CN1123562C - Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester - Google Patents
Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester Download PDFInfo
- Publication number
- CN1123562C CN1123562C CN 00109758 CN00109758A CN1123562C CN 1123562 C CN1123562 C CN 1123562C CN 00109758 CN00109758 CN 00109758 CN 00109758 A CN00109758 A CN 00109758A CN 1123562 C CN1123562 C CN 1123562C
- Authority
- CN
- China
- Prior art keywords
- ala
- phenyl
- substituted
- splitting
- racemization
- 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.)
- Expired - Fee Related
Links
Abstract
The present invention relates to a novel method for preparing R-(+)-N-(substituted phenyl) alanine. In the method, racemic N-(substituted phenyl) alanine is resolved into R-(1)-N-(substituted phenyl) alanine by a resolution agent; after being esterified, isomer S-(-)-N-(substituted phenyl) alanine is easily racemized; then, the yield that racemic N-(substituted phenyl) alanine is converted into the R-(+)-N-(substituted phenyl) alanine can be more than 90% by saponification and resolution, and the optical purity can reach 94 to 99%ee.
Description
Present method relates to the method that its S-configuration piece racemization that racemic N-(substituted-phenyl) L-Ala or its ester is split as R-configuration optical purity product and will splits out prepares R-(+)-N-(substituted-phenyl) L-Ala or its ester.
Efficiently, the agricultural chemicals of low toxicity, low residue becomes a kind of inexorable trend of agricultural chemicals development.In agricultural chemicals, for example metaxanin in the acid amide fungicides, M 9834, furalaxyl, press down the R-isomer of mould prestige etc., have the characteristic of efficient, low toxicity, low residue, and its S-isomer is not only invalid, and antagonistic action is arranged, and be difficult to degraded.It is reported that the physiologically active of the R-isomer of above sterilant is higher than its racemic modification or S-isomer, field test confirms that also the activity of R-isomer is higher.For example, the inhibition of grape being given birth to the single shaft mould is active, and the R-M 9834 is active higher 20 times than S-M 9834, and high 2 times (referring to, " pesticide science " [Pesticide Science] (1985), the 16th rolls up the 277-286 page or leaf than racemic modification M 9834; CN1244770A).Since these R-isomer have good physiologically active and low toxicity, residual quantity little, pollute little characteristics; require under the more and more stricter condition at environment and ecological protection; racemic metaxanin, M 9834, furalaxyl or metolachlor at home and abroad market will be subjected to very big restriction; thereby will constantly increase the demand of R-metaxanin, R-M 9834, R-furalaxyl or S-metolachlor, the synthetic technology of developing these R-isomer will have important use and be worth.
N-(substituted-phenyl) L-Ala, for example N-(2, the 6-3,5-dimethylphenyl) L-Ala is Metalaxyl synthesizing, M 9834 or furalaxyl, and N-(2-ethyl-6-aminomethyl phenyl) L-Ala is the intermediate of agricultural chemicals such as synthetic metolachlor, it has a chiral carbon atom, has a pair of enantiomer.This a pair of enantiomer according to the actual convention in the amino acid, is called D-form and L-configuration, and the sorting technique according to Cahn, Ingold and Prelog proposition is called R configuration and S-configuration.
Can synthesize many useful chirality agricultural chemicals from above optical purity R-(+)-N-(substituted-phenyl) L-Ala, sterilant R-metaxanin for example above-mentioned, R-M 9834, R-furalaxyl.
The synthetic of optically pure R-(+)-N-(substituted-phenyl) L-Ala and ester thereof can be by following three approach:
1, by pyruvate and substituted aniline condensation, asymmetric catalytic hydrogenation then, but this method raw material and catalyzer cost height, enantioselectivity is not high, obtain R-(+)-N-(substituted-phenyl) alanine ester of high-optical-purity, still will be by splitting.
2, the S by substituted aniline and optically-active lactate
N2 substitution reactions obtain R-(+)-N-(substituted-phenyl) L-Ala (referring to EP48994, EP134392), but product purity and enantioselectivity are all poor.Obtain R-(+)-N-(substituted-phenyl) L-Ala of high-optical-purity, still will be by splitting.
3, by substituted aniline and the condensation of optically-active alpha-chloro propionic ester, obtain R-(+)-N-(substituted-phenyl) alanine ester (EP48993), but product purity is poor.Perhaps, by with substituted aniline and the condensation of alpha-chloro propionic acid, obtain R-(+)-N-(substituted-phenyl) L-Ala racemic modification, split then, a kind of method in back is expected to become a kind of effective cheaply preparation method.
The method for splitting of N-(substituted-phenyl) L-Ala racemic modification is known.For example, described employing α-Ben Yian resolution of racemic N-(substituted-phenyl) L-Ala among the US-A4 046911 prevailingly and obtained optical purity R-(+)-N-(substituted-phenyl) L-Ala, esterification under sulphuric acid catalysis then, and then synthetic R-furalaxyl.Also disclose among the EP1154470 with α-Ben Yian resolution of racemic N-(substituted-phenyl) L-Ala and obtained optical purity S-(+)-N-(substituted-phenyl) L-Ala, and then synthetic herbicide S-metolachlor.
Described with D-tartrate or D-camphorsulfonic acid splitting the amino alanine ester of N-3,5-dimethylphenyl-DL-and obtaining R-(+)-N-(substituted-phenyl) alanine ester among the CN1244770A prevailingly, and then be used for synthetic R-M 9834.
Hans Moser; Megden discloses with R-(+)-α-Ben Yian fractionation N-(substituted-phenyl) L-Ala and has got S-(-)-N-(substituted-phenyl) L-Ala; and and then the preparation S-(-)-(1 '-methyl-2 '-methoxy ethyl)-N-chloracetyl-2,6-xylidine (US4 919 709).Once fractionation rate has only about 20% of raceme in this patent, and the inconvenience of R-(+)-phenylethylamine source, cost an arm and a leg, the rate of recovery is low, under alkaline condition, easily racemization, be difficult to use repeatedly, also do not see the method that invalid isomer racemization is turned to racemic N-(substituted-phenyl) L-Ala, this has brought difficulty to suitability for industrialized production.On the one hand, cause a large amount of refuses to produce; On the other hand, product cost increases, thereby industrial application value is little.
But all there is the not high defective of yield and optical purity of products in disclosed method in the prior art.
At the deficiencies in the prior art, the present inventor concentrates on studies, found that, by in solvent, using resolving agent, D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1 for example, ammediol, the sulfonamide derivatives of R-(-)-2-amino butanol and optically pure D-(+)-glucose, can obtain obvious effects, especially the sulfonamide derivatives of D-glucose, effect is more excellent, racemic N-(substituted-phenyl) L-Ala can be split R-(+)-N-(substituted-phenyl) L-Ala that obtains high-optical-purity, follow isolated S-(-)-N-(substituted-phenyl) L-Ala through its salt or ester racemization, finally can prepare R-(+)-N-(substituted-phenyl) L-Ala with high yield, thereby realize the present invention.
The inventive method comprises two steps, that is, and and splitting step and racemization step.
Specifically, the N-of racemization (substituted-phenyl) L-Ala forms salt with optically pure glucosamine alkali in appropriate organic solvent, through recrystallization, suction filtration, with solid and liquid separation, solid analyse with alkaline hydrolysis and R-(+)-N-(substituted-phenyl) L-Ala; And the mother liquor that suction filtration gets through concentrate, resolve S-(-)-N-(3,5-dimethylphenyl) L-Ala, be used for next racemization step.
Specific embodiments of the present invention are, for example, in appropriate organic solvent, will be as D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1 of resolving agent, the sulfonamide derivatives of ammediol, R-(-)-2-amino butanol or optical purity D-(+)-glucose mixes with racemic modification N-(substituted-phenyl) L-Ala of formula I, the dissolving back is incubated 1-6 hour at-20 ℃ to solvent boiling point, the gained crystal is recrystallization again, suction filtration, with solid and liquid separation, solid with alkaline hydrolysis analyse high optically pure R-(+)-N-(substituted-phenyl) L-Ala.
R wherein
1, R
2And R
nRepresent H, halogen, C independently of each other
1-C
4Alkyl, C
1-C
4Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Haloalkyl or phenyl, n=0～3; R preferably
1And R
2Represent C independently of each other
1-C
4Alkyl, particularly methyl or ethyl, n=0.
And the mother liquor that gets from suction filtration through concentrate, resolve S-(-)-N-(substituted-phenyl) L-Ala do racemization and handle.This step comprises, in appropriate organic solvent, the derivative (for example ester or salt) that will split out S-(-)-N-(substituted-phenyl) L-Ala is incubated 1-10 hour, cooling in 0-80 ℃ under highly basic catalysis, with the acid neutralization, extracting and separating and saponification get formula I compound raceme.
The formula I racemic mixture of gained repeats above-mentioned splitting step circulation and racemization step again.
In the methods of the invention, resolving agent adopts D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1, the sulfonamide derivatives of ammediol, R-(-)-2-amino butanol and optically pure D-(+)-glucose, glucosamine compounds preferably wherein, wherein amine is aniline or straight chain, side chain, ring-type C
4-C
10Alkylamine, and preferred especially N-Octylglucamine.The N-of racemization (substituted-phenyl) L-Ala forms salt with optically pure glucosamine alkali in appropriate organic solvent, through recrystallization Cheng Chunpin, resolve and R-(+)-N-(substituted-phenyl) L-Ala.
Suitable fractionation organic solvent is that recrystallization solvent is: alcohols, halogenated alkane, ethers, amides, fat hydrocarbon, aromatic hydrocarbon, particular methanol, ethanol, propyl alcohol, Virahol, butanols, chloroform, glycol dimethyl ether, Di Iso Propyl Ether, sherwood oil, methyl ether, ether, dimethyl formamide, hexanaphthene, normal hexane, benzene, toluene, particularly methyl alcohol, ethanol, propyl alcohol, butanols, benzene, toluene.
The fractionation temperature is :-20 ℃ to solvent boiling point.
Parsing alkali is: the combination alkali of potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, these alkali and organic bases be methylamine, ethamine, triethylamine, pyridine etc. for example.
Resolution temperature is: 0-100 ℃.
The parsing solvent is: water, methyl alcohol, ethanol, propyl alcohol etc.
In method for splitting, the mol ratio of formula I compound raceme and D-(+)-glucosamine derivative is 1: 1.5-1.5: 1.
S-(-)-N-(substituted-phenyl) L-Ala can be with its salt or ester highly basic catalysis and racemization in suitable solvent.
Suitable solvent is: alcohols, aliphatic hydrocarbon, halogenated alkane, aromatic hydrocarbon, ethers, amides, optimum solvent are arene and alcohols, as: benzene, toluene, methyl alcohol, ethanol, Virahol.
Suitable racemization temperature be 0 ℃ to solvent boiling point.
The racemization time is 1-10 hour.
Used highly basic is the mixed base of combination mutually such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium amide, potassium amide, sodium hydride, potassium tert.-butoxide and sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alcoholate.
The derivative of S-(-)-N-(substituted-phenyl) L-Ala and the mol ratio 0.1 of alkali: 1.5-1.5: 0.1, be preferably 1: 0.15-1.
The inventive method has following advantage:
1, used resolving agent has high efficiency.As high resolution yield (90-95%), high-optical-purity (95-99%ee), resolving agent high-recovery (90-97%), resolving agent can be repeatedly used.
2, simple, the easy row of S-(-)-N-(substituted-phenyl) alanine ester and salt racemization thereof.
3, low cost.Prepare R-(+)-N-substituted-phenyl L-Ala by this method, can make racemize N-(substituted-phenyl) L-Ala be transformed into the yield of R-(+)-N-(substituted-phenyl) L-Ala greater than 90%.
4, easy to operate, economical and practical, the no three wastes.
The present invention is further described by following examples, but these embodiment to should not be construed as be limitation of the present invention.
Embodiment one: the preparation of R-(+)-N-(2, the 6-xylyl) L-Ala
With the racemic N-(2 of 19.3g (0.1mol), the 6-xylyl) L-Ala and 2 7.50g (0.08mol) optical purity D-(+)-Portugal's hexahydroaniline is dissolved in the 70ml methyl alcohol, reflux makes its dissolving, be cooled to room temperature step by step, placed 6 hours, recrystallization is once again with methyl alcohol for the gained solid, suction filtration, mother liquor is through concentrating, resolve to such an extent that S-(-)-N-(3,5-dimethylphenyl) L-Ala is used for racemization, the gained crystal is resolved with the sodium hydroxide (0.2mol) of 27g30%, filter, reclaim optical purity D-(+)-hexahydroaniline 10.3g of Portugal, the rate of recovery 37.5%.Mother liquor is neutralized to acidity with concentrated hydrochloric acid, and suction filtration gets optical purity R-(+)-N-(2, the 6-xylyl) L-Ala 7.7g (95%ee), yield 39.9%;
Embodiment two: the preparation of R-(+)-N-(2, the 6-xylyl) L-Ala
With the racemic N-(2 of 19.3g (0.1mol), 6 xylyls) L-Ala and 33.7g (0.12mol) optical purity D-(+)-N-Octylglucamine is dissolved in the 60ml methyl alcohol, reflux makes its dissolving, be cooled to room temperature step by step, placed 6 hours, the gained solid with methyl alcohol (60ml) recrystallization once, suction filtration, mother liquor is resolved to such an extent that S-(-)-N-(2, the 6-xylyl) L-Ala is used for racemization through concentrating, the gained crystal is resolved with the sodium hydroxide (0.2mol) of 27g30%, filter, reclaim optical purity D-(+)-N-Octylglucamine 13.7g, the rate of recovery 40.7%; Mother liquor is neutralized to pH=5.4 with concentrated hydrochloric acid, and suction filtration gets optical purity R-(+)-N-(2, the 6-xylyl) L-Ala 7.6g (98%ee), yield 39.3%.
Embodiment three: the racemization of S-(-)-N-(2, the 6-xylyl) L-Ala
With 16.4g (0.085mol) S-(-)-N-(2, the 6-xylyl) L-Ala and 5.1g (0.128mol) sodium hydroxide is dissolved in 50ml methyl alcohol and the propyl alcohol mixed solvent, reflux 5 hours, be concentrated into dried, be cooled to room temperature, be neutralized to acidity with concentrated hydrochloric acid, suction filtration gets racemize N-(2, the 6-xylyl) L-Ala 15.3g, yield 93.3%.
Embodiment four: the racemization of S-(-)-N-(2, the 6-xylyl) L-Ala
With 16.4g (0.085mol) S-(-)-N-(2, the 6-xylyl) L-Ala and 5.1g (0.128mol) sodium hydroxide is added in the 70ml benzene, reflux 6 hours is cooled to room temperature, is neutralized to acidity with concentrated hydrochloric acid, water layer extracts with 10ml benzene, merge organic layer, use dried over sodium sulfate, concentrated racemize N-(2, the 6-xylyl) L-Ala 15.6g, yield 95.1%.
Embodiment five: the racemization of S-(-)-N-(2, the 6-xylyl) alanine methyl ester
With 20.8g (0.1mol) S-(-)-N-(2, the 6-xylyl) alanine methyl ester and 0.8g (0.015mol) sodium methylate is dissolved in the 50ml methyl alcohol, reflux 5 hours is concentrated into driedly, is cooled to room temperature, be neutralized to acidity with concentrated hydrochloric acid, with 30ml * 3 ethyl acetate extractions, drying, concentrate racemize N-(2, the 6-xylyl) alanine methyl ester 19.7g, yield 94.8%.
Embodiment six: the preparation of R-(+)-N-(2,6-diethyl phenyl) L-Ala
With the racemic N-(2 of 22.1g (0.1mol), 6-diethyl phenyl) L-Ala and 15.4g (0.1mol) optical purity D-(+) N-Octylglucamine are dissolved in the 70ml methyl alcohol, reflux makes its dissolving, be cooled to room temperature step by step, placed 6 hours, the gained solid is used methyl alcohol (60ml) recrystallization-inferior again, suction filtration, mother liquor through concentrate, resolve S-(-)-N-(2,6-diethyl phenyl) L-Ala is used for racemization, and crystal is resolved with 27g30% sodium hydroxide (0.2mol), filters, reclaim D-(+)-N-Octylglucamine 7.1g, the rate of recovery 46.1%.Mother liquor is neutralized to acidity with concentrated hydrochloric acid, and suction filtration gets optical purity R-(+)-(2,6-diethyl phenyl) L-Ala 10.5g (95.3%ee), yield 47.5%.
Embodiment seven: the racemization of S-(-)-N-(2,6-diethyl phenyl) alanine methyl ester
With 23.5g (0.1mol) S-(-)-N-(2,6-diethyl phenyl) alanine methyl ester and 0.8g (0.015mol) sodium methylate are dissolved in the 50ml methyl alcohol, reflux 5 hours is concentrated into driedly, is cooled to room temperature, be neutralized to acidity with concentrated hydrochloric acid, with 30ml * 3 ethyl acetate extractions, combining extraction liquid, dry, concentrate racemize N-(2,6-diethyl phenyl) alanine methyl ester 22.3g, yield 95.1%.
Embodiment eight: the preparation of R-(+)-N-(2, the 6-xylyl) alanine methyl ester
With the racemic N-(2 of 20.7g (0.1mol), the 6-xylyl) alanine methyl ester and 15.0g (0.1mol) optical purity D-tartrate is dissolved in the 60ml methylene dichloride, reflux makes its dissolving, be cooled to room temperature and separate out the solid of salt, the gained solid is used 50ml methylene dichloride recrystallization again, suction filtration, mother liquor is through concentrating, resolve S-(-)-N-(2, the 6-xylyl) alanine methyl ester is used for racemization, and crystal is resolved with 13.5g30% sodium hydroxide (0.1mol) solution, uses 30ml dichloromethane extraction 3 times, dry concentrating, get R-(+)-N-(2, the 6-xylyl) alanine methyl ester 6.2g (85.7%ee), yield 30.0%.
Embodiment nine: the preparation of R-(+)-N-(2, the 6-xylyl) alanine methyl ester
With the racemic N-(2 of 20.7g (0.1mol), the 6-xylyl) alanine methyl ester and 23.2g (0.1mol) D-(+)-camphorsulfonic acid is dissolved in the 50ml chloroform, reflux makes its dissolving, be cooled to-10 ℃ of solids of separating out salt, the gained solid is used 40ml chloroform recrystallization again, suction filtration, mother liquor is through concentrating, resolve S-(-)-N-(2, the 6-xylyl) alanine methyl ester is used for racemization, and crystal is resolved with 6.8g30% sodium hydroxide (0.05mol) solution, uses 20ml chloroform extraction 3 times, dry concentrating, get R-(+)-N-(2, the 6-xylyl) alanine methyl ester 4.2g (87.2%ee), yield 20.3%.
Though the present invention adopts specific embodiments and embodiment to be described, without departing from theon the basis of the spirit of the present invention, those skilled in the art can make many modifications or improvement, and this point is conspicuous.Therefore, this class in the present invention's spirit scope is revised or is improved and all belongs within the scope of protection of present invention.
Claims (11)
1, a kind of method for splitting of formula I compound, it is characterized in that, in organic solvent, will be as D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1 of resolving agent, the sulfonamide derivatives of ammediol, R-(-)-2-amino butanol or optically pure D-(+)-glucose mixes with racemic N-(substituted-phenyl) L-Ala, and the dissolving back is incubated 1-6 hour at-20 ℃ to solvent boiling point, and the gained crystal is recrystallization again, alkaline hydrolysis analyse optically pure R-(+)-N-(substituted-phenyl) L-Ala
R wherein
1, R
2And R
nRepresent H, halogen, C independently of each other
1-C
4Alkyl, C
1-C
4Cycloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Haloalkyl or phenyl, n=0～3.
2, according to the process of claim 1 wherein R
1And R
2Represent C independently of each other
1-C
4Alkyl, n=0.
3, method for splitting according to claim 1, wherein, D-(+)-glucosamine derivative is glucose aniline or straight chain, side chain, ring-type C
4-C
10Alkylamine.
4, the described method for splitting of claim 3, wherein, D-(+)-glucosamine derivative is a N-Octylglucamine.
5, the described method for splitting of one of claim 1 to 4, wherein, organic solvent is methyl alcohol, ethanol, propyl alcohol, butanols, benzene, toluene or its mixture.
6, the described method for splitting of one of claim 1 to 5, wherein, parsing alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide or its mixture.
7, the described method for splitting of one of claim 1 to 6, wherein, the mol ratio of formula I compound raceme and D-glucosamine derivative is 1: 1.5-1.5: 1.
8, a kind of formula I compound S-configuration body racemization method is characterized in that, in organic solvent, with the ester of formula I compound S-configuration body or salt under highly basic catalysis in 0-80 ℃ of insulation 1-10 hour, the cooling back is with the acid neutralization, saponification gets formula I compound raceme.
9. the described racemization method of claim 8, wherein, described highly basic is sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, potassium ethylate, potassium methylate, potassium tert.-butoxide, sodium hydride, sodium amide or its mixture.
10. the described racemization method of one of claim 8 to 9, wherein, the mol ratio of the derivative of alkali and S-(-)-N-(substituted-phenyl) L-Ala is 0.1: 1.5-1.5: 0.1.
11. the described racemization method of one of claim 7 to 10, wherein, neutralizing acid is sulfuric acid, hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00109758 CN1123562C (en) | 2000-07-05 | 2000-07-05 | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00109758 CN1123562C (en) | 2000-07-05 | 2000-07-05 | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1331072A CN1331072A (en) | 2002-01-16 |
| CN1123562C true CN1123562C (en) | 2003-10-08 |
Family
ID=4579847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00109758 Expired - Fee Related CN1123562C (en) | 2000-07-05 | 2000-07-05 | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1123562C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301967C (en) * | 2004-12-15 | 2007-02-28 | 南京大学 | Method of chiral separation for D,L-phenylalanine ester or its salt |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003890B (en) * | 2014-04-30 | 2017-11-28 | 上海康福赛尔医药科技有限公司 | A kind of method for preparing the phenylpropionic acid of 3 amino of S or R types optical isomer 3 |
| CN104531565B (en) * | 2014-12-10 | 2017-09-26 | 浙江工业大学 | Denitrification achromobacter zjut1104 and its application |
| CN106316872A (en) * | 2016-08-23 | 2017-01-11 | 浙江工业大学 | Chemical racemization method of (S)-N-(2,6-dimethylphenyl)methyl aminopropionate |
-
2000
- 2000-07-05 CN CN 00109758 patent/CN1123562C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301967C (en) * | 2004-12-15 | 2007-02-28 | 南京大学 | Method of chiral separation for D,L-phenylalanine ester or its salt |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1331072A (en) | 2002-01-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1185225C (en) | Improved process for preparing nitrogen-substituted aminotetralins | |
| CN1699331A (en) | Process for the synthesis of (is)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane and uses thereof | |
| RU2585762C2 (en) | Method of producing lakosamide | |
| CN1253450C (en) | Method of mycophenolate mofetil prepn. | |
| CN1123562C (en) | Process for prearing R-(t)-N-(substituted phenyl) lactamic acid or its ester | |
| CN1942429A (en) | Processes for the preparation of tomoxetine | |
| CN1042904A (en) | The method of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide | |
| CN1121381C (en) | Novel process for preparing ketimine | |
| CN1247525C (en) | Process for preparing N-(substituted phenyl) alanine and its ester and racemization method of its optical configuration body | |
| CN1173928C (en) | Process for preparing (1R,2S,4R)-(-)-2-[(2'-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1] heptane and pharmaceutically acceptable acid addition salts thereof | |
| CN101597248A (en) | The preparation method of valnemulin and hydrochloride thereof | |
| CN1931855A (en) | Compound 2-methylol-3-substituted phenyl propionic acid with optical activity and its resolving process | |
| CN1046902A (en) | Preparation 1, the method for 5-benzothiazepine derivatives | |
| CN102126944A (en) | Method for preparing single configuration mandelic acid or mandelic acid derivative by using chiral resolving agent | |
| CN1245377C (en) | Method for preparing Tolterodine and tartrate | |
| CN1136318C (en) | Process for producing optically active amines | |
| CN102126961B (en) | Preparation method of R-1-(4-methoxyphenyl)-N-benzyl-2-propylamine | |
| CN1070850C (en) | Novel carbamate compounds containing thiocarbamoyl group and process for preparing the same | |
| CN1252045C (en) | Process for synthesizing omega amine polyoxyvinyl | |
| CN1646477A (en) | Process for the preparation of enantiomerically enriched compounds | |
| CN1442407A (en) | Chemical resolution preparation method of optically pure fesufenadin and its hydrochloride salt | |
| CN1082045C (en) | Synthetic method of a-benzoin oxime | |
| CN1155553C (en) | Process for preparing antimer of 2-fluo-alpha-methyl-[1,1'-diphenyl]-4-acetic acid | |
| CN1993472A (en) | Method for enantioselectively opening 3-substituted oxetan-2-ones under the action of lipases of candida antarctica or burkholderia plantarrii | |
| CN117304071A (en) | Synthesis method of chiral N-alkyl amino acid derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: CHONGQING SANXIA YINGLI CHEMICAL CO., LTD. Free format text: FORMER OWNER: QINGHUAZIGUANG YINGLI CHEMICAL TECHNOLOGY CO. LTD., BEIJING Effective date: 20070309 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20070309 Address after: 631200, Chongqing (longevity) chemical industry park, fine chemical two district Patentee after: Chongqing Sanxia Yingli Chemical Co., Ltd Address before: 100084 purple building, room 506, Tsinghua University, Beijing Patentee before: Beijing Tsinghua Unisplendour Insight Chemical Technology LLC |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1045891 Country of ref document: HK |
|
| DD01 | Delivery of document by public notice |
Addressee: Chongqing Sanxia Yingli Chemical Co., Ltd Document name: Notification to Pay the Fees |
|
| DD01 | Delivery of document by public notice |
Addressee: Xie Yong Document name: Notification of Termination of Patent Right |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20031008 Termination date: 20130705 |