GB2328208A - Resolution of alpha-propionic acids - Google Patents
Resolution of alpha-propionic acids Download PDFInfo
- Publication number
- GB2328208A GB2328208A GB9817577A GB9817577A GB2328208A GB 2328208 A GB2328208 A GB 2328208A GB 9817577 A GB9817577 A GB 9817577A GB 9817577 A GB9817577 A GB 9817577A GB 2328208 A GB2328208 A GB 2328208A
- Authority
- GB
- United Kingdom
- Prior art keywords
- ammonium salt
- isomers
- chiral agent
- amount
- chiral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method of resolving d- and I-isomers of an alpha-arylpropionic acid, wherein the isomers are enantiomers. The method involves forming an ammonium salt of the a-arylpropionic acid, then dissolving in a solvent the ammonium salt, and a chiral agent capable of reacting with the ammonium salt of at least one of the isomers. The reaction product of the chiral agent and the ammonium salt of the one of the isomers can subsequently be purified, then separated into the chiral agent and the isomer.
Description
RESOLUTION OF a-ARYLPROPIONIC ACIDS
This invention relates to the resolution of a-arylpropionic acids.
a-arylpropionic acids are well known as non-steroidal antiinflammatory (NSAI) agents, and include compounds such as naproxen, ibuprofen and ketoprofen. These compounds are chiral, and the routes used to synthesise them result in the formation of a mixture containing d- and l-enantiomers. However, the active compound usually comprises only one of the enantiomers of the racemic mixture.
Naproxen is 26-methoxy-2-naphthyl) propionic acid. When naproxen is synthesised, it is formed as a mixture of d-naproxen and l-naproxen, which will be indicated as dl-naproxen throughout this specification. However, It is the dnaproxen that is pharmaceutically active. As a result, there has been a great deal of interest in finding methods of resolving dl-naproxen, so that the d-naproxen can be separated from the l-naproxen.
South African patent no. 700809 describes a number of resolving agents for the resolution of naproxen. Most of these resolving agents are expensive and/or ecologically unfriendly.
GB-A-2025968 describes the use of an organic base, such as triethylamine, and inorganic bases, such as sodium/potassium hydroxide, for preparing salts with dl-naproxen. The salts are then resolved using N-methyl-Dglucamine or similar resolving agents.
US-A-5235100 also describes the use of an organic base, such as triethylamine, to form a salt, which is then resolved using (-)-a-phenylethylamine without using a solvent.
EP-A-0298395 describes the formation of a monoethylamine salt of dl-naproxen. Resolution is carried out by forming a supersaturated solution of this salt of dl-naproxen in a solvent such as aqueous acetone, then seeding the solution with one of the enantiomers of naproxen.
Indian patent no. 163,260 describes the resolution of the potassium salt of dl-naproxen using (-)-a-phenylethylamine in water.
We have now found another way of resolving optically active acids, particularly a-arylpropionic acids such as dl-naproxen, which involves forming an ammonium salt of the d- and I-isomers of the acid, then reacting the ammonium salt with a chiral agent in a solvent. The invention is based upon the discovery that the ammonium salt of the acid can react with the chiral agent to produce diastereomers having significantly different solubilities in the solvent. This makes it possible to separate the d- and I-isomers much more easily than has been possible in the prior art.
According to the present invention there is provided a method of resolving d- and I-isomers of an a-arylpropionic acid, wherein said isomers are enantiomers, comprising forming an ammonium salt of the d- and I-isomers of the a-arylpropionic acid, and dissolving the ammonium salt and a chiral agent in a solvent, the chiral agent being capable of reacting with the ammonium salt of at least one of the d- and Isomers.
The chiral agent is preferably an organic nitrogenous material, and is more preferably an amine. It is desirable that the chiral agent is a chiral base, or a hydrochloride of a chiral base. The chiral agent is preferably a phenylalkylamine or a hydrochloride of a phenylalkylamine. The alkyl group preferably contains two or three carbon atoms, such as a-phenylpropylamine and a-phenylethylamine Most preferably the alkyl group contains two carbon atoms.
The most preferred chiral agent is either (-)-a-phenylethylamine or (-)a-phenylethylamine hydrochloride for resolution of d-a-arylpropionic acids such as d-Naproxen, and (+)-a-phenylethylamine or (+)-a-phenylethylamine hydrochloride for resolution of R(-)a-arylpropionic acids such as R(-) Naproxen.
It is possible for the phenyl group to contain an alkyl group substituent, particularly a methyl substituent; an example of such a chiral agent is a-(4methylphenyl)ethylamine. In addition, or instead, the phenylalkylamine may contain two phenyl groups; an example of such a chiral agent is 1-phenyl-2-(4methylphenyl )ethylamine.
There are a wide variety of solvents that may be used. The solvent should be capable of dissolving the ammonium salt of the d- and Isomers. We prefer to use water as the solvent, but other possibilities include an aqueous alcohol, like methanol, isopropanol and butanol, or chloroform.
It is preferred that the ammonium salt is formed by reacting the aarylpropionic acid with aqueous ammonia, with ammonia gas, or with ammonia dissolved in an aqueous alcohol. The step of forming the ammonium salt of the aarylpropionic acid results in the formation of the ammonium salt of each of the dand Isomers.
In one conventional process for manufacturing dl-naproxen, the corresponding a-arylproprionitrile is hydrolysed to form crude dl-naproxen which is then purified by conversion to its ammonium salt. It is a feature of the invention to use the ammonium salt formed from the hydrolysed a-arylproprionitrile for the resolution.
The ammonium salt and said chiral agent are preferably dissolved in the solvent at a temperature in the range 80"C to 95"C. The ammonium salt can be dissolved in the solvent before, after, or at the same time as, the chiral agent is dissolved in the solvent.
It has been found that the relative amount of the chiral agent and the a-arylpropionic acid is important. It is preferred that the amount of the chiral agent, in mole equivalent, comprises 45% to 60% of the amount of the ammonium salt. It is particularly preferred that the amount of the chiral agent, in mole equivalent, comprises about 50% of the amount of the ammonium salt.
In an embodiment of the invention it is possible to dissolve an amount of said a-arylpropionic acid in said solvent with said ammonium salt and said chiral agent. In this embodiment, the amount of the a-arylpropionic acid, in mole equivalent, is preferably about equal to the amount of said ammonium salt. The amount of the chiral base, in mole equivalent, preferably comprises 45% to 60%, more preferably about 50%, of the combined amount of the a-arylpropionic acid and the ammonium salt.
It will be clear from the foregoing that the chiral agent should be a material that is capable of reacting with the ammonium salt of at least the d- or 1isomer of the a-arylpropionic acid. In the preferred embodiment, the ammonium salt of both the d- and I-isomers will form reaction products with the chiral agent; in this embodiment, the reaction products will be diastereomers having different solubilities in the solvent, and will therefore be separable by a physical separation process, such as precipitation, followed by filtration. In another embodiment, only the ammonium salt of the d-isomer will form a reaction product with the chiral agent; in this embodiment the reaction product will be separable from the ammonium salt of
I-isomer by a physical separation process, such as precipitation followed by filtration. In a still further embodiment, only the ammonium salt of the isomer will form a reaction product with the chiral agent; in this embodiment the reaction product will be separable from the ammonium salt of d-isomer by a physical separation process, such as precipitation followed by filtration.
Thus, after the chiral agent and the ammonium salt have been added to the solvent, it will be usual to separate the reaction product of the ammonium salt of one of the d- and I-isomers either from the reaction product of the ammonium salt of the other of the d- and Isomers, or from the ammonium salt of the other of the d- and Isomers. This separation is preferably carried out by precipitation, followed by filtration.
The residue of the filtration may be purified by crystallisation, preferably by crystallisation from an aqueous organic solvent, such as an aqueous alcohol; aqueous methanol is particularly suitable as a solvent. The purified residue can be treated in order to convert the reaction product of the ammonium salt of the d- or I-isomer into a mixture of the d- or I-isomer and the chiral agent.
In one embodiment, the treatment involves the addition of an alkali, such as an alkali metal hydroxide, especially sodium hydroxide. The chiral agent may be separated from the alkaline solution by liquid-liquid extraction using a solvent such as toluene; several stages of liquid-liquid extraction may be used. The remaining alkaline solution may be acidified, for example with hydrochloric acid, to yield the d- or I-isomer in a substantially pure form. It is possible that the d- or Iisomer thus formed does not have the required degree of purity, i.e., there may be an undesirably large amount of the other isomer. In this case, it is possible to repeat the process, in order to further purify the d- or I-isomer.
In another embodiment, the treatment involves the addition of an acid, such as hydrochloric acid. In this embodiment, the addition of the acid results in the formation of the d- or I-isomer of the a-arylpropionic acid and the hydrochloride of the chiral agent.
The filtrate will contain either the reaction product of the ammonium salt of the other of the d- and I-isomer, or the ammonium salt of the other of the dand I-isomer, which can be racemised directly. The reaction product may be treated with an acid or alkali, as described above, which will cause the precipitation of the other of the d- or Isomers. The precipitated d- or I-isomer may be racemised by the addition of an alkali, such as an alkali metal hydroxide, especially potassium hydroxide. This step is desirably carried out during the hydrolysis of aarylproprionitrile to dl-naproxen: the other of the d- and I-isomers can be added to the a-arylproprionitrile, and potassium hydroxide can be added, for example, to hydrolyse the a-arylproprionitrile and to racemise the other of the d- and Isomers.
The chiral agent recovered from the process may be purified, then recycled to the start of the process.
The most preferred embodiment of the present invention involves the following steps:
(1) formation of the ammonium salt of dl-a-arylpropionic acid;
(2) formation of the (-)-a-phenylethylamine salt of d-a
arylpropionic acid and of I-a-arylpropionic acid;
(3) purification of the (-)-a-phenylethylamine salt of d-a
arylpropionic acid;
(4) breaking the (-)-a-phenylethylamine salt of d-a-arylpropionic
acid into d-a-arylpropionic acid and (-)-a-phenylethylamine;
(5) separating the d-a-arylpropionic acid from the (-)- - phenylethylamine;
(6) breaking the (-)-a-phenylethylamine salt of l-a-arylpropionic acid into I-a-arylpropionic acid and (-)-a-phenylethylamine; (7) racemisation of the l < -arylpropionic acid to dl-a-arylpropionic
acid.
The invention can be used with a wide variety of a-arylpropionic acids, including naproxen, ibuprofen, ketoprofen, flurbiprofen and 2-(4-methylphenyl) propionic acid. The a-aryl propionic acids have the following general structure:
where Ar represents a group containing at least one phenyl or naphthyl group. The structure of specific acids which can be resolved in accordance with the present invention are as follows:
dl-Naproxen RS-buprofen
St+)Naproxen S(+) buprofen
S(+)iKetoprofen S(+)Flurbiprofen
S-2-(4-Methylphenyl)propionic acid
The method according to the invention has a number of advantages over the prior art. Previous attempts to resolve, for example, dl-naproxen have required several purification steps in order to carry out the resolution effectively.
With the present invention it is possible to obtain d-naproxen of good purity with only a single purification step.
Furthermore, with the present invention it is necessary to use only 0.5 molar equivalent of the chiral agent, and the solvent for the chiral agent and the dlnaproxen may be water.
Moreover, the ammonium salt required for the process of the present invention can be prepared in the course of the conventional manufacturing process for dl-naproxen. This has the effect that fewer process steps are required to obtain the d-naproxen.
The following examples illustrate the invention.
Example 1
The following method was used to resolve dl-naproxen into dnaproxen:
(A) 350 g (1.5217 moles) dl-naproxen was converted into its
ammonium salt by treating it with aqueous ammonia
solution/ammonia gas. The resulting ammonium salt was then
suspended in 4-8 volumes water. To the suspension, 350 g dl
naproxen was added. The slurry was heated to 80-85"C under
a nitrogen blanket.
(B) To the slurry produced in step (A), 184 g (1.5206 moles) (-)-a
phenylethylamine ("PEA") was added, over a period of 30-120
minutes at a temperature of 80-95 C. The reaction mixture was
held at 80-95"C for 1-3 hours, then filtered to obtain 340-360
g of a crude d-naproxen PEA salt (melting range 160-170"C, aD > +300 CH3CN-HOAc) having an optical purity above 70%.
(C) The crude salt from step (B) was then crystallised from 4
volumes of aqueous methanol to yield 250-270 g pure d
naproxen PEA salt (melting range 170-175"C, ao+37o CH3CN-HOAc) having an optical purity above 95%.
(D) The pure d-naproxen PEA salt from step (C) was then reacted
with dilute aqueous hydrochloric acid. PEA remained in the
aqueous solution as hydrochloride. 165-175 g of d-naproxen
was precipitated having a melting point of 156-158"C and a0 CHCI32+63.5 CHCl3.
(E) The aqueous filtrate and washings from step (B) were cooled
to 0-10"C to isolate a mixture of ammonium salt of dl
naproxen, and l-naproxen PEA salt. This salt mixture was then
treated with dilute hydrochloric acid, whereupon naproxen
enriched in I-isomer precipitated out and PEA remained in
aqueous solution as hydrochloride.
(F) The precipitated l-naproxen from step (E) was racemised with
potassium hydroxide to obtain 500-520 g of dl-naproxen.
(G) The dl-naproxen obtained from step (F! and the PEA
recovered from steps (D) and (E) were recycled to step (A),
along with fresh dl-naproxen.
Example 2
The following method was used to resolve dl-naproxen into dnaproxen:
(A) 700 g (3.04034 moles) dl-naproxen was converted into its
ammonium salt by treating it with aqueous ammonia
solution/ammonia gas. The resulting ammonium salt was then
suspended in 5-7 volumes water. The slurry was heated to 80 85"C under a nitrogen blanket.
(B) To the slurry produced in step (A), PEA hydrochloride
equivalent to 184 g (1.5206 moles) PEA was added over a
period of 30-120 minutes at a temperature of 80-95"C. The
reaction mixture was held at 85-95"C for 1-3 hours, then
filtered to obtain 340-360 g of a crude d-naproxen PEA salt
(melting range 160-170"C, aD > +30 CH3CN-HOAc) having an
optical purity above 70%.
(C) The crude salt from step (B) was then crystallised from 4
volumes of aqueous methanol to yield 250-270 g pure d
naproxen PEA salt (melting range 170-175"C, aD2+37 CH3CN-HOAc) having an optical purity above 95%.
(D) The pure d-naproxen PEA salt from step (C) was then reacted
with dilute aqueous hydrochloric acid. PEA remained in the
aqueous solution as hydrochloride. 165-175 g of d-naproxen
was precipitated having a melting point of 156-158"C and a, CHCI3 > +63.5 CHCI3.
(E) The aqueous filtrate and washings from step (B) were cooled
to 0-10"C to isolate a mixture of ammonium salt of dl
naproxen and l-naproxen PEA salt. This salt mixture was then
treated with dilute aqueous hydrochloric acid, whereupon
naproxen enriched in isomer precipitated out and PEA
remained in aqueous solution as hydrochloride.
(F) The precipitated l-naproxen from step (E) was racemised with
potassium hydroxide to obtain 500-520 g of dl-naproxen.
(G) The dl-naproxen obtained from step (F) and the PEA
recovered from steps (D) and (E) were recycled to step (A),
along with fresh dl-naproxen.
Example 3
The following method was used to resolve dl-naproxen into dnaproxen:
(A) Steps (A) and (B) of Example 1 were repeated to obtain 340
360 g of the crude d-naproxen PEA salt (alternatively steps (A)
and (B) of Example 2 could have been repeated instead).
(B) The crude d-naproxen PEA salt was crystallised from aqueous
methanol to obtain 250-270 g of pure d-naproxen PEA salt.
(C) The pure salt was then treated with a dilute aqueous solution of potassium hydroxide at 10-30"C. This resulted in the formation of PEA and an aqueous solution of potassium salt of
d-naproxen. The PEA was separated by extraction with
toluene. The potassium solution of d-naproxen was acidified,
filtered, then dried, yielding 150-170 g of d-naproxen having a melting point of 156-158"C and a, CHCI32.+63.5 CHCl3.
(D) The toluene solution containing the PEA was treated with aqueous hydrochloric acid to separate PEA hydrochloride,
which was recycled. The toluene was washed, then recycled.
(E) Steps (E), (F) and (G) of Example 1 (or, alternatively, Example 2), were repeated.
It will be appreciated that modifications are possible to the invention described above.
Claims (26)
1. A method of resolving d- and I-isomers of an a-arylpropionic acid, wherein said isomers are enantiomers, comprising forming an ammonium salt of the d- and
I-isomers of the a-arylpropionic acid, and dissolving the ammonium salt and a chiral agent in a solvent, the chirai agent being capable of reacting with the ammonium salt of at least one of the isomers.
2. A method according to claim 1 wherein the chirai agent is an organic nitrogenous material.
3. A method according to claim 2, wherein the chiral agent is an amine.
4. A method according to claim 1, 2 or 3, wherein the chiral agent is a chiral base, or a hydrochloride of a chiral base.
5. A method according to claim 1, 2 , 3 or 4, wherein the chiral agent is a phenylalkylamine.
6. A method according to any preceding claim, wherein the chiral agent is (-)-aphenylethylamine or (-)-a-phenylethylamine hydrochloride or (+)- - phenylethylamine or (+)-a-phenylethylamine hydrochloride.
7. A method according to any preceding claim, wherein the solvent is water, an aqueous alcohol or chloroform.
8. A method according to any preceding claim, wherein said ammonium salt is formed by reacting said a-arylpropionic acid with aqueous ammonia, ammonia gas, or ammonia dissolved in an aqueous alcohol.
9. A method according to any preceding claim, wherein said ammonium salt and said chiral agent are dissolved in the solvent at a temperature in the range 80"C to 95"C.
10. A method according to any preceding claim, wherein the amount of the chiral agent, in mole equivalent, comprises 45% to 60% of the amount of the ammonium salt.
11. A method according to claim 10, wherein the amount of the chiral agent, in mole equivalent, comprises about 50% of the amount of the ammonium salt.
12. A method according to any one of claims 1 to 9, further comprising dissolving an amount of said a-arylpropionic acid in said solvent with said ammonium salt and said chiral agent.
13. A method according to claim 12, wherein the amount of the a-arylpropionic acid, in mole equivalent, is about equal to the amount of said ammonium salt.
14. A method according to claim 13, wherein the amount of the chiral base, in mole equivalent, comprises 45% to 60% of the combined amount of the aarylpropionic acid and the ammonium salt.
15. A method according to claim 14, wherein the amount of the chiral base, in mole equivalent, comprises about 50% of the combined amount of the aarylpropionic acid and the ammonium salt.
16. A method according to any preceding claim, further comprising at least partially separating the reaction product of the chiral base and the ammonium salt of one of the d- and Isomers, from the other of the d- and I-isomers and/or from the reaction product of the chiral base and the ammonium salt of the other of the d- and Isomers.
17. A method according to claim 16, wherein said separation step comprises a physical separation process.
18. A method according to claim 16 or 17, wherein the reaction product of the chiral base and the ammonium salt of said one of the d- and I-isomers is separated by filtration.
19. A method according to claim 16,17 or 18, further comprising recovering said one of the d- and I- isomers from said reaction product.
20. A method according to claim 19, comprising treating said reaction product with an acid to produce said one of the d- and Isomers, and recovering said one of the d- and I-isomers in a substantially pure form.
21. A method according to claim 19, comprising treating said reaction product with an alkali metal hydroxide to produce an alkali metal salt of said one of the dand Isomers, recovering said alkali metal salt, acidifying the recovered alkali metal salt to produce said one of the d- and Isomers, and recovering said one of the dand I-isomers in a substantially pure form.
22. A method according to claim 19, 20 or 21, comprising recovering said chiral agent from the reaction product of the chiral agent and said one of the d- and Iisomers, then recycling said recovered chiral agent for dissolution in the solvent.
23. A method according to any one of claims 16 to 22, wherein said other of the d- and I-isomers is racemised to form at least part of the a-arylpropionic acid dissolved in the solvent.
24. A method according to any preceding claim, comprising forming said aarylpropionic acid by hydrolysing a corresponding a-arylproprionitrile, and then forming said ammonium salt directly from the a-arylpropionic acid formed from said hydrolysis.
25. A method according to claim 24, when dependent upon claim 23, wherein said other of the d- and I-isomers is racemised by adding it to the aarylproprionitrile, and hydrolysing the mixture with an alkali metal hydroxide.
26. A method substantially as herein described with reference to the examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN482BO1997 | 1997-08-12 | ||
| GBGB9720226.1A GB9720226D0 (en) | 1997-08-12 | 1997-09-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9817577D0 GB9817577D0 (en) | 1998-10-07 |
| GB2328208A true GB2328208A (en) | 1999-02-17 |
Family
ID=26312301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9817577A Withdrawn GB2328208A (en) | 1997-08-12 | 1998-08-12 | Resolution of alpha-propionic acids |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2328208A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006013581A2 (en) * | 2004-08-02 | 2006-02-09 | Matrix Laboratories Ltd | Resolution of racemic organic acids with (1s, 4s)-4[3,4-dichlorophenyl]-1,2,3,4- tetrahydro-n-methyl-1-naphthaloneamine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993015040A1 (en) * | 1992-01-24 | 1993-08-05 | Ethyl Corporation | Preparation of optically active aliphatic carboxylic acids |
-
1998
- 1998-08-12 GB GB9817577A patent/GB2328208A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993015040A1 (en) * | 1992-01-24 | 1993-08-05 | Ethyl Corporation | Preparation of optically active aliphatic carboxylic acids |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006013581A2 (en) * | 2004-08-02 | 2006-02-09 | Matrix Laboratories Ltd | Resolution of racemic organic acids with (1s, 4s)-4[3,4-dichlorophenyl]-1,2,3,4- tetrahydro-n-methyl-1-naphthaloneamine |
| WO2006013581A3 (en) * | 2004-08-02 | 2007-05-31 | Matrix Lab Ltd | Resolution of racemic organic acids with (1s, 4s)-4[3,4-dichlorophenyl]-1,2,3,4- tetrahydro-n-methyl-1-naphthaloneamine |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9817577D0 (en) | 1998-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2150355C (en) | Process of resolving phenylpropionic acids using alpha-methylbenzylamine | |
| EP0828702B1 (en) | Process for resolving chiral acids with 1-aminoindan-2-ols | |
| US4585595A (en) | Optically active derivatives of mercaptoisobutyric acid and methods of preparation thereof | |
| JPH01135747A (en) | Optical active salt, its production and production of optically active 3-chloro-2-hydroxypropyltrimethyl ammonium chloride | |
| CZ339998A3 (en) | Process for preparing enantiomer pure azetidine-2-carboxylic acid | |
| EP0590685B1 (en) | Process for optical resolution of (+)-cis-4-aminocyclopent-2-en-1-carboxylic acid derivative | |
| GB2328208A (en) | Resolution of alpha-propionic acids | |
| JP3484510B2 (en) | Method for producing optically active carboxylic acid | |
| JPH06184091A (en) | Process for preparation of optically active methioninamide | |
| EP0844230B1 (en) | Optical resolution method of (plus, minus)-3,4-dihydroxybutanoic acid | |
| US4183865A (en) | Process for the resolution of racemic α-aminonitriles | |
| US5578734A (en) | Method for the preparation of S-(+)-ethodolic acid and saline derivatives | |
| EP1029846A1 (en) | Resolution of alpha-arylpropionic acids | |
| US4045450A (en) | Optical resolution of DL-pantolactone | |
| US4985575A (en) | Process for preparing optically active tetrahydro-2-furoic acid | |
| WO1989005787A2 (en) | Processes and compounds useful for resolving 1-methyl-3-phenylpropylamine | |
| JP2001514901A (en) | Biochemical racemic resolution of cis- and trans-pyrrolopiperidine | |
| JPH026348B2 (en) | ||
| JP3888402B2 (en) | Process for producing optically active N-carbobenzoxy-tert-leucine | |
| US4187244A (en) | Process for the resolution of racemic alpha-aminonitriles | |
| JP2840956B2 (en) | Method for producing optically active pantolactone | |
| US7385080B2 (en) | Method for producing optically active β-phenylalanine compounds | |
| JPH09506610A (en) | Preparation of phenylserine amide and phenylserine / phenylserine amide | |
| JPH0778052B2 (en) | Optical resolution method of DL-pantolactone | |
| JP2000505064A (en) | Racemization of amines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |