CN1247525C - Process for preparing N-(substituted phenyl) alanine and its ester and racemization method of its optical configuration body - Google Patents
Process for preparing N-(substituted phenyl) alanine and its ester and racemization method of its optical configuration body Download PDFInfo
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- CN1247525C CN1247525C CN 02117730 CN02117730A CN1247525C CN 1247525 C CN1247525 C CN 1247525C CN 02117730 CN02117730 CN 02117730 CN 02117730 A CN02117730 A CN 02117730A CN 1247525 C CN1247525 C CN 1247525C
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Abstract
The present invention relates to a process of preparing N-(substituted phenyl) alanine phthalate racemic bodies by using alpha-hydroxypropionitrile and substituted aniline as raw material, and a method for separating R or S-isomers thereof.
Description
Invention field
The aniline that the present invention relates to Alpha-hydroxy propionitrile and replacement is feedstock production N-(substituted-phenyl) L-Ala raceme, and splits out its R or S-isomer and with the direct method of racemization under the highly basic effect of the S-shaped body that splits out.
Background of invention
Efficiently, the agricultural chemicals of low toxicity, low residue becomes a kind of inexorable trend of agricultural chemicals development.In agricultural chemicals, the R-isomer of acid amide fungicides such as metaxanin, M 9834, furalaxyl etc. for example, the R-isomer of acetamide-group herbicides such as metolachlor (metolachlor) etc., characteristic with efficient, low toxicity, low residue, and its S-isomer is not only invalid, and adhewsive 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; at for example racemic metaxanin, M 9834, furalaxyl or metolachlor when at home and abroad market is subjected to greatly restriction; demand to R-metaxanin, R-M 9834, R-furalaxyl or R-metolachlor is constantly increasing; therefore, the synthetic technology of developing these R-isomer still has important use and is worth.
N-(substituted-phenyl) L-Ala of formula (I) or its ester are above-mentioned agricultural chemicals synthetic important intermediate,
(I)
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions; R represents H or C
1-C
4-alkyl.
Particularly work as R
1And R
2Represent methyl or ethyl independently of each other, when R represented H or methyl, for example N-(2, the 6-3,5-dimethylphenyl) L-Ala or the methyl esters in formula (I) compound was Metalaxyl synthesizing, M 9834 or furalaxyl; N-(2-ethyl-6-aminomethyl phenyl) L-Ala or methyl esters are the intermediates of agricultural chemicals such as synthetic metolachlor.This formula (I) compound 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 intermediate R-(+)-N-(substituted-phenyl) L-Ala or its ester, sterilant R-metaxanin for example above-mentioned, R-M 9834, R-furalaxyl or R-metolachlor.
The synthetic of intermediate R-(+)-N-(substituted-phenyl) L-Ala of formula (I ') 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) L-Ala 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 EP 48994, EP 134392), 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 acid, obtain R-(+)-N-(substituted-phenyl) L-Ala (EP 48993), but product purity is poor.
In addition, the synthetic of intermediate R-(+)-N-(substituted-phenyl) alanine ester can be by following two approach:
1, adopts directed synthetic mode.For example 2,6-xylidine (IV) with (S)-sulfonic acid esters (V) of alpha-halogen methyl propionate or L-methyl lactate passes through S
N2 reactions (referring to DE 3,328,986, EP 48,993, and DE 3,037,159, Liebigs Ann.Chem.1986, (2), 314-33), route of synthesis is as shown below.
X
1＝Cl，Br，I，CF
3SO
3，PhSO
3，p-MePhSO
3，CH
3SO
3，etc
2, adopt chiral separation to make.For example, racemic ester (VI) hydrolysis is obtained racemic acid (I1), as shown below.
Racemic acid (I
1) split by the chiral separation agent and to obtain corresponding chiral acid, esterification makes corresponding chiral ester (referring to, Chinese patent application CN00109758.X) then.
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-A 4 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 EP 1154470 with α-Ben Yian resolution of racemic N-(substituted-phenyl) alanine methyl ester and obtained optical purity R-(+)-N-(substituted-phenyl) alanine methyl ester, and then synthetic herbicide R-metolachlor.
Described with D-tartrate or D-camphorsulfonic acid splitting the amino L-Ala of N-3,5-dimethylphenyl-DL-and obtaining R-(+)-N-(substituted-phenyl) L-Ala among the CN1244770A prevailingly, and then be used for synthetic R-M 9834.
Chinese patent application CN00109758.X has described with D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1, the sulfonamide derivatives of ammediol, 2-amino butanol or optically pure D-glucose is as resolving agent, racemic N-(substituted-phenyl) L-Ala is split the method that obtains optically pure R-(+)-N-(substituted-phenyl) L-Ala, the corresponding S-isomer acid that splits out is racemized to after esterification or salt-forming reaction and is racemic modification acid, and recovery set is used again.
But in the prior art disclosed method no matter be the preparation racemic modification or N-(substituted-phenyl) L-Ala of R-isomer or prepare its ester all exist yield with and defective not such as R-isomer optical purity is not high, step is numerous and diverse, therefore, still need better method.
At the deficiencies in the prior art, the present inventor has carried out deep research, found that, adopt Alpha-hydroxy propionitrile and substituted aniline under certain pH value and temperature, to react, and with N-(substituted benzene amino) the propionitrile esterification of gained, can obtain racemize the acid esters---(R of formula (I) with high yield, S)-N-(substituted-phenyl) alanine ester, can split R-(+)-N-(substituted-phenyl) alanine ester that can get optically pure formula (I ') by formula (I), and the formula that splits out (S-(-)-N-(substituted-phenyl) alanine ester of I ") is racemization under the highly basic effect directly; recovery set is used; perhaps formula (I) is hydrolyzed into carboxylic acid sodium under the highly basic condition, after regulating pH value, separates out the racemic acid of formula (I); remake further deconsolidation process, thereby finished the present invention.
Summary of the invention
The invention provides N-(phenyl of the replacement) L-Ala of a kind of preparation formula (I) or the method for its ester,
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions; R preferably
1And R
2Represent C independently of each other
1-C
4The methyl of-alkyl, particularly 2-or 6-position or ethyl,
R represents H or C
1-C
4-alkyl is preferably H or methyl,
It comprises the steps:
1) be 5-8 at PH, be preferably 6-7, temperature is 50-150 ℃, be preferably under 80-120 ℃ the condition, with substituted aniline and Alpha-hydroxy propionitrile with 1: 0.5-5 is preferably 1: the molar ratio reaction of 1-3,
2) with N-(phenyl amino of the replacement) propionitrile of gained and excessive alcohol esterification under the catalysis of exsiccant hydrogenchloride, the carboxylicesters of production (I),
Choose wantonly,
3) carboxylicesters with formula (I) is hydrolyzed into its carboxylate salt under the highly basic condition, regulates PH to 3-5, separates out the acid crystal of formula (I).
The present invention also provides R-(+)-N-(substituted-phenyl) L-Ala of a kind of preparation formula (I ') or the method for its ester,
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions; R preferably
1And R
2Represent C independently of each other
1-C
4The methyl of-alkyl, particularly 2-or 6-position or ethyl,
R represents H or C
1-C
4-alkyl, preferably H or methyl,
It comprises the steps:
1) be 5-8 at PH, temperature is under 50-150 ℃ the condition, with substituted aniline and Alpha-hydroxy propionitrile with 1: the molar ratio reaction of 0.5-5,
2) with N-(phenyl amino of the replacement) propionitrile of gained and excessive alcohol esterification under the catalysis of exsiccant hydrogenchloride, the carboxylicesters of production (I),
Choose wantonly
3) carboxylicesters with formula (I) is hydrolyzed into its carboxylate salt under the highly basic condition, regulates PH to 3-5, separates out the acid crystal of formula (I).
4) and with step 2) or 3) (the R of the formula (I) of gained, S)-N-(substituted-phenyl) alanine ester or its acid split R-(+)-N-(substituted-phenyl) alanine ester or its acid of optically pure formula (I '), (I ") S-(-)-N-(substituted-phenyl) alanine ester or acid; described following method among the Chinese patent application CN00109758.X are earlier with S-isomer acid (I for the formula that splits out simultaneously
1 ") esterification or salify under the highly basic effect, again through the strong acid neutralizing hydrolysis, obtain racemic acid (I
1).
For example, adopt 2,6-xylidine and Alpha-hydroxy propionitrile are raw material, and reaction path of the present invention can be expressed as follows:
1) 2, the condensation under certain pH value and temperature condition of 6-xylidine and Alpha-hydroxy propionitrile makes product 2-(2,6-3,5-dimethylphenyl amino) propionitrile;
2) 2-(2, the 6-xylidino) propionitrile is a kind of very important intermediate, with just obtaining carboxylicesters (I) after its esterification, can obtain its carboxylic acid form after the hydrolysis.
2-(2, the 6-xylidino) propionitrile and excessive methyl alcohol esterification under dry hydrogen chloride catalysis obtain (I), (I) are hydrolyzed into carboxylic acid sodium salt under the highly basic condition, regulate the pH value and be the crystal of separating out sour form after 3.5, weigh total recovery 80% after the drying.
The Alpha-hydroxy propionitrile is a known raw material in the chemosynthesis, perhaps can employing itself known method preparation (GB 570,042, and US 2,868,828, and US 2,937,196, JP-A-68-29, and 574, DE 1,254, and 615).
The racemic modification that adopts the inventive method to prepare can adopt the above-mentioned ordinary method of mentioning to split.In preparing the process of chiral ester, the method that adopts chiral separation must obtain the acid of invalid body S-isomer, for example obtain (R)-(+)-N-2-(2 in fractionation, the 6-3,5-dimethylphenyl) can obtain S-(-)-2-(2, the 6-3,5-dimethylphenyl) L-Ala (being called for short " acid of S-isomer ") (I during alanine methyl ester
1 "), for saving production cost and reduce pollution to environment, the racemization recovery set of S-acid is with being very important.
Following method has been described, earlier with S-isomer acid (I among the Chinese patent application CN00109758.X
1 ") esterification or salify under the highly basic effect, again through the strong acid neutralizing hydrolysis, obtain racemic acid (I
1).
Formula of the present invention (I) compound adopts known method to split, and for example adopts that disclosed method splits among the Chinese patent application CN00109758.X.For example, in the organic solvent that is fit to, will be as D-(-)-Erythro-2,3-octadecane-diol-aminophenyl-1 of resolving agent, the sulfonamide derivatives of ammediol, 2-amino butanol or optical purity D-glucose mixes with racemic modification N-(substituted-phenyl) L-Ala or the ester of formula (I),
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions; R preferably
1And R
2Represent C independently of each other
1-C
4The methyl of-alkyl, particularly 2-or 6-position or ethyl,
R represents H or C
1-C
4-alkyl, preferably H or methyl,
After the dissolving ,-20 ℃ of insulations 1-6 hour to the 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 or ester,
And the mother liquor that gets from suction filtration through concentrate, resolve S-(-)-N-(substituted-phenyl) L-Ala or ester do racemization and handle.Following method has been described, earlier with S-isomer acid (I among the Chinese patent application CN00109758.X
1 ") esterification or salify under the highly basic effect, again through the strong acid neutralizing hydrolysis, obtain racemic acid (I
1).
The formula of gained (I) racemic mixture 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, 2-amino butanol and optically pure D-glucose, and glucosamine compounds preferably wherein, wherein amine is aniline or straight chain, side chain, ring-type C
4-C
10-alkylamine, 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: potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate and organic amine 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 or ester can be in suitable solvent highly basic high-temperature catalytic and racemization.
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 is more than 20-250 ℃, is preferably more than the reflux temperature.
The racemization time was generally 0.5-10 hour, was preferably 1-5 hour.
Used highly basic is mixed bases 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.
S-(-)-N-(substituted-phenyl) L-Ala or ester and alkaline mol ratio are 0.1: 1.5-1.5: 0.1, be preferably 1: 0.15-1.
Embodiment
The present invention is further described by following examples, but these embodiment to should not be construed as be limitation of the present invention.
The preparation and the esterification catalysis of embodiment 2-(2,6-dimethyl benzene amido) propionitrile
In the there-necked flask of band thermometer and reflux condensing tube, add 12.1g (0.10mol) 2,6-xylidine and 10.7g (0.15mol) Alpha-hydroxy propionitrile, mix at normal temperatures earlier and stir, the pH value is adjusted to 6.0-6.5, be warming up to 90-100 ℃, stir 3-4hr and obtain 2-(2,6-dimethyl benzene amido) propionitrile 16g, this step yield 92% (with 2,6-xylidine meter).
In the there-necked flask of band thermometer and reflux condensing tube, add 17.4g (0.10mol) 2-(2,6-dimethyl benzene amido) propionitrile and 50mlHCl-methanol solution (the about 12mol.L of HCl concentration
-1), it is molten entirely to mix to solid under the normal temperature, is warming up to 50 ℃ of stir about 3hr.Be warming up to backflow subsequently, insulation is cooled to 0-5 ℃ behind the 5hr, and regulating pH value with diluted alkaline is that the toluene with 50ml * 3 extracts behind the 7-8, extraction liquid obtains product 2-(2 after concentrating, 6-dimethyl benzene amido) methyl propionate 17.6g, this step yield 85% (with 2-(2,6-dimethyl benzene amido) propionitrile meter).
In the there-necked flask of band thermometer and reflux condensing tube, add 20.7g (0.10mol) 2-(2,6-dimethyl benzene amido) methyl propionate, 50ml water, 5ml methyl alcohol and 17g (30%) liquid sodium hydroxide is warming up to 60-70 ℃ after mixing stirring, is cooled to room temperature behind the insulation 1.5-2.0hr.With the salt acid for adjusting pH value is 3.5, separates out 2-(2,6-dimethyl benzene amido) propionic acid, the filtration drying 18.3g that weighs, this step yield 95%.
Claims (6)
1, the method for the N-of a kind of preparation formula (I) (phenyl of replacement) L-Ala or its ester,
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions;
R represents H or C
1-C
4-alkyl,
It comprises the steps:
1) be 5-8 at PH, temperature is under 50-150 ℃ the condition, with substituted aniline and Alpha-hydroxy propionitrile with 1: the molar ratio reaction of 0.5-5,
2) with N-(phenyl amino of the replacement) propionitrile of gained and excessive alcohol esterification under the catalysis of exsiccant hydrogenchloride, the carboxylicesters of production (I),
Choose wantonly,
3) carboxylicesters with formula (I) is hydrolyzed into its carboxylate salt under the highly basic condition, regulates PH to 3-5, separates out the acid crystal of formula (I).
2, according to the process of claim 1 wherein R
1And R
2Represent methyl or ethyl on 2-or the 6-position independently of each other, R represents H or methyl.
3, according to the method for claim 2, wherein, pH value is 6-7 in the step 1), and temperature 80-120 ℃, the mol ratio of substituted aniline and Alpha-hydroxy propionitrile is 1: 1-3.
4, R-(+)-N-(substituted-phenyl) L-Ala of a kind of preparation formula (I ') or the method for its ester,
R wherein
1And R
2Represent H, halogen, C independently of each other
1-C
4-alkyl, phenyl, R
1And R
2Can be on aromatic ring different positions,
R represents H or C
1-C
4-alkyl,
It comprises the steps:
1) be 5-8 at PH, temperature is under 50-150 ℃ the condition, with substituted aniline and Alpha-hydroxy propionitrile with 1: the molar ratio reaction of 0.5-5,
2) with N-(phenyl amino of the replacement) propionitrile of gained and excessive alcohol esterification under the catalysis of exsiccant hydrogenchloride, the carboxylicesters of production (I),
Choose wantonly
3) carboxylicesters with formula (I) is hydrolyzed into its carboxylate salt under the highly basic condition, regulates PH to 3-5, separates out the acid crystal of formula (I).
4) and with step 2) or 3) (the R of the formula (I) of gained, S)-N-(substituted-phenyl) alanine ester or its acid split R-(+)-N-(substituted-phenyl) alanine ester or its acid of optically pure formula (I '), the formula that splits out simultaneously (I ") S-(-)-N-(substituted-phenyl) alanine ester or acid; directly mix; carry out racemization and handle; obtained the racemic acid of formula (I), recovery set is used with highly basic.
5, according to the method for claim 4, wherein, R
1And R
2Represent methyl or ethyl on 2-or the 6-position independently of each other, R represents H or methyl.
6, according to the method for claim 5, wherein, pH value is 6-7 in the step 1), and temperature 80-120 ℃, the mol ratio of substituted aniline and Alpha-hydroxy propionitrile is 1: 1-3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117730 CN1247525C (en) | 2002-05-14 | 2002-05-14 | Process for preparing N-(substituted phenyl) alanine and its ester and racemization method of its optical configuration body |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117730 CN1247525C (en) | 2002-05-14 | 2002-05-14 | Process for preparing N-(substituted phenyl) alanine and its ester and racemization method of its optical configuration body |
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| CN1247525C true CN1247525C (en) | 2006-03-29 |
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| CN103360241B (en) * | 2012-03-29 | 2016-08-03 | 中国药科大学 | Optical voidness 5-oxo three ring [2,2,1,02,6] preparation method of heptane-3-carboxylic acid |
| 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 |
| CN108414664B (en) * | 2018-04-11 | 2020-01-24 | 国家烟草质量监督检验中心 | Method for splitting and determining chiral pesticide metolachlor enantiomer by ultra-efficient combined phase chromatography-tandem mass spectrometry technology |
| CN108689877B (en) * | 2018-07-06 | 2021-08-03 | 浙江工业大学 | Chiral carbon-containing bisamide compound and preparation method and application thereof |
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Granted publication date: 20060329 Termination date: 20110514 |