EP1611084A1 - Verfahren zur herstellung von n-alkoxallylalaninaten - Google Patents

Verfahren zur herstellung von n-alkoxallylalaninaten

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Publication number
EP1611084A1
EP1611084A1 EP04722826A EP04722826A EP1611084A1 EP 1611084 A1 EP1611084 A1 EP 1611084A1 EP 04722826 A EP04722826 A EP 04722826A EP 04722826 A EP04722826 A EP 04722826A EP 1611084 A1 EP1611084 A1 EP 1611084A1
Authority
EP
European Patent Office
Prior art keywords
reaction
alanine
process according
base
alkyl
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Withdrawn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
EP04722826A
Other languages
English (en)
French (fr)
Inventor
Andrew George Gum
Jocelyn Fischesser
Ralph HÄRTER
Reinhard Karge
Vincent John Jephcote
Werner Bonrath
Jiaan Gan
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.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
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 DSM IP Assets BV filed Critical DSM IP Assets BV
Priority to EP04722826A priority Critical patent/EP1611084A1/de
Publication of EP1611084A1 publication Critical patent/EP1611084A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines

Definitions

  • the present invention relates to a process useful in the multistep process for the manufacture of vitamin B 6 . More particularly, the present invention relates to a process for the manufacture of alkyl N-alkoxalyl-alaninates, i.e. compounds which may be represented structurally as alkylO-CO-CO-NH-CH(CH 3 )-CO-Oalkyl and which are useful intermediates in the multistep process. Furthermore, the invention also relates to novel intermediates generated in the process of the present invention, i.e. certain N-alkoxalyl- alanines, being monoesters corresponding to the aforementioned alaninates and which may be represented structurally as alkylO-CO-CO-NH-CH(CH 3 )-COOH.
  • a further known approach involves the synthesis of alkyl N-alkoxalyl-alaninates directly from alanine as the free acid.
  • French Patent Publication (Application) No. 2,010,601 Japanese Patent No. 46.002,969 (1971) and Bull. Chem. Soc. Japan 45, 1917- 1918 (1972) describe the reaction of alanine itself with oxalic acid in the presence of an alkanol, particularly methanol or ethanol, to produce the appropriate alkyl N-alkoxalyl- alaninate.
  • the alkyl (ethyl) N-formyl alaninate was produced as a by-product in up to 10% yield under these conditions.
  • Japan reference disclose a modified approach which minimizes the formation of said by-product to trace levels by reacting alanine with oxalic acid and both alkanol (ethanol) and dialkyl (diethyl) oxalate.
  • a still further approach, using acidic conditions, is disclosed in the Chinese Patent Publication No. 86101512A and in Zhongguo Yiyao Gongye Zazhi 25(9), 385-389 (1994) of H. Zhou et al.
  • alanine is reacted with oxalic acid in an aqueous hydrogen chloride- ethanol solvent mixture with azeotropic removal of the formed water using benzene to afford ethyl N-ethoxalyl-alaninate, and addition of diethyl oxalate and anhydrous sodium carbonate to the crude ester product.
  • the required multistep work-up is complicated and thus a disadvantage in this particular approach.
  • German Offenlegungsschrift (DOS) No. 4,015,255 describes inter alia mono- and diesters of N-oxalyl-alanine as medicaments, refers to French Patent Publication No. 2,010,601 (see above) for the synthesis of such mono-and diesters and exemplifies the preparation of the diesters generally by reacting "alanine ester hydrochloride” with “oxalic ester chloride” in methylene chloride as the solvent in the presence of a mixture of triethylamine and N,N-dimethylaminopyridine as the base.
  • N-alkoxalyl-alanines are claimed as medicaments, and the synthesis of methyl N-methoxalyl-alanine, named as "(N-oxalyl)-L- alanine dimethyl ester", is actually exemplified in the pertinent Example 1, there is no specific disclosure/ example of the synthesis of N-alkoxalyl-alanines such as N-ethoxalyl- alanine.
  • the process of the present invention enables the manufacture of alkyl N-alkoxalyl- alaninates from alanine itself in high yield while avoiding the drawbacks inherent to known processes.
  • the process of the present invention avoids the generation of large amounts of inorganic salt waste normally encountered in the known acid catalyzed processes for the manufacture of these alaninates.
  • the present invention provides a process for the manufacture of alkyl N-alkoxalyl-alaninates which comprises reacting alanine with a dialkyl, preferably a di(lower alkyl), oxalate under substantially non-acidic conditions.
  • alanine as used herein comprises racemic (D,L)-alanine as well as the individual enantiomers L- and D-alanine and mixtures of both enantiomers in any ratio.
  • the di(lower alkyl) oxalate features in particular C 1-8 -alkyl groups, preferably - - alkyl groups, which when containing 3 or more carbon atoms maybe straight chain or branched.
  • These dialkyl oxalates are in many cases known compounds which are commercially available. Any novel ones may be produced by methods analogous to the known methods, e.g. by conventional esterification of oxalic acid with the appropriate alkanol using an acid catalyst, e.g. sulphuric acid.
  • That the reaction is carried out under substantially non-acidic conditions means that apart from alanine [H 2 N-CH(CH 3 )-COOH] itself no further acid is present in the reaction mixture, so that no acid apart from alanine is deliberately added or otherwise included in the reaction mixture.
  • a base may be included in the reaction mixture.
  • the reaction is carried out without the presence of an added base in the reaction mixture.
  • said base is suitably an organic base, in particularly a trialkylamine; a cyclic tertiary amine (including a base of the type heteroaromatic compound), such as pyridine, quinoline (both also examples of heteroaromatic compounds), N-methyl-pyrrolidine or N-methyl-piperidine; or a cyclic tertiary amide, such as N-methyl-pyrrolidone; or any mixture of two or more of such bases.
  • the term "alkyl” as used in trialkylamine refers to straight chain or branched alkyl groups containing 1-8, preferably 1-4, carbon atoms. The most preferred types of bases, i.e.
  • alkyl N-alkoxalyl- alaninates those which promote the best yields of alkyl N-alkoxalyl- alaninates, are trialkylamines, triethylamine and tripropylamine being particularly preferred.
  • trialkylamines triethylamine and tripropylamine being particularly preferred.
  • cyclic tertiary amines N-methyl-pyrrolidine and N-methyl-piperidine are preferred.
  • a low boiling base i.e. a base having a boiling point at atmospheric pressure which is substantially below about 135°C, is preferably used.
  • the latter reactant is preferably in excess molar amount. More particularly, the molar ratio of alanine to dialkyl oxalate is suitably from about 1 : 2 to about 1 : 10, preferably from about 1 : 3 to about 1 : 6, and most preferably about 1 : 4.
  • the molar ratio of base to the reactant which is used in the lesser molar amount, usually, as indicated above, the alanine is suitably from about 0.25 : 1 to about 2 : 1, preferably from about 1 : 1 to about 1.5 : 1.
  • the amount of base used is suitably from about 25 mol% to about 200 mol%, preferably from about 100 mol% to about 150 mol%, of the amount of that reactant.
  • the temperatures at which the process of the present invention is suitably carried out depend, amongst other factors, on whether an added base is present in the reaction mixture or not, and are generally in a higher range when no base is present. In the latter case the reaction is suitably carried out at a temperature from about 120°C to about 200°C, preferably from about 135°C to about 160°C. In the other case, i.e. when a base is present, the reaction is suitably carried out at a temperature from about 60°C to about 160°C, preferably from about 80°C to about 120°C, and most preferably from about 90°C to about 110°C.
  • the reaction of the alanine with the dialkyl oxalate central to the process of the present invention apparently proceeds by a mechanism which involves an initial formation of the appropriate N-alkoxalyl-alanine of the formula alkylO-CO-CO-NH-CH(CH3)- COOH with release of the appropriate alkanol, followed by the involvement of the generated alkanol in the esterification of said N-alkoxalyl-alanine to the desired alkyl N- alkoxalyl-alaninate of the formula alkylO-CO-CO-NH-CH(CH 3 )-CO-Oalkyl. Accordingly, it is appropriate either to perform the reaction under temperature and pressure conditions which ensure minimal loss of the pertinent generated alkanol, or to perform the reaction with added alkanol.
  • the reaction is carried out in such a way as to ensure that as much as possible of the alkanol produced during the reaction remains in the reaction system either by carrying out the reaction under atmospheric pressure with cooling of the vapour phase of the reaction mixture to promote the return of the alkanol into the reaction system, or by carrying out the reaction at elevated pressure in a closed system, e.g. in an autoclave. In both cases it is clearly unnecessary to carry out of the reaction in the presence of added alkanol.
  • the reaction is carried out in the presence of added alkanol, preferably alkanol featuring the alkyl group corresponding to that of the employed dialkyl oxalate.
  • alkanol preferably alkanol featuring the alkyl group corresponding to that of the employed dialkyl oxalate.
  • the reaction can be performed at atmospheric pressure and a certain loss of alkanol from the reaction system can be tolerated.
  • the molar ratio of alkanol to the reactant which is used in the lesser molar amount, usually, as indicated above, the alanine is suitably from about 1 : 1 to about 10 : 1, preferably from about 3 : 1 to about 6 : 1. If the reaction is carried out under atmospheric pressure in the presence of an organic base the reaction is suitably performed by initially heating the reaction mixture for about 4 to about 12 hours, preferably for about 6 to about 10 hours, to a temperature below the boiling point of the organic base.
  • the temperature during heating is then suitably from about 60°C to about 160°C, preferably from about 80°C to about 120°C, most preferably from about 90°C to about 110°C, and furthermore a low boiling base, i.e. a base having a boiling point substantially below about 135°C under atmospheric pressure, is preferably used.
  • a low boiling base i.e. a base having a boiling point substantially below about 135°C under atmospheric pressure
  • This final heating step for the formation of the desired diester product is usually completed in about 4 to 12 hours, preferably about 6 to 10 hours.
  • N-alkoxalyl-alanine of the formula alkylO-CO-CO-NH-CH(CH 3 )-COOH, e.g. N-ethoxalyl-alanine in the case where the alkyl group is ethyl.
  • the isolated N-alkoxalyl-alanines can be readily so converted by heating in the presence of a dialkyl oxalate such as diethyl oxalate, and the produced alkyl N-alkoxalyl-alaninate can subsequently be isolated from the reaction mixture.
  • a dialkyl oxalate such as diethyl oxalate
  • the process of the present invention can be carried out with or without isolation of the N-alkoxalyl-alanine intermediate, and if said isolation is desired the reaction conditions can be adjusted appropriately to promote an optimal generation of the intermediate for subsequent isolation.
  • the N- alkoxalyl-alanine is generated as the major product after an initial heating period, and so these conditions may suitably be used to produce and isolate the novel N-alkoxalyl-alanine in a major quantity.
  • the process is carried out without a base and with the removal of the alkanol and water generated during the initial heating period, thereby forming the desired N-alkoxalyl-alanine as the major product.
  • Said product e.g.
  • N-ethoxalyl-alanine can then be isolated from the mixture in the reaction vessel by column chromatography over silica gel, for example, or more preferably by crystallization.
  • a so-obtained alkyl N-alkoxyoxalyl alaninate can be converted by known methods into vitamin B 6 , e.g. by cyclization to form the appropriate 4-methyl-5-alkoxy-2-
  • alkoxycarbonyl-oxazole which on treatment with alkali and subsequently acid can be converted into the appropriate 4-methyl-5-alkoxy-oxazole.
  • the latter on reaction with a 2- unsubstituted, 2-monosubstituted or 2,2-disubstituted 4,7-dihydro-(l,3)-dioxepin such as 2-isopropyl-4,7-dihydro-(l,3)-dioxepin can be further converted into vitamin B 6 , as disclosed for example in French Patent No. 1,533,817, U. S. Patents Nos. 3,250,778, 3,296,275 and 3,822,274, and Indian Patent No. 175,617.
  • GC gas chromatography
  • the reaction mixture contained EOAE in 1.0 w/w % amount and EOA in 3.0 w/w % amount as the major product.
  • the overall yield of EOAE + EOA based on the employed amount of alanine was 26.5%, and the corrected yield of the reaction based on the recovery of the unreacted alanine was 95.6%.
  • Alanine was completely dissolved after about 6 hours reaction time. During the course of the reaction, the internal temperature dropped from 145°C to 115°C. After a further 26 hours the dephlegmator was heated to 70°C and ethanol and other low boiling constituents were distilled off from the reaction mixture over 30 minutes at an internal temperature of 116°C and a reduced pressure from 0.9 bar to 0.4 bar ((90 kPa to 40 kPa) into a prefraction collecting flask. The collecting flask was changed and the dephlegmator heated to 110°C.
  • the unreacted excess diethyl oxalate was distilled off from the reaction products over a period of 2 hours at an internal temperature from 116°C to 154°C and a reduced pressure from 400 mbar to 40 mbar (40 kPa to 4 kPa).
  • the resulting mixture containing the crude desired product was cooled to room temperature, analyzed by GC, and found to contain 77.0 w/w % of EOAE and 5.5 w/w % of EOA.
  • the overall yield of EOAE + EOA based on the employed amount of alanine was 75.0%.
  • the triethylamine was first removed by rotary evaporation at 20 mbar (2 kPa) and 60°C, and then the excess diethyl oxalate was removed under high vacuum rotary evaporation at 0.01 mbar (1 Pa) and 70°C.
  • the remaining crude product (14.5 g), a yellowish gold oil, was analysed by GC. EOA was found as the major product in 80.2 w/w % amount, corresponding to a yield based on the employed amount of alanine of 62%.
  • the crude organic products including EOAE and EOA, were contained in the lower phase and were separated from the trioctylamine using a separating funnel.
  • GC analysis of the crude product after removal of ethanol and water indicated that diethyl oxalate remained in the product mixture.
  • the GC analysis indicated a 12.43 w/w % amount of EOAE and a 8.97 w/w % amount of EOA.
  • the ethanol and further low-boiling constituents were continuously removed from the reaction mixture in a stream of argon over the dephlegmator into a prefraction collecting flask.
  • the reaction mixture was heated for a further 8 hours 10 minutes at the same temperature, during which period the alanine became completely dissolved.
  • the dephlegmator was heated to 110°C (mantle temperature 110°C).
  • the unreacted excess diethyl oxalate was distilled off from the reaction products at an initial internal temperature of 119°C/mantle temperature of 140°C/ reduced pressure of 55 mbar (5.5 kPa) and a final internal temperature of 133°C/mantle temperature of 140°C/reduced pressure of 20 mbar (2 kPa) via the dephlegmator within about 35 minutes.
  • the resulting mixture containing the crude desired product was cooled to room temperature (becoming viscous) and analyzed by GC, and found to contain 63.3 w/w % of EOA and 15.8 w/w % of EOAE (the yield based on alanine totalled 79.1%).
  • a double-jacketed, 4-necked 500 ml glass reactor equipped with a circulation thermostatic temperature control, an overhead stirrer with propeller, a thermometer /controller, a dephlegmator (partial condensation head), a reflux cooler, a vacuum system, cold traps and argon degassing means were introduced at room temperature under an argon atmosphere 160 g of a reaction mixture of EOA and EOAE dissolved in 200 ml of demineralized water. The aqueous solution was extracted three times with a total of 300 ml of toluene at room temperature, and the combined aqueous phases stirred in the reactor at 18°C for about 16 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP04722826A 2003-04-04 2004-03-24 Verfahren zur herstellung von n-alkoxallylalaninaten Withdrawn EP1611084A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04722826A EP1611084A1 (de) 2003-04-04 2004-03-24 Verfahren zur herstellung von n-alkoxallylalaninaten

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP03007749 2003-04-04
EP04722826A EP1611084A1 (de) 2003-04-04 2004-03-24 Verfahren zur herstellung von n-alkoxallylalaninaten
PCT/EP2004/003109 WO2004087640A1 (en) 2003-04-04 2004-03-24 Process for the manufacture of n-alkoxalyl-alaninates

Publications (1)

Publication Number Publication Date
EP1611084A1 true EP1611084A1 (de) 2006-01-04

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EP (1) EP1611084A1 (de)
CN (1) CN100579955C (de)
WO (1) WO2004087640A1 (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20070225A2 (en) * 2007-05-15 2008-11-30 Institut Ruđer Bošković Colorimetric sensors for detection of fluoride anion in solution and gel
WO2009059188A1 (en) 2007-11-02 2009-05-07 Emisphere Technologies, Inc. Method of treating vitamin b12 deficiency
CN101830823A (zh) * 2010-05-12 2010-09-15 浙江工业大学 一种n-丁氧草酰氨基酸丁酯的化学合成方法
CN101830821B (zh) * 2010-05-12 2013-09-11 浙江工业大学 一种n-烷氧草酰丙氨酸酯的化学合成方法
CN109293525B (zh) * 2018-09-26 2021-04-20 山东新和成精化科技有限公司 一种微通道反应器及利用该微通道反应器制备n-烷氧基草酰丙氨酸酯的方法
CN114195666B (zh) * 2021-11-29 2024-05-28 湖北文理学院 N-乙氧草酰基-l-丙氨酸乙酯的制备方法
CN114702405A (zh) * 2022-04-25 2022-07-05 浙江花园营养科技有限公司 一种n-乙氧草酰丙氨酸乙酯的制备方法
CN117486748B (zh) * 2023-11-07 2025-12-16 湖北惠生药业有限公司 维生素b6中间体n-乙氧草酰-l-丙氨酸乙酯的生产工艺
CN119613282B (zh) * 2024-12-09 2026-02-27 万华化学集团股份有限公司 一种制备n-乙氧基草酰丙氨酸酯的方法

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
US3646061A (en) * 1968-06-10 1972-02-29 Ajinomoto Kk Method of preparing n-alkoxalyl and n-formyl derivatives of alpha-amino acid esters
US20040146964A1 (en) * 2001-03-21 2004-07-29 Maxwell Patrick Henry Assays, methods and means

Non-Patent Citations (1)

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Title
See references of WO2004087640A1 *

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Publication number Publication date
WO2004087640A1 (en) 2004-10-14
CN100579955C (zh) 2010-01-13
CN1802346A (zh) 2006-07-12

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