,324, filed Jan. 12, 2006 (herein, "the '324 application"), the disclosure of which is incorporated herein in its entirety by reference, himbacine analogs are useful as thrombin receptor antagonists. Thrombin is known to have a variety of activities in different cell types. Thrombin receptors are known to be present in such diverse cell types as human platelets, vascular smooth muscle cells, endothelial cells, and fibroblasts. Thrombin receptor antagonists may be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role, for example, as described in U.S. Pat. No. 6,063,847, the disclosure of which is incorporated by reference. Additional examples of thrombin receptor antagonists useful in the treatment of thrombotic, inflammatory, atherosclerotic, and fibroproliferative disorders, and the synthesis of these compounds, are described in published U.S. Patent Application No. 2003/0216437 (herein, "the '437 publication"), the disclosure of which is incorporated herein in its entirety by reference.
One thrombin receptor antagonist identified is an orally bioavailable compound derived from himbacine having the structure of the compound 11:
Processes for the synthesis of this and similar himbacine analog thrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847, and U.S. publication no. 2003/0216437, methods of using thrombin receptor antagonists are disclosed in U.S. publication no. 2004/0192753, and the synthesis of the bisulfate salt of a particular himbacine analog is disclosed in U.S. publication no. 2004/0176418, the disclosures of which are incorporated by reference herein.
As described in the '324 application mentioned herein above, compound 11 may be synthesized from Compound 15:
by treatment with compound 16 in accordance with Scheme I.

Compound 15 is in turn prepared from compound 1:
wherein R5 and R6 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, in four steps in accordance with the synthesis scheme shown in the copending '324 application, which synthetic schemes are incorporated herein by reference.
The copending '324 application describes the preparation of compound 16 in accordance with Scheme II, below.
With reference to Scheme II, L is a leaving group selected from halogens, esters, sulfonates and phosphates, R9 is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms, and R11 is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms and hydrogen. As described in the '324 application, in the scheme for preparation of compound 16, compound 36 is converted to compound 37 by first treatment with sodium carbonate to liberate the pyridyl alcohol free base, and the alcohol is subsequently reacted to convert the hydroxyl group to a leaving group (L) which can be displaced by a phosphite reagent to form the corresponding phosphonate ester. Accordingly, as described in the '324 application, preferably compound 37 is prepared by heating a solution of the alcohol intermediate isolated from compound 36 with a reagent that converts the hydroxyl functional group to a leaving group which can be displaced by a diorgano-phosphite compound. Preferably, L is a halogen, preferably Cl, and is preferably prepared by treating the alcohol with a halogenation reagent, for example, PBr3, PCl3, PCl5, and thionyl chloride, preferably thionyl chloride, followed by quenching the reaction with sodium carbonate, and extracting the product into toluene.
Compound 37 contained in the toluene extract is converted to compound 38 by reacting a solution of compound 37 with a diorgano-phosphite in the presence of a strong base, for example, a metal alkyl, for example, lithium alkyl and a metal amide, for example lithium bis(trimethylsilyl) amide.
The conversion of compound 38 to compound 16 is done by reacting compound 38 with boronate, the reaction catalyzed by a palladium catalyst. The catalyst used can be a homogeneous catalyst, for example, a palladium phosphine, for example, palladium tristriphenyl phosphine, and palladium tris-ortho-tolyphosphine, and amine catalysts, for example, bispalladium-trisbipyridine, or a heterogeneous catalyst, for example, palladium supported on carbon black.
The scheme presented in the '345 application for the synthesis of compound 16, a critical intermediate in the preparation of a variety of thrombin receptor antagonists, requires isolation or extraction of intermediates in two of the four steps, and utilizes in one step a powerful base and a water sensitive diorgano-phosphite compound. Moreover, the step shown in Scheme II of reacting unisolated compound 38 with boronate to form compound 16 proved to provide variable results, rendering the process of Scheme II undesirable for use in the preparation of commercial quantities of material.

Abstract: wherein R9 is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms, and R11 is selected independently for each occurrence from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms and hydrogen, X2 is Cl, Br, or I; X3 is selected from Cl and Br; and PdLn is a supported palladium metal catalyst or a soluble heterogeneous palladium catalyst. The L-derivatizing reagent is a moiety which converts the alcohol functional group of compound 137D to any leaving group which can be displaced by a triorgano-phosphite phosphonating agent.


A computing system obtains computer model(s) configured to predict response(s) based on variable(s). The system obtains a specification defining an allowed response set for the response(s) and receives an initial setting for bound(s). The system generates an initial design space for the variable(s) defined by the initial setting. The system displays in a graphical user interface (GUI) an initial representation of a specification rate. The specification rate indicates a portion of the initial design space predicted to generate a response within the allowed response set defined by the specification. The system receives an updated setting. The system generates an updated design space for the variable(s) defined by the updated setting. The system displays in the GUI an updated representation of an updated specification rate. The updated specification rate indicates a portion of the updated design space predicted to generate a response within the allowed response set defined by the specification.

Manufacturers and regulatory authorities can set standards or specifications for the outcome of a process. A specification, for example, can indicate that if a product exceeds a particular size or weight, the product cannot be used in certain environments or scenarios. A specification rate can be used to express how many manufactured products satisfy, or are predicted to satisfy, a specification or set of specifications. For example, an in-specification rate defines a portion of products that will satisfy specification criteria or an out-of-specification rate defines a portion of products that will not satisfy specification criteria.

Interactive graphical user interface for specification rate settings and predictions


An externally testable redundant seal connector for a well comprising a connector body and a ferrule disposed on an end of the connector body. The ferrule is adapted for forming a primary seal between an outer diameter of the connector body and a profile in a mandrel. A sealing groove can be formed on the outer diameter of the connector body. A sealing device can be disposed in the sealing groove. A conduit can be formed in the connector body parallel to but disconnected from the thru-bore. Ports can be disposed in the connector body for receiving fluid and introducing fluid to at least one conduit. A plug can be insertable in each port upon completion of testing wherein each plug forms a secondary seal between the connector and the mandrel.

A need exists for an externally testable redundant seal connector for an oil well that resists being pulled from a profile of a mandrel.
A further need exists for an externally testable redundant seal connector that is more robust, and can withstand more vibration and axial pull than other single seal connectors for well.
A need also exists for an externally testable redundant seal connector that is easy to install.
The present embodiments meet these needs.
The present embodiments are detailed below with reference to the listed Figures.

Externally testable redundant seal connector


A process for producing an alkoxycarbonylfluoroalkanesulfonate represented by the formula [1] is provided. This process includes the steps of (a) reacting a halofluoroalkanoate represented by the formula [2], with a sulfinating agent, thereby obtaining an alkoxycarbonylfluoroalkanesulfinate represented by the formula [3]; and (b) reacting the alkoxycarbonylfluoroalkanesulfinate with an oxidizing agent, thereby obtaining the target alkoxycarbonylfluoroalkanesulfonate. Furthermore, it is possible to react the obtained alkoxycarbonylfluoroalkanesulfonate with a monovalent onium salt to conduct a salt exchange, thereby obtaining a alkoxycarbonylfluoroalkanesulfonic acid onium salt represented by the formula [4].

In recent years, the trend toward micro-scale pattern rule has been increasing with the trend toward large-scale integration and high-speed LSI circuits. The trend toward a shorter wavelength of the exposure light source lies behind it. For example, it became possible to mass-produce 64M-bit (processing dimension: 0.25 μm or less) DRAM (dynamic random-access memory) by the wavelength shortening from mercury lamp i-line (365 nm) to KrF excimer laser (248 nm). Nowadays, a lithography using ArF excimer laser (193 nm) has increasingly been examined, and a 65 nm node device has been examined by a combination with a high NA lens (NA≧0.9). Although the use of F2 laser (wavelength: 157 nm) had been named as a candidate for the production of the next 45 nm node devices, its application was postponed by many problems, such as cost increase of scanner, change of optical system, and low etching resistance of resist. As an alternative to F2 lithography, proposed was ArF immersion lithography. Now, its development is going on toward an early introduction.
As a resist suitable for such exposure wavelength, "chemically amplified resist material" attracts much attention. This material contains a radiosensitive acid generator (hereinafter referred to as "photoacid generator"), which generates an acid by radiation irradiation (hereinafter, referred to as "exposure"). Furthermore, it is a pattern-forming material that forms a pattern by making a difference in solubility between the exposed portion and the unexposed portion through a reaction using the acid generated by the exposure as a catalyst.
Examples of the photoacid generator used for such chemically amplified resist material include onium sulfonates, such as iodonium sulfonate and sulfonium sulfonate, sulfonic acid esters, N-imidosulfonate, N-oximesulfonate, o-nitrobenzylsulfonate, and tris(methane)sulfonate of pyrogallol.
Examples of the acid generated from the photoacid generator upon exposure include alkanesulfonic acids, arylsulfonic acids, and partially or entirely fluorinated arylsulfonic acids and alkanesulfonic acids.
Of these, acid generators that generate partially or entirely fluorinated alkanesulfonic acids have a sufficient acid strength in deprotection reactions of protective groups that are difficult in deprotection, and therefore many of them have been put into practical use. Their examples include triphenylsulfonium trifluoromethanesulfonate and triphenylsulfonium perfluoro-n-octane sulfonate. Although triphenylsulfonium trifluoromethanesulfonate generates a sufficiently strong acid to have a sufficiently high-resolution performance, it has a defect of high mask dependency as a photoresist due to low boiling point of the acid and due to long diffusion length of the acid. Triphenylsulfonium perfluoro-n-octanesulfonate has a sufficient acidity and is almost appropriate in terms of acid boiling point and diffusion length. Therefore, it attracts much attention in recent years. However, it should be noted that perfluorooctyl sulfonates might be hazardous to human health and the environment (see "Perfluorooctyl Sulfonates; Proposed Significant New Use Rule" dated Oct. 18, 2000 (Volume 65, Number: 202) from the U.S. Environmental Protection Agency).
Under such background, there have been the developments of acid generators that generate partially or entirely fluorinated alkanesulfonic acids and that have characteristics of having a sufficient acidity, being appropriate in terms of acid boiling point and diffusion length, and having less load on the environment. Thus, there have been the developments of alkoxycarbonylfluoroalkanesulfonic acid onium salts as acid generators, such as triphenylsulfonium methoxycarbonyldifluoromethanesulfonate (see Japanese Patent Application Publication No. 2004-117959), (4-methylphenyl)diphenylsulfonyl t-butoxycarbonyldifluoromethane-sulfonate (see Japanese Patent Application Publication No. 2002-214774 corresponding to U.S. Patent Application Publication Nos. 2002/0102491, 2005/0130060 and 2007/0003871), and triphenylsulfonium (adamantane-1-ylmethyl)oxycarbonyldifluoromethanesulfonate (see Japanese Patent Application Publication No. 2004-4561 corresponding to US Patent Application Publication No. 2003/0194639).
The following reaction scheme [1] is known to obtain an alkoxycarbonylfluoroalkanesulfonic acid onium salt [vii] (see Japanese Patent Application Publication No. 2004-117959 and U.S. Pat. No. 2,852,554). In this reaction scheme, 3,3,4,4-tetrafluoro-[1,2]oxathiethane 2,2-dioxide [iii] is synthesized by reacting tetrafluoroethylene [i] with sulfur trioxide [ii]. Then, the compound [v] is synthesized by a ring-opening reaction of the compound [iii] using an alcohol (ROH). Alternatively, the compound [v] is synthesized by a two-step reaction, that is, a ring-opening isomerization of the compound [iii] to obtain an oxyfluoride [iv] and then an esterification of the oxyfluoride [iv] into the compound [v] by an alcohol (ROH). Then, the compound [v] is turned into a sulfonate (a sodium sulfonate) [vi] by an alkali metal containing base, followed by a salt exchange with an onium salt such as sulfonium salt (Q+X− where Q+ is a monovalent onium cation and X− is usually a halogen ion), thereby obtaining the target acid generator, an alkoxycarbonylfluoroalkanesulfonic acid onium salt [vii].

Process for producing alkoxycarbonylfluoroalkanesulfonates


A video stream (for example, H.264 video) includes intra-encoded portions. Decoding an intra-encoded portion utilizes the result of decoding one or more other portions (called predecessors) in the frame. Frame reconstruction involves identifying a portion that has no predecessor portions that have not been decoded and then initiating decoding of the identified portion(s). When the decoding of a portion is substantially complete, then the remaining portions to be decoded are examined to identify portions that have no predecessors that have not been decoded. By carrying out this method, multiple portions may be decoded simultaneously. Each can be decoded on a different work entity, thereby increasing the rate of decoding of the overall frame. Because deblock filtering a predecessor destroys information needed in the intra-decoding of other portions, prefiltered predecessor information is stored in a buffer for subsequent use during intra-decoding, thereby facilitating simultaneous decoding of multiple portions.

1. Field
The disclosed embodiments relate to video decoding.
2. Background Information
Cellular telephones provide their users more functionality than just an ability to make and receive wireless telephone calls. Cellular telephone manufacturers are incorporating more and more functionality into their cellular telephones in order to compete for user interest with other cellular telephone manufacturers. A cellular telephone manufacturer may, for example, build a video receiving capability into their cellular telephones. The cellular telephone is to be usable to receive a stream of compressed video information transmitted from a satellite, to decode the compressed information into video, and to display the video on the display of the cellular telephone. The cellular telephone user may therefore watch satellite television programming on the display of the cellular telephone. The manufacturer, however, also wants the cellular telephone to be inexpensive to manufacture. In one example, an older semiconductor processing technology is to be used to realize digital processing circuitry of the cellular telephone in order to reduce the cost of the integrated circuits making up the cellular telephone. Using the older processing technology is less expensive than using a higher speed, newer processing technology.
In one example, the older processing technology limits the clock speed of a digital signal processor that can be realized to about one hundred megahertz. It is desired to be able to use this older technology to video decode thirty frames per second of VGA (640×480 pixels) compressed video information, and to display the resulting VGA resolution video in real time on the display of the cellular telephone. Unfortunately, a one hundred megahertz digital signal processor does not have adequate throughput to carry out the required amount of processing. A digital signal processor having a clock frequency of 250 to 300 megahertz would be required to decode the VGA video stream at thirty frames per second. Accordingly, if the inexpensive semiconductor processing technology is used, then it may only be possible for the cellular telephone to display one third the desired resolution images at the desired thirty frames per second frame rate.
There also may be reasons other than cost for limiting the frequency of clock signal that clocks the digital signal processing circuitry within a cellular telephone.

Parallel decoding of intra-encoded video


A method for interpreting data that is produced after a group of amino acids and acylcarnitines are derivatized from blood spots taken from newborn babies and scanned by a tandem mass spectrometer. Concentration levels of each metabolite, which are directly proportional to the butyl ester fragment after derivatization, are compared to threshold flags for determining a significance of any deviation of the metabolite relative to the flag threshold. The threshold flags are diagnostic limits to the data retrieved from each blood spot. The data includes metabolite concentrations and molar ratios of metabolites with other metabolites. Samples are labeled normal for a disease if the concentration of any of the metabolite concentrations or molar ratio concentration do not deviate from the flag threshold, but, in contrast, the sample must be further evaluated if a value is elevated or deficient to some degree. Thus, as each metabolite fragments at a different mass to charge value (m/z), corresponding data is compared to the respective flag thresholds for determining a next course of action that must be taken to ultimately assist a physician in the diagnosis of a genetic disorder such as hypermethionemia resulting from an elevation or deficiency of the metabolite particular for that disorder.

1. Field of the Invention
The present invention relates to a method for interpreting data used for clinical diagnostic purposes. In particular, a decision tree is disclosed for interpreting tandem mass spectrometry data relating to the quantification of metabolites used for diagnosing newborn babies.
2. Description of the Related Art
Automated methods for assessing a patient's condition are known. Computerized systems can be integrated to produce data that can be compared to a known result to allow for proper diagnosing. Such data might be produced by a MRI or CAT scanner, which is used to identify components within the human body.
One particular instrument used for identifying components of interest, whether they are of medicinal or chemical interest, is the mass spectrometer. In reference to U.S. Pat. No. 5,453,613, compounds, when introduced to the electrospray tandem mass spectrometer, are ionized and essentially fragmented. Each fragment produces a peak having local maximums that are matched to reference spectra. A compound can be identified by its associated fragments, each having a mass to charge ratio, which is then relative to the concentrations-of each fragment. All of the reference spectra and compound names can then be stored in a library for correlation and determination. Thus, mass/charge ratios can be used to identify components from known spectra stored in a database.
More recently, however, the use of spectrometry has been implemented in the field of clinical diagnosis. See Chace, U.S. application Ser. No. 09/277,119.
Inborn errors of metabolism usually result from defective enzymes or cofactors. Resulting genetic disorders can be diagnosed by the metabolic profiling of amino acids and acylcarnitines taken from blood spots subjected to a sampling protocol and thereafter introduced into an electrospray tandem mass spectrometer. An electrospray tandem mass spectrometer is very sensitive and specific and can detect a broad spectrum of disorders at the genetic level. With proper standards, data produced from the spectrometer includes values for particular metabolites. The metabolites that are of interest in detecting these disorders are, in particular, amino acids and acylcarnitines/carnitines and the derivatives thereof.
The spectra and resulting concentration values of each metabolite, as derived from mass spectrometry, are then compared to thresholds as a means for evaluating the contents of the blood sample. These thresholds determine the appropriate course of action necessary as a follow-up to the spectral analysis.
As seen in Wright et al., U.S. Pat. No. 5,545,895, spectrometry data is applied to a computerized search database for matching each component as a means of identification. In a clinical diagnostic setting, there must be further methods for evaluation beyond just that of the identification itself. The numbers must be quantified. Newborns can be born with metabolic disorders, which, if not treated within days, can result in death. Thus, after obtaining MS/MS (tandem mass spectrometer) data from blood samples from newborns, generally of the age of less than seven days old, there is a need for efficiently interpreting this data in relation to pre-determined metabolite concentration thresholds. This interpretation allows for proper decision-making necessary for the diagnosing and follow-up testing of newborns.

This patent is subject to a terminal disclaimer.

Method for interpreting tandem mass spectrometry data for clinical diagnosis of genetic disorders such as hypermethionemia


Disclosed is a silver halide color photographic material which contains a particular epoxy compound having slight solubility in water, an acylacetamide type yellow dye forming coupler the acyl group of which is a cycloalkane type and a pyrazolotriazole type magenta dye forming coupler which contains specified substituents and splitting-off group to produce color images of high keeping quality, especially to produce a yellow dye image with excellent hue and reduced discoloration upon long-range storage in the dark, and, what is more, to inhibit magenta color stain from generating in the yellow dye image.

In semipermanently storing color photographic materials as image recorded matter, it is required of them to hold color balance among three colors, namely yellow, magenta and cyan colors, of dye images even after they have undergone discoloration by preventing as greatly as possible the dye images from causing discoloration in the light (light discoloration) and that in the dark (dark discoloration) to maintain their initial color balance. However, yellow, magenta and cyan dye images are different from one another in extent of discoloration in the light and in the dark, and so color balance among the three colors is broken through imbalance of discoloration after long-range storage to cause a disadvantage that an image quality is deteriorated. For instance, since dark discoloration under high humidity circumstances is greater in yellow and cyan dye images than in a magenta dye image, a marked break in color balance occurred occasionally. When stored under the foregoing circumstances, it further occurred sometimes that molds and the like propagate themselves over the surface of a photographic material to cause marked deterioration of yellow images and, in case of color prints, to generate red spots in an image area.
For the purpose of solving the foregoing problems, using cyclic ether compounds or epoxy group-containing compounds is disclosed with respect to cyan dye images in JP-B-58-45017 (the term "JP-B" as used herein means an "examined Japanese patent publication"), JP-A-62-75447 (the term "JP-A" as used herein means an "unexamined published Japanese patent application"), JP-A-62-129853, JP-A-62-172353, JP-A-62-198859, JP-A-62-196657, JP-A-64-21447 and JP-A-64-23255, while with respect to yellow dye images, e.g., in JP-A-64-50048 and JP-A-64-50049. Concrete compounds disclosed in those patents were able to achieve some effect in improving dark discoloration, but failed to bring about a satisfactory solution. In addition, it occurred occasionally that the density of magenta color in a yellow image area was increased with a decrease of the density of yellow dye image. Generation of magenta color stain as described above presented a problem that it spoiled considerably a yellow dye image, which originally possessed excellent color reproducibility. Therefore, further heightening the keeping quality of yellow images is necessary also for retaining excellent color reproducibility over a long period of time.
As for the couplers forming yellow dye images, yellow couplers of the benzoyl and pivaloyl types which contain acetanilide as basic skeleton are known generally. In comparison with those conventional yellow couplers, the cycloalkanecarbonyl group-containing yellow couplers disclosed in EP-A-0447969 can produce yellow dye images having excellent spectral absorption characteristics and high density by the coupling reaction with the oxidation product of an aromatic primary amine developing agent. However, they are inferior to conventional yellow couplers in image keeping quality under high temperature and high humidity conditions.
As for the couplers forming magenta dye images, on the other hand, pyrazoloazole type magenta couplers are now used practically in place of pyrazolone type couplers because the images formed therefrom are superior in hue. Of such pyrazoloazole type couplers, 1H-pyrazolo[1,5-b][1,2,4]triazole type couplers disclosed in JP-A-03-141350 form magenta dye images excellent in spectral absorption characteristics, color reproducibility and fastness by the reaction with the oxidation product of an aromatic primary amine developing agent, and are appreciably reduced in a change for yellow in the white area (yellow stain) with the lapse of time. However, the magenta coupler of the above-described kind have problems of their generating magenta color stain in a yellow image area upon storage under high temperature and high humidity, particularly when used in combination with the above-cited cycloalkanecarbonyl group-containing yellow couplers.

Silver halide color photographic material having reduced magenta color stain


A filtering process is carried out on an image signal representing a color image and with an infinite impulse response (IIR) filter to form an unsharp image signal, which represents an unsharp image of the color image. Dynamic range compressing is performed out on the image signal in accordance with the unsharp image signal, and a processed image signal is thereby obtained. A visible image is reproduced from the processed image signal. The dynamic range compressing process can be carried out with relatively few line memories such that the apparatus for carrying out the processing may be kept small, and the printed image having good image quality can thereby be obtained.

1. Field of the Invention
This invention relates to an image reproducing method and apparatus for reproducing a visible image from an image signal, which is obtained from a color image carried on a reflection type of image storage sheet, such as a photograph or printed matter, or a transmission type of image storage sheet, such as negative film or reversal film.
2. Description of the Prior Art
Recently, research has been performed in the area of digital photo printers. In digital photo printers, an image recorded on photographic film (hereinbelow referred to as the film), such as negative film or reversal film, or on printed matter is photoelectrically read out, and an image signal thus obtained is converted into a digital signal. The digital signal is then subjected to various kinds of image processing, and a processed image signal is thereby obtained. Thereafter, recording light is modulated with the processed image signal, and a photosensitive material, such as photographic paper, is scanned with and exposed with the modulated recording light. In this manner, a visible image is printed on the photosensitive material.
With the digital photo printers, layout of printed images, such as combining a plurality of images, division of an image, editing of characters and images, and various other kinds of image processing, such as color/image density adjustment, conversion of magnification, and contour emphasis, can be carried out freely. Therefore, prints may be edited and processed freely in accordance with such a system. In cases where the conventional surface exposure techniques are employed, image density information recorded on film, or the like, cannot be reproduced perfectly due to limitation imposed by the reproducible image density range of photosensitive materials. However, with digital photo printers, prints can be obtained such that the image density information recorded on film, or the like, can be reproduced nearly perfectly.
Basically, the digital photo printers are formed of a read-out means for reading out an image having been recorded on an image storage sheet, such as film, and an image reproducing means. The image reproducing means carries out image processing on the image signal having thus been detected by the read-out means, and adjusts exposure conditions. Also, the image reproducing means carries out a scanning exposure operation on a photosensitive material under the adjusted exposure conditions and carries out development processing on the exposed photosensitive material. Further, the image reproducing means can reproduce a visible image from the image signal having been obtained from the image processing and can display the visible image on a monitor.
For example, in a read-out apparatus for reading out an image recorded on film, or the like, wherein slit scanning is carried out, reading light having a slit-like shape extending in a one-dimensional direction is used to irradiate the film, and the film is moved in a direction, which is approximately normal to the one-dimensional direction of the reading light. (Alternatively, the reading light and a photoelectric converting device are moved in the direction, which is approximately normal to the one-dimensional direction.) In this manner, the film is scanned in two-dimensional directions. An image of the light, which has passed through the film and carries the film image information, is formed on a light receiving face of the photoelectric converting device, such as a CCD line sensor, and is thus photoelectrically converted into a light amount signal. The thus detected light amount signal is amplified and is then converted into a digital signal by an analog-to-digital converter. Thereafter, the digital signal is subjected to various kinds of image processing, such as compensation for a fluctuation in the characteristics among the CCD elements of the CCD line sensor, image density conversion, and conversion of magnification, and a processed signal obtained from the image processing is transferred to a reproducing means.
In the reproducing means, for example, a visible image is reproduced from the received image signal and displayed on a display device, such as a cathode ray tube (CRT) display device. When necessary, the operator, who views the reproduced image, corrects the gradation, the color, the image density, or the like, of the reproduced image (i.e., sets the set-up conditions). In cases where the reproduced image is judged to be acceptable as a finished print, the image signal is transferred as the recording image information into a development means or a monitor.
In an image reproducing apparatus, in which the image reproduction with raster scanning (i.e., light beam scanning) is utilized, three kinds of light beams corresponding to exposure of the layers (which are formed on a photosensitive material and are sensitive to three primary colors, e.g. red (R), green (G), and blue (B)) are modulated in accordance with the recording image information and deflected in a main scanning direction (which corresponds to the aforesaid one-dimensional direction). Also, the photosensitive material is conveyed in a sub-scanning direction, which is approximately normal to the main scanning direction. (The photosensitive material is thus moved with respect to the deflected light beams and in the sub-scanning direction.) In this manner, the photosensitive material is scanned in two-dimensional directions with the light beams, which have been modulated in accordance with the recording image information, and the image having been read out from the film is thereby reproduced on the photosensitive material.
The photosensitive material having thus been scanned with and exposed to the light beams is then subjected to development processing in accordance with the kind of the photosensitive material. For example, in cases where the photosensitive material is a silver halide photographic material, it is subjected to the development processing comprising the steps of color development, bleach-fixing, washing, drying, and the like. A finished print is thereby obtained.
Such a photosensitive material can record a comparatively wide range of luminance of the object. However, the maximum image density on the photosensitive material is limited. Therefore, in cases where a print of a scene having a large difference in luminance is obtained with an ordinary printing technique, details become imperceptible due to insufficient gradation in either a bright portion (a highlight) or a dark portion (a shadow) on the print. For example, in cases where a picture of a person is taken against the light, if the picture is printed such that the image of the person may become clear, the bright portion, such as the sky region, will become white and its details will become imperceptible. Also, if the picture is printed such that the bright portion, such as the sky region, may become clear, the image of the person will become black and its details will become imperceptible. In order to solve the problems, a shutting light technique or a masking print technique has heretofore been employed.
With the shutting light technique, an ordinary level of exposure is given to a region having an intermediate level of image density in a scene. Also, a long time of exposure is given selectively to a region, which is to become white and the details of which are considered to become imperceptible on the print, by using a perforated blocking sheet. Further, as for a region, which is to become black and the details of which are to become imperceptible on the print, the exposure time is kept short selectively by using a blocking sheet. In this manner, the print is obtained such that the contrast of each object may be kept appropriate, and the details of the highlight and the shadow may be kept perceptible. A method has been proposed, in which unsharp image film having been photographically formed by the negative-positive reversal of original image film is used as a blocking sheet for locally controlling the exposure time, and in which the printing is carried out by superposing the original image film and the unsharp image film one upon the other.
Also, various masking print techniques have been proposed in, for example, Japanese Unexamined Patent Publication Nos. 58(1983)-66929 and 64(1989)-35542 and Japanese Patent Publication No. 64(1989)-10819. With the proposed masking print techniques, the same effects as those of the shutting light technique can be obtained by locally changing the brightness of a light source for illuminating a photographic original image.
With the apparatus proposed in Japanese Unexamined Patent Publication No. 58(1983)-66929, a CRT is employed as the illuminating light source, and a photometric operation with memory scanning is carried out on an original image. In this manner, an unsharp mask signal is formed from the color original image. In an exposure mode, a CRT is controlled with the unsharp mask signal, and the contrast is thereby controlled such that the original image maybe reliably recorded within the contrast reproduction limit of a photosensitive material.
With the apparatus proposed in Japanese Unexamined Patent Publication No. 64(1989)-35542, a CRT is employed as the illuminating light source, and an optical path for the photometric operation carried out on an original image and an optical path for the exposure of a photosensitive material are provided such that they may be changed over to each other. Also, a signal for controlling the luminance of the CRT during the exposure and thereby correcting the gradation and the saturation of the reproduced image is formed in accordance with the photometric signal obtained from the original image. Further, a signal for displaying the reproduced image on a monitor is formed. The image displayed on the monitor is viewed, and the amount of light of the CRT is thereby controlled such that a desired image may be reproduced.
With the apparatus proposed in Japanese Patent Publication No. 64(1989)-10819, a matrix device, such as a liquid crystal, which is capable of locally changing the light transmittance, is located between a uniform surface light source and an original image. The transmittance of the liquid crystal is controlled in accordance with the photometric signal obtained from the original image, and the contrast of the reproduced image is thereby adjusted.
Further, for example, in Japanese Unexamined Patent Publication No. 6(1994)-242521, a method is proposed wherein, in order for the gray balance in image reproduction to be corrected, conversion is carried out such that the maximum image density value and the minimum image density value of each color on an original image may become equal to predetermined values on the reproduced image. With the proposed method, the control of the gradation can be carried out for each of the frames of film. Therefore, as for a scene having a large difference in luminance, the gradation of the entire area of the image can be rendered soft such that the range of luminance of the scene may fall within the dynamic range of the photosensitive material. In this manner, the problems can be prevented from occurring in that the details of the highlight and the shadow become imperceptible due to insufficient gradation.
However, with the aforesaid shutting light technique and the aforesaid masking print techniques, the blocking sheet must be prepared and used regardless of the image, which is to be reproduced. Therefore, a very high level of processing is required. Also, considerable labor and time are required to form the unsharp image film, and the printing efficiency cannot be kept high.
Also, with the aforesaid apparatuses described in Japanese Unexamined Patent Publication Nos. 58(1983)-66929 and 64(1989)-35542 and Japanese Patent Publication No. 64(1989)-10819, the contrast of a comparatively large structure can be reproduced by adjusting with the distribution of the luminance of the illuminating light source. However, local structures in the reproduced image correspond to the projected image of the original image film. Therefore, the aforesaid apparatuses have the drawbacks in that the reproduction of colors of the local structures, including their edges, cannot be controlled freely, in that the sharpness of the edges cannot be controlled freely, and in that the gradation of over-exposure portions, under-exposure portions, or the like, in the original image cannot be controlled freely.
Further, with the aforesaid apparatuses described in Japanese Unexamined Patent Publication Nos. 58(1983)-66929 and 64(1989)-35542 and Japanese Patent Publication No. 64(1989)-10819, the processing for the photometric operation and the exposure is carried out sequentially. Therefore, the problems occur in that the processing capacity cannot be kept high. Also, the problems occur in that, in cases where the distance of movement of the original image becomes different between when the photometric operation is carried out and when the exposure is carried out, the printed image becomes disturbed. Further, with the apparatus described in Japanese Patent Publication No. 64(1989)-10819, wherein the liquid crystal is used, since the transmittance of the liquid crystal is at most approximately 30%, the exposure time cannot be kept short. Furthermore, the tube surface of the CRT is covered with glass, and the side inward from the glass becomes luminous. Therefore, even if the film is brought into close contact with the tube surface of the CRT, a spacing will substantially occur between the luminous surface of the CRT and the film. Accordingly, with the apparatus proposed in Japanese Unexamined Patent Publication No. 64(1989)-35542, wherein the image represented by the photometric signal is displayed, a blur occurs with the photometric and image forming system due to the spacing between the luminous surface of the CRT and the film surface during the photometric operation, and therefore a clear monitor image cannot be obtained.
With the method proposed in Japanese Unexamined Patent Publication No. 6(1994)-242521, even though the problems can be prevented from occurring in that the details of the highlight and the shadow become imperceptible due to insufficient gradation, the problems occur in that the contrast of each object becomes weak and the printed image becomes monotonous.
Therefore, novel image reproducing methods have been proposed, wherein an unsharp image signal, which represents only the structures of low frequencies in a color image, is subtracted from a digital image signal representing the color image, a difference signal being thereby obtained, processing for changing the image density, the saturation, and/or the gradation is carried out on the difference signal, and a visible image is reproduced by an image reproducing means from a processed image signal, which has been obtained from the processing carried out on the difference signal. In this manner, even if the contrast of the entire area of the original image is strong, a reproduced image can be obtained such that the contrast of the entire area of the image may be weakened, such that the contrasts of fine structures in the highlight and the shadow in the image may remain, and such that the details of the highlight and the shadow can be prevented from becoming imperceptible in the reproduced image due to insufficient gradation. Such image reproducing methods are described in, for example, Japanese Unexamined Patent Publication No. 2(1990)-226375 and U.S. Ser. No. 08/672,939.
In the image reproducing methods descried above, a filtering process is carried out on the image signal by using a low-pass filter, and an unsharp image signal is thereby obtained. However, if the size of the low-pass filter is very small, the sharpness of the resulting processed image will be emphasized unnaturally, and the same effects as those obtained with the aforesaid shutting light technique cannot be obtained. Therefore, in the image reproducing methods described above, the filtering process is carried out by using a filter having a comparatively large size (for example, a size of approximately 100.times.100). However, in cases where the unsharp image signal is formed with the low-pass filter, it is necessary for the processing to be carried out not only along the horizontal direction of the image but also along the vertical direction of the image. Accordingly, for the formation of the unsharp image signal, a number of line memories, which number is equal to the mask size minus 1, must be used (for example, in cases where the filter size is equal to 100.times.100, 99 line memories must be used). As a result, the size of the apparatus for carrying out the processing cannot be kept small.

Image reproducing method and apparatus using dynamic range compression based on an unsharp signal generated by IIR filter


A three-dimensional measuring apparatus has an optical probe built therein The optical probe includes a laser source onto a surface to be measured, a beam laser source, an objective lens for condensing a light from splitter for separating from an incident optical path a laser light reflected from the surface to be measured, a non-polarizing beam splitter for separating a separated light into two separated lights by a fixed separating ratio, independent of a direction of polarization, a first pin hole provided in front of a condensing point of one of the two separated lights separated by the non-polarizing beam splitter, a first photodetector for receiving the light passing through the first pin hole, a second pin hole provided in the rear of a condensing point of the other of the two separated lights separated by the non-polarizing beam splitter, a second photodetector for receiving the light passing through the second pin hole, and a driving means for driving the objective lens by a difference of outputs between the first and second photodetectors as an error signal for automatic focus control. Thus, the optical probe is free of focusing errors even if the inclining direction of the surface to be measured is changed.

The present invention relates to a three-dimensional measuring apparatus having an optical probe built therein for measuring the three-dimensional shape of a curved face such as an aspherical lens or the like in a non-contacting manner with superhigh accuracy.
The simplest three-dimensional measuring apparatus incorporating an optical probe is equipped with a microscope as a probe. The microscope is moved to a position where an image is monitored most clearly, and the x, y, and z coordinates at the position are read. The measuring apparatus of this type has the drawbacks, for example, that an image is not clearly found at a point of an error in focal depth or at a smooth surface without a flaw such as a lens surface. Even a measuring apparatus with an auto-focusing function based on an optical trigonometrical measurement cannot measure an inclined surface.
In a focus adjusting optical system disclosed in U.S. Pat. No. 2,897,722, the light is condensed at a surface to be measured and the reflecting light from the surface is divided into two by a beam splitter. The difference of the quantities of light passing through pin holes provided in front of and to the rear of (behind) the focal point is used as an error signal for focus adjustment. Accordingly, the prior system makes it possible to measure an inclined surface inclined in an optional direction. Nevertheless, errors occur with the prior art system, depending on the inclining direction of the surface.
That is, in the focus adjusting method of U.S. Pat. No. 2,897,722, since the direction of light passing through the beam splitter differs depending on the inclining direction of the surface to be measured, the separating or dividing ratio of light is changed according to the focus adjusting method disclosed in U.S. Pat. No. 2,897,722. This results in the focal point being different for different inclining directions of the surface to be measured, thus causing a measuring error.
Another prior art shape measuring apparatus, revealed in Japanese Laid-open Patent Publication No. 2-134506 by one of the inventors of the present invention, utilizes a focus controlling method which is capable of controlling an optical probe supported by a coil spring with considerably high accuracy, i.e., within approximately 0.01 .mu.m to the focus in about 20 mm range in the z-axis direction by means of a linear motor.
However, the following disadvantages are inherent in the structure of the shape measuring apparatus of Japanese Laid-open Patent Publication No. 2-134506, wherein a linear motor for driving the optical probe is arranged above an optical probe and a coil spring is arranged above the linear motor:
(1) It is desirable that the driving position of the linear motor is in the vicinity of the center of the z-axis movable section. Otherwise, during driving of the linear motor the torque for rotating the movable section worsens the moving perpendicularity in the z-axis direction. If the moving perpendicularity in the z-axis direction is poor, the measuring accuracy is deteriorated and the focus controlling efficiency is lowered. Although it is better to support the supporting spring at the center of gravity thereof, the prior art structure cannot realize this.
(2) It is difficult to extend the movable range in the z-axis direction of the optical probe so as to obtain a larger measuring area, because the space is too limited to provide a magnetic circuit of a length not smaller than the movable range of the linear motor.
Moreover, in the above shape measuring apparatus, the optical probe of the shape measuring apparatus is supported by the coil spring, and the tension of the coil spring is changed due to the expansion/contraction thereof in accordance with the movement of the optical probe, thus bringing about errors in focus servo. Moreover, if the movable range of the optical probe in the z-axis direction is increased, it causes the optical probe to become unable to track the focal point.

Matsushita Electric Industrial Co., Ltd.


A pipe joint has a body, and an annular packing is mounted to the opening of the body into which a fluid tube is inserted. The packing is provided with: a body section having a substantially rectangular cross-sectional shape; and a seal section protruding in the radial direction from the inner peripheral surface of the body section. The seal section is formed at substantially the center of the body section in the widthwise direction thereof and is formed in a triangular cross-sectional shape tapering to the inner peripheral side. When the fluid tube is inserted in the opening, the seal section of the packing makes sliding contact with the outer peripheral surface of the fluid tube.

Heretofore, a pipe joint has been used for connecting fluid tubes to a fluid pressure device such as a cylinder. Such a pipe joint, for example as disclosed in Japanese Laid-Open Patent Publication No. 03-140697, is equipped with a cylindrical shaped coupling main body portion. In the interior of the coupling main body portion, a ring shaped sealing member is installed, and adjacent to the sealing member, latching pawls are provided, for engagement with a flow passage pipe, which is inserted into the interior of the coupling main body portion. In addition, when the flow passage pipe is inserted from one end side of the coupling main body portion, the sealing member, which has a rectangular shape in cross section, abuts against the outer peripheral surface of the flow passage pipe, so that leakage of the fluid via the outer peripheral surface of the flow passage pipe is prevented. Together therewith, the latching pawls bite into the outer peripheral surface of the flow passage pipe, thus preventing the flow passage pipe from being pulled out.
However, with the pipe joint of Japanese Laid-Open Patent Publication No. 03-140697, when a fluid is supplied from the other end side of the coupling main body portion and flows into the flow passage pipe that is connected to the other end side, the sealing member is pressed toward the latching pawls as a result of the fluid, and by pressing of the latching pawls, the depth at which the pawls bite into the flow passage pipe is made deeper. As a result thereof, when the supply of fluid is halted and the flow passage pipe is taken out from the coupling main body portion, cases are known to occur in which separation of the flow passage pipe is difficult due to the latching pawls biting excessively into the flow passage pipe.
Further, when the flow passage pipe is installed with respect to the coupling main body portion, the sealing member is pressed by the flow passage pipe, thereby deforming and displacing the sealing member. However, in this case, since there is no space into which the contact portion with the flow passage pipe can move, deformation of the contact portion is obstructed, and as a result, resistance occurs when the flow passage pipe is inserted.
Furthermore, in a situation where the flow passage pipe is installed with respect to the coupling main body portion, as a result of the sealing member being pressed upon and displaced by the fluid that flows through the interior of the coupling main body, the contact area of the sealing member with respect to the outer circumferential surface of the flow passage pipe is reduced, and there is a concern that the sealing characteristics of the sealing member may be deteriorated.


A wireless communication device comprising a housing comprising a plurality of edges and configured to serve as an external surface for the wireless communication device, and an antenna adjacent to at least a first edge of the housing, wherein the antenna comprises at least a conductive strip and at least one slot and wherein the antenna is configured to receive and transmit wireless signals, wherein the first edge of the housing is one of an edge of the housing nearest an ear piece and an edge of the housing that is opposite the edge of the housing nearest the ear piece, and wherein the conductive strip and the slot are adjacent to at least the first edge of the housing.

An antenna can be used to transmit or receive RF signals in the range of about 3 kilohertz to 300 gigahertz. For cellular communications within the United States, the relevant frequency range is between 824 and 2690 megahertz. While numerous types of antennas exist, the use of slot antennas in cellular communication devices is on the rise. A slot antenna consists of a conductive surface, usually a flat metal plate, comprising an aperture or slot of a removed surface portion. The slot radiates electromagnetic (EM) waves when a driving frequency, e.g., RF, is applied to the plate. The shape and size of the antenna, the slot, and the driving frequency determine the radiation distribution pattern.

Wireless communication device with an antenna adjacent to an edge of the device


Provided are chemically modified ribonucleic acid (RNA) aptamers comprising one or more of 2′F guanylate, 2′OMe cytidylate, 2′OMe adenylate, and a deoxy pyrimidine nucleotide with a moiety on the 5 position of the pyrimidine; and methods of making the aptamers.

Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification. The disclosures of all publications, patents and patent applications mentioned herein are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Nucleotide aptamers are oligonucleotides that bind to a specific target molecule and have the potential to serve both diagnostic and therapeutic purposes. Nucleotide aptamers can be ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) molecules, or comprise both ribonucleotide residues and deoxyribonucleotide residues, and are generally generated from large combinatorial libraries (1014-1015) of nucleic acids. This may be done by any method known in the art, such as by a process of in vitro selection or by SELEX (Systematic Evolution of Ligands by Exponential Enrichment) that targets a specific protein or molecular target. This is an iterative process consisting of essentially 1) an immunoprecipitation to partition away library molecules which bind a target and 2) amplification steps to regenerate the library. The cycle is typically repeated multiple times (typically 5-15) before functional molecules are identified. Aptamers are generated through a process that relies on binding. Aptamers are thus nucleic acids (oligonucleotides) that bind a specific protein or molecular target, typically with nanomolar or subnanomolar affinity. Generally, aptamers discriminate against molecules closely related to the target molecule.
To date, aptamers have been selected to bind hundreds of different targets ranging from small molecules to peptides to proteins (5-7). The approach has also been used to target whole cells and has even identified aptamers that can discriminate between different cell types without prior knowledge of specific ligands (8-10). Aptamers typically bind their targets with affinities in the nanomolar to picomolar range and can have specificities on par with the best monoclonal antibodies (11). One aptamer, Macugen®, which binds the vascular endothelial growth factor (VEGF), has been approved for the treatment of macular degeneration, and a number of other aptamers are in the pipeline or in various stages of development (1, 12).
As nucleic acids, aptamers possess some limitations that in recent years the field has strived to overcome. Most notably two major challenges faced by the field are 1) the in vivo stability of nucleic acids and 2) the lack of chemical diversity of nucleic acids.
The present invention combines advances in both these areas and provides a method that allows generation of highly stabilized, backbone modified RNA molecules that display enhanced chemical functionality.

Chemically modified RNA aptamers and uses thereof