EP0308451A1 - Verfahren zur herstellung von asparaginsäure-4-(phenylmethyl) ester - Google Patents

Verfahren zur herstellung von asparaginsäure-4-(phenylmethyl) ester

Info

Publication number
EP0308451A1
EP0308451A1 EP88902789A EP88902789A EP0308451A1 EP 0308451 A1 EP0308451 A1 EP 0308451A1 EP 88902789 A EP88902789 A EP 88902789A EP 88902789 A EP88902789 A EP 88902789A EP 0308451 A1 EP0308451 A1 EP 0308451A1
Authority
EP
European Patent Office
Prior art keywords
aspartic acid
phenylmethyl
reaction
ester
moles
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Withdrawn
Application number
EP88902789A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ludwig Wilschowitz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Diamalt AG
Original Assignee
Diamalt AG
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Diamalt AG, Schering AG filed Critical Diamalt AG
Publication of EP0308451A1 publication Critical patent/EP0308451A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the invention relates to a process for the preparation of aspartic acid 4- (phenylmethyl) ester from aspartic acid and benzyl alcohol.
  • the object of the present invention was to develop a process which is less complex than the previously known processes and which makes it possible to prepare the 4- (phenylmethyl) aspartic acid ester in a higher yield.
  • This object has been achieved by the provision of a process which is characterized in that a reaction mixture is used which contains 10 to 40 moles of benzyl alcohol and 1 to 5 moles of acetyl chloride per mole of aspartic acid, that the reaction is carried out at a temperature of -10 ° C. to 50 ° C and that the process product is separated after the reaction by neutralization with organic bases.
  • the process according to the invention is suitable for the targeted esterification of the ⁇ -carboxyl groups of L-aspartic acid, D-aspartic acid and D, L-aspartic acid.
  • reaction mixture which contains 10 to 40 (preferably 15 to 30 and in particular 20 to 30) moles of benzyl alcohol and 1 to 5 (preferably 1 to 4 and in particular 1.5 to 3.0) moles per mole of aspartic acid Contains acetyl chloride.
  • the reaction is carried out at from -10 ° C. to + 50 ° C. It has proven expedient to carry out the reaction at a temperature of -10 ° to + 20 ° C (preferably -10 ° C to + 15 ° C and in particular at -5 ° C to + 10 ° C) while it is still there is exothermic.
  • the aspartic acid is expediently introduced in portions into the benzyl alcohol / acetyl chloride mixture with stirring. The time required for this is usually 1 to 4 hours.
  • the further reaction is expediently carried out at a temperature of from 10 ° C.
  • reaction time is normally 2 to 4 days.
  • the reaction product is precipitated by neutralizing the reaction mixture with organic bases (such as triethylamine, N-methylmorpholine and in particular pyridine).
  • organic bases such as triethylamine, N-methylmorpholine and in particular pyridine.
  • 1 mol of organic base is required per mole of acetyl chloride used.
  • the use of an excess of organic base is not critical, so that it is expedient to use 1 to 1.25 moles of organic base per mole of acetyl chloride used, and the neutralization is usually carried out at a temperature of from 10 to 40 ° C., preferably at room temperature
  • the neutralized mixture is expediently left to stand for a further 6 to 20 hours, if desired with cooling to 0 ° C. to 15 ° C.
  • the excess benzyl alcohol and aspartic acid can be easily recovered from the filtrate in the following manner:
  • the filtrate is extracted with 3 to 7 molar aqueous sodium hydroxide solution.
  • the organic phase is washed again, dried and the benzyl alcohol is obtained.
  • the aqueous phase is acidified to the isoelectric point of the aspartic acid by means of acids, the precipitated aspartic acid is filtered off and dried. In this way, 9 to 10% of the aspartic acid used as the starting substance is obtained.
  • the crude aspartic acid 4- (phenylmethyl) ester product produced by the process according to the invention can be purified, for example, by recrystallization from water - to which 0.05 to 0.5% pyridine has been added. If you do so, it is advisable to evaporate the resulting filtrate to dryness in vacuo, to dissolve the residue obtained in 3 to 7 molar aqueous sodium hydroxide solution, to acidify it to the isoelectric point of aspartic acid and to obtain about 15 to 20% of that used as the starting substance Aspartic acid back.
  • the 4- (phenylmethyl) aspartic acid represented by the process according to the invention is known to be a valuable intermediate product which is used, for example, for the synthesis of N-protected 4- (phenylmethyl) aspartic ester, such as 4- (N- (phenylmethoxycarbonyl) aspartic acid).
  • the aspartic acid 4- (phenylmethyl) ester can be converted into the N- (phenylmethoxy) carbonyl-aspartic acid 4- (phenylmethyl) ester, which is known to be a valuable intermediate, among other things, under the conditions of the application example which appear to be very expedient Synthesis of N- ⁇ -aspartyl-phenylalanine methyl ester (aspartame) is.
  • the crude product obtained is washed with methyl tert-butyl ether and dried in vacuo. Then it is dissolved in hot water to which a few drops of pyridine have been added, the solution is filtered hot and, after cooling, is kept at 5 ° C. for 12 hours.
  • the deposited crystals are filtered off, washed with water and dried in vacuo over calcium chloride.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP88902789A 1987-03-27 1988-03-17 Verfahren zur herstellung von asparaginsäure-4-(phenylmethyl) ester Withdrawn EP0308451A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3710192 1987-03-27
DE19873710192 DE3710192A1 (de) 1987-03-27 1987-03-27 Verfahren zur herstellung von asparaginsaeure-4-(phenylmethyl)-ester

Publications (1)

Publication Number Publication Date
EP0308451A1 true EP0308451A1 (de) 1989-03-29

Family

ID=6324171

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88902789A Withdrawn EP0308451A1 (de) 1987-03-27 1988-03-17 Verfahren zur herstellung von asparaginsäure-4-(phenylmethyl) ester

Country Status (6)

Country Link
US (1) US4888440A (ja)
EP (1) EP0308451A1 (ja)
JP (1) JPH01502826A (ja)
DE (1) DE3710192A1 (ja)
FI (1) FI885487A0 (ja)
WO (1) WO1988007520A1 (ja)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1303057C (zh) * 2003-12-24 2007-03-07 上海中远化工有限公司 L－天冬氨酸－β－苯甲酯的合成方法
GB2583146B (en) 2019-04-18 2021-08-11 Henkel IP & Holding GmbH Process for preparing cyanoacetates

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB969132A (en) * 1961-12-02 1964-09-09 Teikoku Jinzo Kenshi Kk Process for producing optically active or inactive ª†-methyl glutamate hydrochloride
DE1493991A1 (de) * 1963-11-12 1969-10-23 Merck & Co Inc Verfahren zur Herstellung von Glutaminsaeure-gammamethylester-hydrochlorid
US4026915A (en) * 1975-08-27 1977-05-31 S. C. Johnson & Son, Inc. Di-mixed alky aspartate salts
US4394308A (en) * 1980-05-27 1983-07-19 Chimicasa Gmbh Method of producing α-L-aspartyl-L-phenylalanine methylesters
FR2558471B1 (fr) * 1984-01-19 1987-11-20 Isochem Sa Procede de preparation d'aspartyl peptides, et nouveaux intermediaires de synthese
US4622413A (en) * 1984-08-31 1986-11-11 Ppg Industries, Inc. Method for preparing amino acid ester hydrohalides
DE3520808A1 (de) * 1985-06-11 1986-12-11 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von 4-benzyl-aspartat

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8807520A1 *

Also Published As

Publication number Publication date
FI885487A (fi) 1988-11-25
DE3710192A1 (de) 1988-10-13
JPH01502826A (ja) 1989-09-28
US4888440A (en) 1989-12-19
WO1988007520A1 (en) 1988-10-06
FI885487A0 (fi) 1988-11-25

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