| 序号 | 专利名 | 申请号 | 申请日 | 公开（公告）号 | 公开（公告）日 | 发明人 |
|---|---|---|---|---|---|---|
| 61 | Continuous racemization of benzylic alcohols, ethers, and esters by solid acid catalyst | US342460 | 1994-11-21 | US5476964A | 1995-12-19 | David W. House |
| Benzyl alcohols having a chiral center at the benzylic carbon can be conveniently racemized by treatment with solid acids which are strongly acidic cation exchange materials. Racemization may be effected generally in the range from 20.degree.-150.degree. C. in aqueous or partly aqueous systems in combination with a water-miscible organic solvent to improve solubility of the alcohol. Similar racemizations may be effected for benzyl ethers and esters. This process is valuable for recycling of unwanted enantiomers obtained in the resolution of racemic mixtures. | ||||||
| 62 | Optical resolution method | US974826 | 1992-11-16 | US5395962A | 1995-03-07 | Masatoshi Kawashima |
| The present invention provides three optical resolution methods. The first aspect comprises the steps of adding an optically active bifunctional resolving reagent to a bifunctional compound to form a liquid material, precipitating crystals therefrom, and treating the crystals and the liquid material separately with an acidic material, a basic material, or a basic material and an acidic material, to obtain a pair of enantiomers of an optically active bifunctional compound. The second aspect comprises an optical resolution method by which one necessary enantiomer of a pair of enantiomers in an optically active bifunctional compound is exclusively obtained. The third aspect comprises a method for racemizing one unnecessary enantiomer of a pair of enantiomers in an optically active bifunctional compound which is formed by the optical resolution method of the present invention. | ||||||
| 63 | Racemization process for an optically active carboxylic acid or ester thereof | US825150 | 1992-01-24 | US5221765A | 1993-06-22 | Deepak R. Patil; Azfar A. Choudhury; Abbas Kadkhodayan |
| A method for racemizing an optically active carboxylic acid, or ester thereof, of the formula: ##STR1## where R.sub.1 is hydrogen or C.sub.1 to C.sub.6 linear or branched alkyl; R.sub.2, R.sub.3 and R.sub.4 are different and are hydrogen or C.sub.1 to C.sub.6 linear or branched alkyl, C.sub.1 to C.sub.6 linear or branched haloalkyl, aralkyl, cycloalkyl, alkyl substituted cycloalkyl, C.sub.6 to C.sub.10 aryl, C.sub.1 to C.sub.6 linear or branched alkoxy, C.sub.6 to C.sub.10 aryloxy, C.sub.1 to C.sub.6 alkylthio, C.sub.2 to C.sub.8 cycloalkylthio, C.sub.6 to C.sub.10 arylthio, C.sub.6 to C.sub.10 arylcarbonyl, C.sub.4 to C.sub.8 cycloalkenyl, trifluoromethyl, halo, C.sub.4 to C.sub.5 heteroaryl, C.sub.10 to C.sub.14 aryl, or biphenyl unsubstituted or substituted with methyl or halo, comprising heating said optically active carboxylic acid or ester thereof in the presence of water at a temperature of from about 75.degree. C. to about 200.degree. C. in the presence of a catalytically effective amount of an aliphatic, aromatic or mixed aliphatic and aromatic tertiary amine for a time sufficient to racemize said carboxylic acid or ester thereof. | ||||||
| 64 | Novel racemization process | US789843 | 1977-04-22 | US4151195A | 1979-04-24 | Julien Warnant; Jacques Prost-Marechal; Philippe Cosquer |
| A process for the preparation of an ester of chiral (A) acid with a racemic (R,S) .alpha.-cyano-3-phenoxybenzyl alcohol (B) by reacting an ester of chiral (A) acid with .alpha.-cyano-3-phenoxybenzyl alcohol of the formula ##STR1## in its optically active (R) form or (S) form or a mixture of esters of said (R) alcohol and (S) alcohol in non-equimolecular proportions with a base selected from the group consisting of ammonia, primary, secondary and tertiary amines, quaternary ammonium compounds, liquid amines of high molecular weight and a catalytic amount of a strong base in at least one solvent for the starting esters and in which the ester of racemic alcohol is soluble and recovering from the resulting solution the ester of chiral (A) acid with racemic (R,S) alcohol. | ||||||
| 65 | Process of racemizing an optically active phenyl glycine amide with or without a substituted phenyl group | US748398 | 1976-12-08 | US4094904A | 1978-06-13 | Wilhelmus H. J. Boesten |
| The invention is directed to a process for the racemization of optically active phenyl glycine amide with or without a substituted phenyl group by heating the opticaly active phenyl glycine amide in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.BACKGROUND OF THE INVENTIONThe resolution of a mixture of D- and L-phenyl glycine amide by means of an optically active acid is described in my co-pending U.S. patent applications Ser. No. 623,928, filed Oct. 20, 1975, and now U.S. Pat. No. 4,036,852 and Ser. No. 733,851, filed Oct. 19, 1976. An improved process for the resolution of a mixture of D- and L-phenyl glycine amide by means of an optically active acid is described in my co-pending U.S. patent application Ser. No. 748,399 filed concurrently herewith. The entire specification and claims of each of these three patent applications is incorporated by reference in the present specification.The invention relates to a process of racemizing an optically active phenyl glycine amide with or without a substituted phenyl group. The phenyl group may be substituted by a substituent such as a hydroxy, halogen, nitro, or amino group. These substituted optically active phenyl glycine amides can be prepared from the corresponding amino acid by esterification followed by aminolysis of the ester with ammonia as described in the Journal of the American Chemical Soc. vol. 71 (1949) page 78, 79.If desired, the racemized amide can be hydrolyzed to yield the corresponding amino acid again. Phenyl glycine amide can be hydrolyzed in a simple manner to form phenyl glycine, for example, by treatment with sulfuric acid, as described in the Journal of the Chemical Society, pages 393-397 (1966).In the preparation of an optically active phenyl glycine amide from a mixture of D- and L-phenyl glycine amide, both antipodes of the racemate are produced. If unequal amounts of the antipodes are desired, the undesired antipode can be racemized and the resulting racemate subjected to further resolution. As used in the present specification, "a mixture of L- and D-phenyl glycine amide" means either a racemate of phenyl glycine amide, or mixtures of the racemate with either L-phenyl glycine amide or D-phenyl glycine amide.The optically active phenyl glycines which can be easily obtained from the resolved optically active phenyl glycine amides are valuable compounds. For example, D-phenyl glycine is employed as a starting material for the preparation of .alpha.-amino benzyl penicillin. L-phenyl glycine provides a starting material for the sweetening agent L-asparagin-L-phenyl glycine alkyl ester.SUMMARY OF THE INVENTIONAccording to the invention, a process has been discovered comprising racemizing an optically active phenyl glycine amide, the phenyl group of which may be substituted, in an accelerated manner. It has been found that the racemization of a optically active phenyl glycine amide can be desirably conducted by heating the optically active phenyl glycine amide to be racemized in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4. As used in the present application, it is to be understood that "an optically active phenyl glycine amide" includes both unsubstituted optically active phenyl glycine amide and optically active phenyl glycine amide in which the phenyl group is substituted with, for example, a hydroxy, halogen, nitro or amino group.It is therefore an object of the present invention to racemize an optically active phenyl glycine amide in an accelerated manner.Surprising, it has been found that the object of the present invention can be realized by racemizing an optically active phenyl glycine amide in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.DETAILED DESCRIPTION OF THE INVENTIONThe invention is directed to a process of racemizing an optically active phenyl glycine amide, the phenyl group of which may be substituted, in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.Suitable acids are, for example, formic acid and acetic acid. In addition, use may be made of optically active acids e.g. optically active pyrrolidone-5-carboxylic acid and optically active N-acetyl phenyl glycine. These optically active acids are also suitable for the optical resolution of mixtures of D- and L-phenyl glycine amide, as described in my co-pending applications incorporated herein by reference.In the process of the present invention, preferably a quantity of acid is used which is equivalent to the quantity of phenyl glycine amide. An amount less than an equivalent amount, e.g. half the equivalent amount, of acid can also be used, but in that case undesirable side reactions may occur. A quantity of acid which is in excess of the equivalent of the phenyl glycine amide present may also be used, although there is no particular advantage in using excess acid.The racemizing process of the present invention is preferably effected at a temperature between about 35.degree. and about 150.degree. C. It is preferred to effect the racemizing process of the present invention at a temperature between about 50.degree. and about 100.degree. C.The ketone used in the racemizing process of the present invention may be selected from the group consisting of acetone, methyl ethyl ketone, pentanone, cyclohexanone, and mixtures thereof. It is believed that other ketones will also be operative in the process of the present invention.The amount of ketone used in the process of the present invention may be varied within wide limits. It has been found that a small quantity of ketone, for example 0.1 mole of ketone per mole of phenyl glycine amide is effective in the process of the present invention. Of course, larger amounts of ketone may also be used. If the amount of ketone used is sufficiently large, the ketone can also serve as a solvent for the racemizing mixture. However, it is also contemplated in the process of the present invention that other solvents may be used. For example, water, an alcohol, benzene, toluene, chloroform, and ethyl acetate may also be used as solvents.The process of the present invention will be further illustrated by the following examples, which are intended to be illustrative only and are meant to include all techniques equivalent thereto.EXAMPLESEXAMPLE IIn a flask equipped with a stirrer and a reflux cooler a solution of 1.5 g (0.01 gmole) L-phenyl glycine amide and 0.6 ml (0.01 gmole) acetic acid in 20 ml water and 80 ml acetone is boiled for 24 hours (58.degree. C), with stirring and reflux.After cooling to 20.degree. C, the rotation of this solution is determined. It is[.alpha.].sub.D.sup. 20 = 0.3.degree.The rotation of the original solution is:[.alpha.].sub.D.sup. 20 = 5.1.degree..Comparison of these rotation values shows (50 - 50 .times. 0,3/5,1) .times. 2 = 94% of the L-phenyl glycine amide to have been racemized.EXAMPLE IIIn a flask equipped with a stirrer and a reflux cooler a solution of 1.5 g (0.01 gmole) L-phenyl glycine amide, 0.4 ml (0.011 gmole) formic acid in 50 ml methyl ethyl ketone and 10 ml water is boiled with reflux for 20 hours (80.degree. C).After cooling to 20.degree. C, the rotation of this solution is[.alpha.].sub.D.sup. 20 = +0.9.degree..the rotation of the original solution is[.alpha.].sub.D.sup. 20 = +7.7.degree..comparison of the rotation values shows 88% of the L-phenyl glycine amide to have been racemized.EXAMPLE IIIIn a flask equipped with a stirrer and a reflux cooler 1.5 g (0.01 gmole) L-phenyl glycine amide and 0.6 ml (0.01 gmole) acetic acid in a mixture of 50 ml methanol and 0.45 ml (0.005 gmole) methyl ethyl ketone is boiled with reflux for 6 hours at 60.degree. C.After cooling to 20.degree. C the rotation of the resulting solution is measured. It is[.alpha.].sub.D.sup. 20 = 5.05.degree.the rotation of the original solution is[.alpha.].sub.D.sup. 20 = 8.90.degree.comparison of the rotation values shows 44% of the L-phenyl glycine amide to have been racemized.EXAMPLE FOR COMPARISONExample III is repeated, this time without addition of methyl ethyl ketone.After 6 hours' boiling, the rotation of the solution is[.alpha.].sub.D.sup. 20 = 8.40.degree..comparison of the rotation values shows only 6% of the L-phenyl glycine amide to have been racemized.EXAMPLE IVIn a flask equipped with a stirrer and a reflux cooler 4.5 g L-phenyl glycine amide and 3.9 g D-2-pyrrolidone-5-carboxylic acid in 200 ml methanol and 10 ml acetone is heated at boiling temperature for 25 hours whilst being stirred.After cooling to 20.degree. C, 3 ml concentrated hydrochloric acid (35%-wt.) is added. Next, the reaction mixture is concentrated in vacuo (12 mm Hg) at 30.degree. C to a volume of 40 ml. The DL-phenyl glycine amide.HCl formed in this way is recovered on a filter and washed on this filter with 5 ml[.alpha.].sub.D.sup. 20 = +0.4.degree. (c = 0.8; water)In Beilstein 14, III, p. 1189. the specific rotation of L-phenyl glycine amide. HC1 is given as[.alpha.].sub.D.sup. 20 = +100.8.degree. (c = 0.8; water).Comparison of the rotation values shows 99,5% of the L-phenylglycine amide to have been racemized.Thus it is apparent that there has been provided in accordance with the invention, a process for the racemization of optically active phenyl glycine amide that fully satisfies the objects, aims, and advantages set forth above. While the invention has been described in conjunction with specific embodiments thereof, it is apparent that many alternatives, modifications, and variations will be evident to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the following claims. methanol. After drying, the resulting salt weighs 4.4 g. The specific rotation of this salt is | ||||||
| 66 | Resolution of racemic reticuline and racemization of its enantiomers | US38418573 | 1973-07-31 | US3894027A | 1975-07-08 | SOHAR PAUL; SCHOENEWALDT ERWIN F |
| Racemic reticuline is resolved by forming a crystalline diastereomeric acid salt with a mandelic acid enantiomer. The reticuline enantiomers are racemized by treatment with a reduced noble metal or noble metal oxide catalyst. (-)-Reticuline is a valuable intermediate useful in the synthesis of thebaine, and (+)-reticuline is useful as a precursor of pallidine, sinoacutine, coreximine, and the berberine alkaloids.
|
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| 67 | Preparation of pantolactone | US15737551 | 2016-06-17 | US10150746B2 | 2018-12-11 | Klaus Fischer; Benjamin Nehls; Jürgen Deschler; Walter Dobler; Arnulf Lauterbach; Sabine Schlautmann |
| The present invention relates to a novel process for the preparation of pantolactone by reaction of hydroxypivalaldehyde cyanohydrin in a phase separation process. | ||||||
| 68 | Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals | US15073324 | 2016-03-17 | US10130635B2 | 2018-11-20 | Jayaraman V. Raman; Swaroop K. Vakkalanka |
| The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. | ||||||
| 69 | METHOD FOR PREPARING RACEMIC OR OPTICALLY ACTIVED D- OR L-A-GLYCEROPHOSPHORYLCHOLINE SOLIDS | US15907352 | 2018-02-28 | US20180273555A1 | 2018-09-27 | Soon Ook HWANG; Dae Myoung YUN; Chang-min KIM |
| Racemic or optically active D- or L-α-glycerophosphoryl choline solids are prepared from liquid type racemic or optically active D- or L-α-glycerophosphoryl choline using an organic solvent. The solids are produced at a high yield more easily through phase transformation than an existing method using a difference in solubility in a solvent. | ||||||
| 70 | METHOD FOR THE PRODUCTION OF PRAZIQUANTEL | US15528282 | 2015-11-17 | US20180155339A1 | 2018-06-07 | Andreas WAECHTLER; Hadia SALEH-KASSIM; Christian JASPER; Joern KOLB; David MAILLARD |
| The present invention relates to a method for the racemization of enantiomerically pure or enantiomerically enriched Praziquantel under basic conditions and a method for the production of (R)-Praziquantel in enantiopure or enantiomerically enriched form, which comprises the racemization method. | ||||||
| 71 | PREPARATION OF PANTOLACTONE | US15737551 | 2016-06-17 | US20180111911A1 | 2018-04-26 | Klaus FISCHER; Benjamin NEHLS; Jürgen DESCHLER; walter DOBLER; Arnulf LAUTERBACH; Sabine SCHLAUTMANN |
| The present invention relates to a novel process for the preparation of pantolactone by reaction of hydroxypivalaldehyde cyanohydrin in a phase separation process. | ||||||
| 72 | PROCESS FOR PREPARATION OF OPTICALLY PURE AND OPTIONALLY SUBSTITUTED 2-(1-HYDROXY-ALKYL)-CHROMEN-4-ONE DERIVATIVES AND THEIR USE IN PREPARING PHARMACEUTICALS | US15073324 | 2016-03-17 | US20180098994A9 | 2018-04-12 | Jayaraman VENKAT RAMAN; Swaroop K. VAKKALANKA |
| The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals. | ||||||
| 73 | METHOD FOR PREPARING RACEMIC OR OPTICALLY ACTIVE D- OR L-A-GLYCEROPHOSPHORYL CHOLINE SOLIDS | US15468136 | 2017-03-24 | US20170190724A1 | 2017-07-06 | Soon Ook HWANG; Dae Myoung YUN; Chang-min KIM |
| The present invention is characterized in that racemic or optically active D- or L-α-glycerophosphoryl choline solids are prepared from liquid type racemic or optically active D- or L-α-glycerophosphoryl choline using an organic solvent. The present invention can produce solids at a high yield more easily through phase transformation rather than a method using a difference in solubility in a solvent, which is an existing method. | ||||||
| 74 | METHOD FOR PRODUCING RACEMATE OF COMPOUND | US14439597 | 2013-10-28 | US20150266805A1 | 2015-09-24 | Tomoaki Takahashi; Taro Hirose |
| A method for producing a racemate of a compound represented by Formula (1), including bringing a transition metal catalyst into contact with an optically active form of the compound represented by Formula (1): [in Formula (1), a ring X1 represents an aromatic ring; R1 represents a C1-6 alkyl group, a C3-8 cycloalkyl group, or a C1-6 halo-alkyl group; R2 is a group different from R1 and represents a C1-6 alkyl group, a C3-8 cycloalkyl group, or a C1-6 halo-alkyl group, or R2 and the ring X1 are bonded to each other to form a ring; a hydrogen atom(s) of the ring X1 is optionally replaced with a C1-6 alkyl group, a C1-6 halo-alkyl group, a cyano group, a nitro group, a C1-6 alkoxy group, or a halogen atom; and * represents an asymmetric carbon atom]. | ||||||
| 75 | Method for the production of a mixture of lactide derivatives | US13060553 | 2009-08-28 | US08957229B2 | 2015-02-17 | Rainer Hagen; Adam B. Verweij; Udo Muhlbauer; Joachim Schulze; Wolfgang Tietz; Klaus-Dieter Göhler |
| A mixture of cyclic diesters derived from lactic acid and in cases a mixture of a racemate of dilactide may be produced in several different processes. In some instances, the process can thereby start from the corresponding alpha-hydroxycarboxylic acids, the corresponding cyclic diesters or oligomers of the corresponding alpha-hydroxycarboxylic acids. | ||||||
| 76 | Method for obtaining optically pure amino acids | US13258948 | 2010-03-19 | US08865933B2 | 2014-10-21 | Kwan-Mook Kim; Hojun Kim |
| This invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. This method significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a enantioselective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids. | ||||||
| 77 | Method for producing cis-3-substituted-3-azabicyclo[3.2.1]octan-8-ol derivative | US12674326 | 2008-08-27 | US08461340B2 | 2013-06-11 | Hiroshi Hakuta; Tsutomu Imagawa; Hirohito Oooka; Shinya Fukuhara |
| There are provided, according to the present invention, a method for producing a cis-3-substituted-3-azabicyclo[3.2.1]octan-8-ol derivative, the method characterized in that a trans-3-substituted-3-azabicyclo[3.2.1]octan-8-ol derivative or a mixture of the trans- and cis-3-substituted-3-azabicyclo[3.2.1]octan-8-ol derivatives is isomerized in the presence of an aluminum compound represented by a formula Al(OR1)3 (wherein R1 represents a hydrocarbon group in which a carbon atom having an oxygen atom bonded thereto is a secondary carbon atom). In the process, a ketone compound may be further added, in addition to the aluminum compound. | ||||||
| 78 | Process for producing α-substituted ester | US13127955 | 2009-10-22 | US08278476B2 | 2012-10-02 | Akihiro Ishii; Manabu Yasumoto |
| There is provided a process for producing an α-substituted ester by reaction of a fluorosulfuric acid ester of α-hydroxyester with a Grignard reagent in the presence of a zinc catalyst. It is newly found that the reaction for production of α-substituted esters, in which the raw reaction substrate is limited to expensive trifluoromethanesulfonic acid esters, can proceed favorably with the use of fluorosulfuric acid esters suitable for mass-production uses. By the use of the fluorosulfuric acid ester high in optical purity, it is possible to obtain the α-substituted ester with high optical purity upon inversion of the asymmetric carbon configuration. The process of the present invention can solve all of the prior art problems and can be applied for industrial uses. | ||||||
| 79 | Method for the production of optically active alpha alkyl carbonyl compounds | US12679125 | 2008-09-18 | US08212065B2 | 2012-07-03 | Bernhard Breit; Christopher Studte |
| A method for the production of optically active α-alkylcarbonyl compounds with retention of the stereo information of the starting compound. The starting compound used here is a carbonyl compound which has, in the α-position, a leaving group which is substituted by an alkyl group with inversion of the configuration. The substitution of the leaving group is effected with the use of an alkylmagnesium Grignard and a zinc (II) salt or a zinc organyl. The method permits the production of optically active α-alkylcarbonyl compounds at very mild temperatures (for example 0° C.) with the use of starting compounds which are easy to prepare and economical and nontoxic catalysts, it also being possible to achieve a very high yield. | ||||||
| 80 | METHOD FOR PRODUCING OPTICALLY ACTIVE DIAMINE DERIVATIVE | US13231081 | 2011-09-13 | US20120035369A1 | 2012-02-09 | Koutarou Kawanami |
| The problem to be solved is to provide an important intermediate for production of an FXa inhibitor. The solution thereto is a method for industrially producing a compound (1) or a compound (4), comprising: [Step 1]: adding a quaternary ammonium salt and a metal azide salt to water to prepare an aqueous solution of an azidification reagent complex comprising quaternary ammonium salt-metal azide salt, and subsequently dehydrating the aqueous solution using an aromatic hydrocarbon solvent to form a mixed solution of the azidification reagent complex comprising quaternary ammonium salt-metal azide salt and the aromatic hydrocarbon solvent with a water content of 0.2% or less; and [Step 2]: adding, to the mixed solution prepared in [Step 1], a compound (2) wherein L represents a leaving group. | ||||||
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