CN107778194B - Preparation and resolution method of phenylalanine ester compound - Google Patents

Preparation and resolution method of phenylalanine ester compound Download PDF

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CN107778194B
CN107778194B CN201610717733.6A CN201610717733A CN107778194B CN 107778194 B CN107778194 B CN 107778194B CN 201610717733 A CN201610717733 A CN 201610717733A CN 107778194 B CN107778194 B CN 107778194B
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ester compound
phenylalanine
reaction
acid
preparation
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CN107778194A (en
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吴晓明
钱灵锋
陈小华
詹东凯
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a preparation method of phenylalanine ester compound, which is prepared by alkylation reaction of alkylating reagent and Schiff base compound and hydrolysis reaction, can obtain product with high yield, and is a route suitable for industrialization. And the chiral amino acid ester compound with higher optical purity can be obtained after resolution, and the method has application prospect. The invention can also prepare the phenylalanine ester compound in the form of acid salt by adjusting the amount of acid in the hydrolysis reaction.

Description

Preparation and resolution method of phenylalanine ester compound
Technical Field
The invention belongs to the field of medical chemistry, and relates to a preparation and resolution method of a phenylalanine ester compound.
Background
Phenylalanine compounds are disclosed in U.S. Pat. No. 5,943 (application date: 1992-5-19, Applicant: Warner-Lambert Company) and the reaction scheme is as follows:
Figure BDA0001089005340000011
in another U.S. Pat. No. 5,567,943 (application date: 1995-1-5, applicant: Warner-Lambert Company), phenylalanine compounds have been reported for the preparation of phenylalanine derivatives, which are endothelin antagonists. In addition, phenylalanine ester in the form of hydrochloride is also prepared in example 1 of the U.S. patent.
Figure BDA0001089005340000012
In view of the role of phenylalanine-like compounds in the production of phenylalanine derivatives, it is necessary to develop a process for producing phenylalanine-like compounds for industrial production.
Disclosure of Invention
The invention provides a preparation and resolution method of phenylalanine ester. Not only is the yield high and is suitable for an industrialized route, but also the chiral phenylalanine ester compound can be obtained after resolution.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the alkylation agent reacts with the schiff base to produce alkylated schiff base. The reaction formula is as follows:
Figure BDA0001089005340000021
the alkylated schiff base is hydrolyzed under the action of acid to prepare the phenylalanine ester compound. The reaction formula is as follows:
Figure BDA0001089005340000022
wherein R is1，R2Is C1-C8 alkyl, PGIs a hydroxyl protecting group. The hydroxyl protecting group is benzyl, p-methoxybenzyl and p-nitrobenzyl.
The acid used in the hydrolysis reaction is an inorganic acid. The inorganic acid is hydrochloric acid. The salt of the phenylalanine ester compound such as hydrochloride can be controlled by the amount of the added acid. The molar ratio of the acid to the alkylated schiff base compound is 1.5 to 3.0, preferably 1.5. At this time, a phenylalanine ester compound is produced. When the molar ratio is 3.0-4.0, the phenylalanine ester compound in the form of acid salt is generated.
Wherein the reaction of the alkylating agent with the Schiff base is carried out under the action of a base. The base is an inorganic base such as sodium ethoxide, pyridine, triethylamine or N, N-diisopropylethylamine. Preferably, it is sodium ethoxide. The reaction solvent is an ether solvent, halogenated alkane, aromatic hydrocarbon or ester solvent, such as tetrahydrofuran, dichloromethane, toluene, ethyl acetate and the like. The reaction temperature is 0-20 ℃, and preferably 0-5 ℃.
The alkylating reagent is prepared by reacting a compound shown in the formula I with a chlorinating reagent, and the reaction route is as follows:
Figure BDA0001089005340000023
wherein R is1Is C1-C8 alkyl, PGIs a hydroxyl protecting group.
The chlorinating agent is thionyl chloride, phosphorus trichloride or phosphorus oxychloride. The reaction temperature is 0-50 ℃, preferably 10-20 ℃.
One preferred embodiment of the present invention is: preparing the phenylalanine ethyl ester compound. Comprises two steps of alkylation reaction and hydrolysis reaction. Respectively, alkylation reaction of an alkylating reagent and Schiff base, and the reaction formula is as follows:
Figure BDA0001089005340000031
the hydrolysis of alkylated schiff base compounds with an acid, the reaction scheme is as follows:
Figure BDA0001089005340000032
further, the invention provides a resolution method of the phenylalanine ester compound. Chiral acid is used as a resolving agent. The resolving agent can be L-tartaric acid, L-benzoyl tartaric acid, L-malic acid, proline, camphorsulfonic acid, lactic acid, mandelic acid, di-p-methoxybenzoyl tartaric acid, etc. Preferably tartaric acid.
The reaction solvent is an ester solvent, a ketone solvent, an alcohol solvent or a single solvent or a mixed solvent of water. Preferably an ester solvent. The ester solvent is ethyl acetate; the ketone solvent is acetone, and the alcohol solvent is ethanol.
The reaction temperature is 20-70 ℃, preferably 20-30 ℃.
The invention provides a preparation method of phenylalanine ester compound, which is prepared by alkylation reaction of alkylating reagent and Schiff base compound and hydrolysis reaction, can obtain product with high yield, and is a route suitable for industrialization. And the chiral amino acid ester compound with higher optical purity can be obtained after resolution, and the method has application prospect.
Detailed Description
In order to further understand the present invention, the following examples are provided to illustrate the preparation and resolution of phenylalanine ester compounds. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
Example 1:
Figure BDA0001089005340000033
putting 12.2g of the compound shown in the formula I and 100ml of dichloromethane into a reaction bottle, cooling to 0-5 ℃, slowly dripping 6.0g of thionyl chloride, heating to 20-30 ℃ after dripping, and keeping the temperature until the reaction is completed. Evaporating the solvent to dryness, adding ethyl acetate to dissolve the solvent, washing with a sodium bicarbonate aqueous solution, evaporating the solvent to dryness, and performing silica gel column chromatography to obtain 12.2g of a product, wherein the yield is as follows: 93.0 percent.
Example 2:
Figure BDA0001089005340000041
putting 13.1g of alkylating reagent, 10.5g of schiff base and 150ml of tetrahydrofuran into a reaction bottle, cooling to 0-5 ℃, slowly dripping sodium ethoxide solution, heating to 30-50 ℃ after dripping, keeping the temperature until the reaction is completed to obtain alkylated schiff base compound, cooling to room temperature, dripping diluted hydrochloric acid, keeping the temperature until the reaction is completed, adding sodium bicarbonate aqueous solution, and adjusting the pH to 8-9. Layering, extracting a water layer with ethyl acetate, evaporating to dryness, and performing silica gel column chromatography to obtain 14.5g of phenylalanine ethyl ester compound, wherein the yield is as follows: 88.3 percent.
Example 3:
putting 16.5g of phenylalanine ethyl ester compound, 3.8g of L-tartaric acid and 100ml of ethyl acetate into a reaction bottle, heating to 30-70 ℃, preserving heat for 1-2 h, slowly cooling to 20-30 ℃, and performing suction filtration to obtain 11.0g of resolution salt, wherein the yield is as follows: 45.9 percent. Putting 11.0g of the resolving salt, 60ml of ethyl acetate and 30ml of water into a reaction bottle, putting sodium bicarbonate in batches, adjusting the pH value to 8-9, layering, extracting a water layer with ethyl acetate, combining organic layers, evaporating to dryness to obtain 6.6g of an S-configuration phenylalanine ethyl ester compound, wherein the yield is as follows: 87.3 percent.

Claims (4)

1. A process for preparing phenylalanine ethyl ester compound features that the phenylalanine ester compound is prepared from alkylating reagent and schiff base through reaction, acid hydrolysis,
Figure FDA0003500794590000011
wherein R is1Is C1-C8 alkyl, PGIs a hydroxyl protecting group which is benzyl, p-methoxybenzyl or p-nitrobenzyl; the reaction of the alkylating reagent with schiff base is carried out under the action of alkali, and the alkali is sodium ethoxide.
2. The process of claim 1, wherein the alkylating agent is prepared by reacting a compound of formula I with a chlorinating agent,
Figure FDA0003500794590000012
wherein R is1As defined in claim 1; pGIs a hydroxyl protecting group which is benzyl, p-methoxybenzyl or p-nitrobenzyl.
3. The method of claim 2, wherein the chlorinating agent is thionyl chloride, phosphorus trichloride or phosphorus oxychloride.
4. The preparation method according to claim 1, wherein the phenylalanine ester compound is resolved to prepare a chiral phenylalanine ester compound, and the resolving agent is L-tartaric acid.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5658943A (en) * 1995-01-05 1997-08-19 Warner-Lambert Company Phenylalanine derivatives as endothelin antagonists
CN1660794A (en) * 2004-12-15 2005-08-31 南京大学 Method of chiral separation for D,L-phenylalanine ester or its salt
CN106478502A (en) * 2015-08-29 2017-03-08 上海翰森生物医药科技有限公司 1,2,3,4- tetrahydro isoquinoline derivative, its preparation method and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1181046C (en) * 2000-12-29 2004-12-22 海门慧聚药业有限公司 Prepn of chiral compound L-homophenprobamate and its salt

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5658943A (en) * 1995-01-05 1997-08-19 Warner-Lambert Company Phenylalanine derivatives as endothelin antagonists
CN1660794A (en) * 2004-12-15 2005-08-31 南京大学 Method of chiral separation for D,L-phenylalanine ester or its salt
CN106478502A (en) * 2015-08-29 2017-03-08 上海翰森生物医药科技有限公司 1,2,3,4- tetrahydro isoquinoline derivative, its preparation method and application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Catalytic asymmetric synthesis of the common amino acid component in the biosynthesis of tetrahydroisoquinoline alkaloids;Ryo Tanifuji，等;《Tetrahedron Letters》;20160203;第57卷(第5期);Scheme 3，Supporting Information第S4、S5页 *
DL-苯丙氨酸的合成和拆分;俞一军;《中国优秀硕士学位论文全文数据库（电子期刊）工程科技I辑》;20021215;第26页倒数第1段，第9页倒数第1段 *
俞一军.DL-苯丙氨酸的合成和拆分.《中国优秀硕士学位论文全文数据库（电子期刊）工程科技I辑》.2002,第26页倒数第1段，第9页倒数第1段. *

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