WO2003078381A1 - Procede de preparation d'acides trans-4-aminocyclohexane carboxyliques - Google Patents

Procede de preparation d'acides trans-4-aminocyclohexane carboxyliques Download PDF

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Publication number
WO2003078381A1
WO2003078381A1 PCT/JP2003/003141 JP0303141W WO03078381A1 WO 2003078381 A1 WO2003078381 A1 WO 2003078381A1 JP 0303141 W JP0303141 W JP 0303141W WO 03078381 A1 WO03078381 A1 WO 03078381A1
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Prior art keywords
trans
base
cis
salt
treatment
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PCT/JP2003/003141
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English (en)
Japanese (ja)
Inventor
Masataka Hikota
Yuichi Koga
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Tanabe Seiyaku Co., Ltd.
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Publication date
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Priority to JP2003576390A priority Critical patent/JP4202269B2/ja
Priority to AU2003221404A priority patent/AU2003221404A1/en
Publication of WO2003078381A1 publication Critical patent/WO2003078381A1/fr

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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
    • C07C227/16—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 not involving the amino or carboxyl groups
    • 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
    • C07B2200/09—Geometrical isomers

Definitions

  • the present invention relates to a novel process for producing trans-4-aminoaminohexane carboxylic acids useful as a raw material compound of a medicament, etc., from a cis-form or a mixture of cis-form and trans-form of 4-aminocyclohexanecarboxylic acid.
  • the present invention relates to a novel method for obtaining a high-purity trans form.
  • trans-4-Aminocyclohexancarboxylic acid and its amino-protected derivative are useful compounds as raw materials for pharmaceuticals and agricultural chemicals and as intermediates, for example, dipeptides / reptidases used as therapeutic drugs for diabetes and the like. It is useful as a starting compound for IV (DPP IV) inhibitors (WO 2002-30891).
  • 4-aminocyclohexanecarboxylic acid (mixture of cis-form and trans-form) can be obtained inexpensively and in large quantities by catalytic reduction of 4-aminobenzoic acid.
  • a method for obtaining a trans form by a fractional recrystallization method is known [Journal of Medicinal Chemistry, Vol. 36, Nos. 1, 100-1103 (1993)].
  • this method has a problem that the yield of the obtained trans form is very low.
  • a methyl ester of 4-isopropyl-hexane carboxylic acid is obtained by methyl esterification. Heating in the presence of sodium hydride (Patent Publication No. 0196222), and a method of heating hexanecarboxylic acid in the mouth of 4-isopropinoleic acid in the presence of sodium hydroxide.
  • Japanese Patent Application Laid-Open No. 10-237015 discloses a cyclohexanecarboxylic acid having an alkyl group, a fluorine-substituted alkyl group or a carboxyl group at the 4-position or a reactive derivative thereof in the presence of potassium hydroxide. A method of isomerizing by heating calo is described. However, it has been found that when this method is applied to 4-aminocyclohexanecarboxylic acid, there are problems such as a long reaction time.
  • An object of the present invention is to provide an efficient and excellent method for producing trans-4-aminocyclohexanecarboxylic acids. More specifically, it is an object of the present invention to provide a method for efficiently obtaining a highly pure trans form from a cis form or a mixture of a cis form and a trans form of 4-aminocyclohexanecarboxylic acid or a reactive derivative thereof.
  • the present inventors have conducted intensive studies to solve the problems, and as a result, using inexpensive sodium hydroxide or potassium alkoxide, the cis-form or cis-form of 4-aminocyclohexanecarboxylic acid. It has been found that a mixture of trans forms can be isomerized very efficiently.
  • the present invention provides a cis-form or a cis-form-trans-form mixture of 4-aminocyclohexanecarboxylic acid or a reactive derivative thereof, selected from the group consisting of sodium hydroxide and potassium alkoxide.
  • Trans-4-aminocyclohexanecarboxylic acid or a salt thereof, or trans-4-aminocyclohexanecarboxylic acid characterized by treating with a base and, if desired, further adding a protecting group to the amino group of the product. And a method for producing an amino-protected derivative or a salt thereof.
  • the reactive derivative of 4-aminocyclohexanecarboxylic acid is a carboxylic acid whose protective group is eliminated in the presence of sodium hydroxide or potassium alkoxide used in the isomerization reaction of the present invention and which can be converted into a carboxylic acid. Refers to a protected derivative.
  • the reactive derivative of 4-aminoaminohexane carboxylic acid include, for example, esters of 4-aminohexanecarboxylic acid (e.g., lower alkyl esters such as methinole ester and ethyl ester, benzyl esters, and the like).
  • Optionally substituted aryl lower alkenyl esters such as benzyl ester benzoyl ester, benzhydrinole ester, trityl ester enole, and anthranyl methyl ester.
  • sodium hydroxide or potassium hydroxide is used as a base.
  • potassium alkoxide include potassium tert-butoxide, potassium methoxide, potassium methoxide and the like.
  • sodium hydroxide and potassium tert-butoxide are preferable, and sodium hydroxide is particularly preferable.
  • the amount of sodium hydroxide or potassium hydroxide used is 2 to 10 equivalents, more preferably 2 to 3 equivalents, based on 4-aminocyclohexancarboxylic acid or a reactive derivative thereof. And most preferably 2 equivalents.
  • the sodium salt or potassium salt of trans-4-aminoaminohexane carboxylic acid obtained by the isomerization reaction of the present invention may be free trans-4-aminocyclohexanecarboxylic acid or other salt (for example, lithium salt, magnesium salt, calcium salt, barium salt, zinc salt, aluminum salt and the like can be converted. Such a conversion can be performed according to a one-way method. That is, according to the present invention, trans-4-aminocyclohexane sulfonic acid or a salt thereof (sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, norium salt, zinc salt, aluminum salt) Salt etc.) can be produced.
  • This heterologous reaction preferably proceeds at 100 to 250 ° C, particularly at 150 to 240 ° C.
  • the reaction proceeds more favorably at 170 to 240 ° C. when sodium hydroxide is used as the base, and at 150 to 220 ° C. when potassium alkoxide is used.
  • the present isomerization reaction can be carried out in a solvent.
  • a solvent at least at a temperature at which the present isomerization reaction is carried out, at least a part of the formed trans-4-aminoaminohexanecarboxylic acid salt is solidified. It is desirable to use a solvent which can be present and in which the salt of the cis-4-aminocyclohexancarboxylic acid to be formed does not solidify but exists in a dissolved or molten state.
  • Such solvents include xylene (o-xylene, m-xylene, p-xylene, and mixtures thereof), mesitylene, cymene (o-cymene, m-cymene, p-xylene Hydrocarbons having 8 or more carbon atoms such as decaline (trans-decalin, cis-decalin, and mixtures thereof), naphthalene, decane, pendecane, dodecane, dodecene, bifunyl, etc.
  • C6 or more ethers such as diethyleneglycorenoretheneoleatenore, anisol, diethyleneglycorelejetinoleatenole, triethyleneglycoldimethylether, diphenylether, etc., or C8 or more carbon atoms such as triptyluamine or triphenyleamine And amines and mixtures thereof.
  • hydrocarbons having 8 or more carbon atoms, ethers having 6 or more carbon atoms, and mixtures thereof are more preferable, and xylene (o-xylene, m-xylene, p-xylene, and mixtures thereof) , Mesitylene, cymene (o-cymene, m-cymene, p-cymene, and mixtures thereof), decalin (trans-decalin, cis-decalin, and mixtures thereof), naphthalene, decane, pendecane, dodecane, More preferred are bihue-nore, diethyleneglycone resin methinole ethere, diethyleneglycol cholesterol, dipheneylenothene, and mixtures thereof.
  • solvents When sodium hydroxide is used as the base, the solvent is stable under the reaction conditions, sodium salt of trans-4-aminocyclohexanecarboxylic acid can be present as a solid, and cis-4-aminocyclohexane Solvents in which the sodium salt of xan carboxylic acid can be present in a dissolved or molten state without solidification are preferred, and such solvents include xylene (o-xylene, m-xylene, p-xylene, and mixtures thereof).
  • Examples thereof include amines having 8 or more carbon atoms, such as tributylamine and trifluoramine, and mixtures thereof. Further, those having a boiling point of 180 ° C. or more are more preferable, and such solvents include decalin (trans-decalin, cis-decalin, and mixtures thereof), naphthalene, pendecane, dodecane, dodecene, and bidecane. Examples include phenole, diethyleneglycoreleetinoleatenole, triethyleneglycorelate methinoleatenole, dipheneoleatenole, tributinoleamine, trifenenoleamine, and mixtures thereof.
  • decalin trans-decalin, cis-decalin, and mixtures thereof
  • naphthalene pendecane
  • dodecane bipheninole
  • diethyleneglycosolejetinole ethere triethyleneglyconoresinetinoetelle
  • Dipheninoleatenole and a mixture thereof
  • decalin such as trans-decalin, cis-decalin, and a mixture thereof
  • dodecane diethylene glycol dimethyl ether, and the like Mixtures are particularly more preferred.
  • a solvent in the case of using a potassium alkoxide as a base the solvent is stable under the reaction conditions, and a solid salt of trans-4-aminocyclohexacarboxylic acid hexacarboxylic acid can be present.
  • a solvent which can exist in a dissolved or molten state without the solidification of a hexaaminocarboxylic acid hexacarboxylic acid potassium salt is preferable, and such a solvent is xylene (o-xylene, m-xylene, p-xylene).
  • a solvent examples include mesitylene, cymene (o-cymene, m-cymene,; -cymene, and a mixture thereof), decalin (trans —Decalin, cis-decalin, and mixtures thereof), naphthalene, decane, pendecane, Dodecane, dodecene, biphenyl, diethylene glycol dimethyl ether, dimethylene glycolone resin, methylene glycolone resin, diphenyl ether, triptinoleamine, triphenylamine, and mixtures thereof. No.
  • mesitylene, cymene o-cymene, m-cymene, p-cymene, and mixtures thereof
  • decalin trans-decalin, cis-decalin, and mixtures thereof
  • naphthalene decane, ⁇ Decane
  • dodecane bifeninole
  • acetylene glycolone resin / loethenole dimethylene glycol ethyleneol ether, diphenezoleether, and mixtures thereof
  • mesitylene, cymene o -Cymene, m-cymene, p-cymene, and mixtures thereof
  • decalin trans-decalin, cis-decalin, and mixtures thereof
  • dodecane diethyleneglycol-glycerol ester, and mixtures thereof are more particularly preferred.
  • This isomerization reaction suitably proceeds under normal pressure or under pressure, but is preferably performed under normal pressure to 3 atm, and more preferably under normal pressure.
  • the completion of the reaction can be monitored by a commonly used method, for example, analysis by high performance liquid chromatography (HPLC), thin layer chromatography (TLC), etc., usually for 6 to 30 hours.
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the reaction is preferably completed in 6 to 24 hours.
  • Amino group-protected derivatives of trans-4-monoaminohexacarboxylic acid have better crystallinity than cis isomers. By utilizing this property, a higher purity trans form can be efficiently isolated and obtained.
  • the obtained amino group-protected derivative is crystallized and separated and washed by a conventional method, and if necessary, recrystallized and separated and washed by a conventional method to further increase the purity of the trans form. it can.
  • a sodium salt or potassium salt of trans-4-aminocyclohexancarboxylic acid produced by the isomerization reaction may be provided, or these produced by the isomerization reaction may be subjected to a conventional method.
  • trans-4-aminohexan carboxylic acid produced by the isomerization reaction or free trans-4-amino hexane carboxylic acid or other salt obtained by converting these is used.
  • the solution may be subjected to an amino group protection reaction, but without isolation, a solution containing these may be directly subjected to an amino group protection reaction.
  • Examples of the protecting group for an amino group include, for example, an optionally substituted lower alkoxy group, a lower alkanol group, an aryloyl group, and the like. Specific examples include a benzyloxy group and a 4-methoxybenzyloxy group. Carboxyl group, 9-fluorenylmethoxycarboxyl group, tert-butoxycarbol group, 2,2,2-trichloroethyloxycarbonyl group, formyl group, acetyl group, propioyl group, butyroyl group And a benzoyl group. Among these, a lower alkoxycarbol group which may be substituted may be mentioned, and a benzyloxycarbonyl group and a tert-butoxycarbonyl group are particularly preferred.
  • trans-4- (benzyloxycarbonylamino) cyclo is used as an amino-protected derivative of trans-4-aminohexanoic acid. Mouth hexane carboxylic acid can be produced.
  • trans-4- (tert-butoxycarpoelamino is used as an amino-protected derivative of trans-4-aminocyclohexanecarboxylic acid.
  • Cyclohexanecarboxylic acid can be produced.
  • the amino group protection reaction in the present invention can be carried out by a conventional method.
  • the reaction of adding a benzyloxycarbonyl group to an amino group can be carried out by reacting with a benzyloxycarbonyl halide in a solvent in the presence of a base.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, methanol, and ethanol.
  • the base include sodium hydroxide, hydroxylated lime, and carbonated lime.
  • the benzyloxycarbonyl halide a benzyloxycarbyl chloride is preferable.
  • the present reaction suitably proceeds at a temperature of from 140 ° C to 100 ° C, particularly from 0 ° C to room temperature.
  • the reaction of adding a tert-butoxycarbonyl group to an amino group can be carried out by reacting with di-tert-butyl dicarbonate in a solvent in the presence of a base.
  • the solvent may be any solvent that does not adversely affect the reaction, and examples include water, methanol, and ethanol.
  • the base include sodium hydroxide, potassium hydroxide and the like.
  • the present reaction suitably proceeds at a temperature of from 20 ° C to 40 ° C, particularly from 0 ° C to room temperature.
  • the amino group-protected derivative of trans-4-aminocyclohexancarboxylic acid obtained in the present invention is subjected to crystallization and separation / washing, and if necessary, recrystallization and separation / washing. By doing so, it can be isolated and purified. Washing of the crystals is preferably performed with a solvent such as diisopropyl ether, hexane, ether, and ethyl acetate, and particularly preferably with diisopropyl ether.
  • the isolation / purification operation by crystallization and recrystallization can be performed by a conventional method, but is particularly preferably performed by a trituration operation.
  • the amino-4-protected derivative of trans-4-aminocyclohexancarboxylic acid obtained in the present invention may optionally contain a salt (for example, sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, norium salt). Salt, zinc salt, aluminum salt, etc.). Such a conversion can be performed according to a conventional method.
  • a salt for example, sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, norium salt. Salt, zinc salt, aluminum salt, etc.
  • amino-protected derivatives of trans-4-aminocyclohexanecarboxylic acid or salts thereof sodium salt, potassium salt, lithium salt, magnesium salt, potassium salt, barium salt, zinc salt, Aluminum-salt, etc.
  • commercially available cis form or a mixture of cis form and trans form of 4-aminocyclohexanecarboxylic acid or a reactive derivative thereof can be used.
  • a mixture of cis- and trans-forms of 4-aminocyclohexanecarboxylic acid is described, for example, in the literature [Organic Syntheses Collective Volume Vol.
  • trans-4-aminocyclohexancarboxylic acid or its salt or the amino group-protected derivative of trans-4-aminocyclohexancarboxylic acid or its salt produced by the method of the present invention can be used as a starting compound.
  • R is the formula
  • trans-4-aminoaminohexanoic acid sulfonic acid or a salt thereof produced by the method of the present invention or an amino-protected derivative of trans-4-aminocyclohexanecarboxylic acid or a salt thereof is represented by the general formula [ 2)
  • the ratio of the trans-isomer to the cis-isomer of the obtained 4-aminocyclohexanecanoleponic acid was determined by HP LC analysis under the following measurement conditions after derivatization to 4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid. Go and decide.
  • Cis body retention time 13.8 minutes.
  • the ratio of the obtained trans- and cis-forms of 4- (tert-butoxycarbonylamino) cyclohexanecarbonic acid was determined by HP LC analysis under the following measurement conditions.
  • Cis body retention time 15.4 minutes.
  • the ratio between the trans-form and the cis-form of the obtained 41- (pentinoleoxycanoleponinoleamino) cyclohexanecarbonic acid was determined by HPLC analysis under the measurement conditions described in Example 1 above.
  • high-purity trans-4-aminoaminohexanecarboxylic acids can be easily and efficiently produced in a short time.
  • the trans-isomer can be obtained with higher purity by performing the isomerization reaction in a solid-liquid heterogeneous system. Further, in the present invention, a trans form can be obtained with higher purity by adding a protecting group to the amino group of the product after the isomerization reaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé permettant de préparer des acides trans-4-aminocyclohéxane, des sels ou des dérivés aminés protégés de ceux-ci ou des sels de ces dérivés. Ledit procédé est caractérisé en ce qu'on traite un isomère cis d'acide 4-aminocyclohéxane carboxylique ou un dérivé réactif de celui-ci ou un mélange d'isomères cis et trans de l'acide ou le dérivé réactif de celui-ci à l'aide d'une base sélectionnée dans le groupe constitué par un hydroxyde de sodium et des alcoxydes de potassium et, le cas échéant, protégeant le groupe aminé du composé obtenu.
PCT/JP2003/003141 2002-03-18 2003-03-17 Procede de preparation d'acides trans-4-aminocyclohexane carboxyliques WO2003078381A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2003576390A JP4202269B2 (ja) 2002-03-18 2003-03-17 ｔｒａｎｓ−４−アミノシクロヘキサンカルボン酸類の製法
AU2003221404A AU2003221404A1 (en) 2002-03-18 2003-03-17 PROCESS FOR PREPARATION OF trans-4-AMINOCYCLOHEXANE- CARBOXYLIC ACIDS

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JP2002073454 2002-03-18
JP2002-073454 2002-03-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017090656A1 (fr) * 2015-11-27 2017-06-01 住友化学株式会社 Procédé de production d'un acide trans-cyclohexanecarboxylique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085296B (zh) * 2015-09-09 2017-08-08 常州齐晖药业有限公司 一种制备反式‑4‑(叔丁氧羰基氨基)环己甲酸中间体异构化的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4945040A (fr) * 1972-09-08 1974-04-27
JPS4962446A (fr) * 1972-10-19 1974-06-17
JPS57122062A (en) * 1981-01-22 1982-07-29 Nippon Chemiphar Co Ltd Novel trans-4-guanidinocyclohexanecarboxylic acid derivative and its preparation
EP0814073A1 (fr) * 1996-06-18 1997-12-29 KATAYAMA SEIYAKUSYO CO. Ltd. Epimérisation d'acides cyclohexane carboxyliques 2- ou 4-substitués
JPH10298144A (ja) * 1997-04-23 1998-11-10 T Hasegawa Co Ltd トランス−４−アルキルシクロヘキサンカルボン酸エステル類の製法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4945040A (fr) * 1972-09-08 1974-04-27
JPS4962446A (fr) * 1972-10-19 1974-06-17
JPS57122062A (en) * 1981-01-22 1982-07-29 Nippon Chemiphar Co Ltd Novel trans-4-guanidinocyclohexanecarboxylic acid derivative and its preparation
EP0814073A1 (fr) * 1996-06-18 1997-12-29 KATAYAMA SEIYAKUSYO CO. Ltd. Epimérisation d'acides cyclohexane carboxyliques 2- ou 4-substitués
JPH10298144A (ja) * 1997-04-23 1998-11-10 T Hasegawa Co Ltd トランス−４−アルキルシクロヘキサンカルボン酸エステル類の製法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017090656A1 (fr) * 2015-11-27 2017-06-01 住友化学株式会社 Procédé de production d'un acide trans-cyclohexanecarboxylique

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TWI280232B (en) 2007-05-01
TW200400165A (en) 2004-01-01
JP4202269B2 (ja) 2008-12-24
JPWO2003078381A1 (ja) 2005-07-14
AU2003221404A1 (en) 2003-09-29

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