ES2349833T3 - PROCEDURE FOR THE PREPARATION OF AMINOALCOHOLES. - Google Patents

Abstract

Process for preparing an amino alcohol of the formula in the form of the racemate or of one of its optically active isomers, comprising the hydrolysis of a cyclopentene derivative of the general formula in the form of the racemate or of one of its optically active isomers, wherein R means alkyl C1-4 or aryl, with an alkali metal hydroxide.

Description

The present invention relates to a process for preparing an amino
formula alcohol

image 1

in the form of the racemate or the optically active isomers.
(1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene is an important intermediate product for the preparation of carbocyclic nucleosides such as, for example, Carbovir® (Campbell et al., J. Org. Chem. 1995, 60, 4602-4616).

For example, Campbell et al. (J. Org. Chem. 1995, 60, 4602-4616) describe a process for preparing (1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene. The preparation is carried out by reduction and hydrolysis of bicyclic carbamates, with cleavage of a tert-butoxycarbonyl protecting group and ring opening. In Park K. H.

15 and Rapoport H. (J. Org. Chem. 1994. 59, 394-399) another method for preparing (1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene is described. Both procedures are expensive, complicated and not applicable on a large scale. WO 93/17020 describes a process for preparing (1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene, where (1R, 4S) -4-amino acid is reduced

20 -2-cyclopentene-1-carboxylic acid with lithium aluminum hydride to give the desired product. The drawback of this procedure, on the one hand, is that the double bond of the cyclopentene ring is also reduced and the poor handling of lithium aluminum hydride and, on the other hand, that it is too expensive.

Tanaka, M. et al. (J. Org. Chem. 1996, 61, 6952-6957) describe the formation of a 1-amino-4-hydroxymethyl-2-cyclopentene by heating an alkyl carbamate, hydroxymethyl-3 - [(methoxycarbonyl) amino] cyclopentene, with potash bleach.

Similarly, Katagiri, N. et al. (Nucleosides & Nucleotides, 1996, 15, 631-647) describe the preparation of 1-amino-4-hydroxymethyl-2-cyclopentene by treating a carbamate with trifluoroacetic acid.

30 Taylor S. J. et al. (Tetrahedron: Asymmetry, vol. 4, No. 6, 1993, 1117-1128) describe a process for preparing (1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene starting from (±) -2- azabicyclo [2.2.1] hept-5-en-3-one as an educt. In this case the educt is transformed by means of microorganisms of the species Pseudomonas solanacearum or Pseudomonas fluorescens in (1R, 4S) -2-azabicyclo [2.2.1] hept-5-in-3-one, which is then reacted with di-tert-butyl dicarbonate to give (1R, 4S) -N-tert-butoxycarbonyl-2-azabicyclo [2.2.1] hept-5-en-3-one, and the latter is reduced with sodium borohydride and trifluoroacetic acid to give

5 the desired product. This procedure is too expensive.

In addition, Martinez et al. (J. Org. Chem. 1996, 61, 7963-7966) describe a 10-stage synthesis of (1R, 4S) -1-amino-4- (hydroxymethyl) -2-cyclopentene from diethyl esters of dialkylmalonic acids. This procedure also has the disadvantage that it is complicated and not applicable on a large scale.

10 It is also known that (±) -2-azabicyclo [2.2.1] N-substituted hept-5-en-3-ones, which carry an electron-attracting substituent, can be reduced with a metal hydride to give the corresponding amino alcohols N-substituted (Katagiri et al., Tetrahedron Letters, 1989, 30, 1645-1648; Taylor et al., Ibid.). On the contrary, it is known that (±) -2-azabicyclo [2.2.1] hept-5-en-3-one does not

15 tituted formula

image2

it is reduced with lithium aluminum hydride to give (±) -2-azabicyclo [2.2.1] octene

20 (Malpass and Tweedle, J. Chem. Soc., Perkin Trans 1, 1977, 874-884), and that direct reduction of (±) -2-azabicyclo [2.2.2] hept-5-en-3- One to give the corresponding amino alcohol was not considered until now possible (Katagiri et al., Tetrahedron Letters, 1989, 30, 1645-1648; Taylor et al., ibid). It is also known to unfold 1-amino-4- (hydroxymethyl) -2-cyclopentene race

Mico by (-) - dibenzoyltartaric acid (US-A 5 034 394). This reaction has, on the one hand, the disadvantage that (-) - dibenzoyltartaric acid is expensive and, on the other, that the separation must occur in the presence of a precisely defined mixture of acetonitrile and ethanol. This solvent mixture cannot be separated and must be sent to incinerate.

The mission of the present invention was to make available a simple, economical and cost-effective process for preparing 1-amino-4- (hydroxymethyl) -2-cyclopentene. Surprisingly, it has been found that when a cyclopentene derivative of the general formula is hydrolyzed

image2

in the form of the racemate or one of its optically active isomers, wherein R means C1-4 alkyl or aryl, with an alkali metal hydroxide, the amino alcohol of formula is readily obtained

image2

in the form of the racemate or one of its optically active isomers.

C1-4 alkyl may be substituted or unsubstituted. Hereinafter, C1-4 alkyl substituted by a C1-4 alkyl substituted by one or more halogen atoms. They can be used as halogen atoms F, Cl, Br or I. Examples of C1-4 alkyl are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, isopropyl, chloromethyl, bromomethyl, dichloromethyl, dibromomethyl. Preferably, methyl, ethyl, propyl, butyl, isobutyl or chloromethyl are used as C 1-4 alkyl.

As aryl, for example, phenyl or benzyl, substituted or unsubstituted, can be used. Hereinafter, phenyl or benzyl substituted means a phenyl or benzyl substituted with one or more halogen atoms, such as, for example, chlorobenzyl, dichlorobenzyl, bromophenyl or dibromophenyl.

As alkali metal hydroxide, sodium or potassium hydroxide can be used.

The amino alcohol of the formula I can be transformed with an acid into the corresponding salts, for example into hydrohalogenide salts. Hydrobromides and hydrochlorides are suitable as hydrohalogenide salts.

The cyclopentene derivative of the general formula III is preferably prepared by reduction of the acyl-2-azabicyclo [2.2.1] hept-5-en-3-one of the general formula

image2

in the form of the racemate or one of its optically active isomers, wherein R has the indicated meaning, with a metal hydride in an anhydrous solvent.

As an anhydrous solvent, protic or aprotic organic solvents can be used, especially anhydrous protic organic solvents such as a tertiary alcohol. Tertiary alcohols tert-butyl alcohol and tert-amyl alcohol can be used as tertiary alcohols.

As metal hydrides, alkali metal or alkaline earth metal hydrides can be used, as well as binary or complex metal hydrides of the boron or aluminum group, such as alkali metal or alkaline earth metal borohydrides and aluminum and alkali metal or aluminum hydrides and alkaline earth metal. LiH, NaH, KH, BeH2, MgH2 or CaH2 are suitable as alkali metal or alkaline earth metal hydrides. As binary alkali metal or alkaline earth metal borohydrides, NaBH4, LiBH4, KBH4, NaAIH4, LiAIH4, KAIH4, Mg (BH4) 2, Ca (BH4) 2, Mg (AIH4) 2, Ca (AIH4) 2 can be used. Complex hydrides of the boron or aluminum group may have the general formula M1 M2 HnLm, where n is an integer from 1 to 4 and m is an integer from 4 to 4 minus the corresponding number n, M1 is an atom of alkali metal, M2 means boron or aluminum and L is C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, CN or an amine, or complex metal hydrides can have the general formula M2HOLp, where M2 has the meaning indicated, O is an integer from 0 to 3 and p is an integer from 3 to 3 minus the corresponding p number. As M1 M2 HnLm can be used LiBH (C2H5) 3, LiBHx (OCH3) 4-x, where x means an integer from 1 to 3, LiAIH (OC (CH3) 3) 3, NaAIH2 (OC2H4OCH3) 2, NaAIH2 (C2H5) 2 or NaBH3CN. Preferably, the reduction is carried out with a metal borohydride.

As is known to the specialist, the mentioned metal hydrides such as, for example, LiBH4, can also be produced "in situ". Common methods of obtaining LiBH4 are, for example, the reaction of an alkali metal borohydride with a lithium halide (HC Brown et al., Inorg. Chem. 20, 1981, 4456-4457), the reaction of LiH with B2O3 in the presence of hydrogen and a hydrogenation catalyst (EP-A 0 512 895), the reaction of LiH with (H5C2) OBF3 (document DE-OS 94 77 02) and the reaction of LiH with B (OCH3) 3 (document US-A 2,534,533).

The reduction is preferably carried out in the presence of an additive, for example in the presence of a C1-6 alcohol such as methanol, especially in the presence of 2 moles of methanol per mole of acyl-2-azabicyclo [2.2.1] hept -5-in-3-one of formula IV.

Conveniently, the reaction is carried out at a temperature from 0 to 50 ° C, preferably from 15 to 30 ° C.

The amino alcohol of racemic formula I, preferably the cis-racemic, thus obtained, can be subjected to a racemate cleavage, preferably biotechnologically with a hydrolase in the presence of an acylating agent or chemically with an optically active tartaric acid such as D- ( -) - tartaric acid or L - (+) - tartaric acid.

Examples:

Example 1

Reduction of 2-azabicyclo [2.2.1] hept-5-en-3-one not substituted with acyl

Preparation of cis- (±) -acetyl-1-amino-4- (hydroxymethyl) -2-cyclopentene in anhydrous protic organic solvent by means of sodium borohydride

280 g of 2-methyl-2-butanol (amyl alcohol) and 15.2 g of sodium borohydride (0.4 ml) were placed in a sulfonation flask at 20 ° C. To this suspension was added dosed within 2 hours, at 20 ° C, a mixture of 907 g of (±) -acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one (0, 6 moles) and 37.5 g of methanol (2 equivalents with respect to (±) -acetyl-2-azabicyclo [2.2.1] hept-5-en-3-one. Then the reaction mixture was stirred at 20 ° C for a further 3 hours The solvent was removed as completely as possible (at 40 ° C) 280 g of methanol and 27.2 g of formic acid were added to remove the boron, the mixture was heated to 25-30 ° C , and the methyl borate azeotrope was removed by distillation (at 130 to 80 mbar) at that temperature, the precipitated sodium formate was filtered off and the filtrate was concentrated 93.4 g of crude product were obtained as of viscous transparent oil, gross yield with content: approximately 84-85%.

Example 2

Alkaline hydrolysis of acetyl- (±) -1-amino-4- (hydroxymethyl) -2-cyclopentene

88.9 g of racemic acetyl-1-amino-4- (hydroxymethyl) -2-cyclopentene (content 77.2%) were suspended (70.2%) in 70 g of water. 84 g of 30% NaOH (1.1 equivalents) were added thereto, and the mixture was refluxed for 3 hours. Hydrolysis was complete by thin layer chromatography (TLC). The resulting acetate was removed by electrodialysis. The aqueous solution obtained was concentrated, and dried by azeotropic distillation with butanol. For the splitting of the racemate, the residue was taken in methanol. The hydrolysis performance at

5 (±) -1-amino-4- (hydroxymethyl) -2-cyclopentene was 90%.

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Claims (1)

1. Procedure for preparing an amino alcohol of formula image 1 in the form of the racemate or one of its optically active isomers, which comprises the hydrolysis of a cyclopentene derivative of the general formula image2 10 in the form of the racemate or one of its optically active isomers, wherein R means C1-4 alkyl or aryl, with an alkali metal hydroxide. Method according to claim 1, characterized in that the cyclopentene derivative of the general formula image2 In the form of the racemate or one of its optically active isomers, where R has the indicated meaning, it will be prepared by reducing an acyl-2-azabicyclo [2.2.1] -hept-5-en-3-one of general formula image2 in the form of the racemate or one of its optically active isomers, wherein R has the indicated meaning, with a metal hydride in an anhydrous solvent.