EP0000745A1 - Salt of an optically active isomer of phenylglycine and an optically active isomer of 2-amino butanol and process for its preparation - Google Patents

Abstract

Separation of amino acids into optical antipodes. The present application relates to salts consisting of an optical isomer of a compound of the formula <IMAGE> in which X is a hydrogen atom or an optionally etherified or esterified hydroxyl group and Y is, inter alia, an acyl group, and an optical isomer of 2-aminobutanol and a process for Production of such salts. The optically active compounds of the formula mentioned are used as the starting material for the production of semisynthetic antibiotics of the cephalosporin or penicillin type.

Description

worin X H, OH, C₁-C₄-Alkoxy, Aryloxy, C₁-C₄-Acyloxy, Aralkyloxy, das gegebenenfalls.mit höchstens 3 Halogenatomen oder Nitrogruppen substituiert ist und höchstens 4 Kohlenstoffatome im Alkylrest enthält, tert.-Alkoxy mit einem tertiären an das Sauerstoffatom gebundenen Kohlenstcffatom, Alkoxycarbonyloxy oder Picolyloxycarbonyloxy bedeutet und Y aliphatisches Acyl, das gegehenenfalls substituiert sein kann mit bis zu 3-Halogenatomen oder das weitere Carbonylgruppen enthalten kann, gegebenenfalls halogen-substituiertes Aroyl, oder Alkyl, Alkoxy, Nitro, Phthalyl, Trityl, gegebenenfalls alkyl-, alkoxy- oder halogen-substituiertes Benzyliden, Acetylisopropyliden, Benzoylisopropyliden,.5,5-Dimethyl-3-oxo-cyclohexen-1-yl, Trichlorethyloxycarbonyl, Benzyloxycarbonyl gegebenenfalls alkyl-, alkoxy- oder halogensubstituiert- oder substituiert mit einer Nitrogruppe oder -B(OH)₂, tert.-Alkoxy mit einem tertiären Kohlenstoffatom, das an das Sauerstoffatom gebunden ist, Adamantyloxycarbonyl, Diphenylisopropyloxycarbonyl, Fluorenyl-9-methyloxycarbonyl, Methylsulfonylethy-loxycarbonyl, 3,5-Dimethoxyphenylisopropyloxycarbonyl, Isobornyloxycarbonyl, Nitrophenylsulfenyl, Tosyl, Dibenzylphosphoryl, Diphenylphosphin oder Trimethylsilyl bedeutet.The present invention relates to the separation into optical antipodes of compounds of the formula I.

wherein XH, OH, C ₁ -C ₄ alkoxy, aryloxy, C ₁ -C ₄ acyloxy, aralkyloxy, which is optionally.substituted with at most 3 halogen atoms or nitro groups and contains at most 4 carbon atoms in the alkyl radical, tert.-alkoxy with one tertiary carbon atom bonded to the oxygen atom, alkoxycarbonyloxy or picolyloxycarbonyloxy and Y is aliphatic acyl, which may optionally be substituted with up to 3-halogen atoms or which may contain further carbonyl groups, optionally halogen-substituted aroyl, or alkyl, alkoxy, nitro, phthalyl, trityl , optionally alkyl, alkoxy or halogen substituted Benzylidene, acetylisopropylidene, benzoylisopropylidene, .5,5-dimethyl-3-oxo-cyclohexen-1-yl, trichloroethyloxycarbonyl, benzyloxycarbonyl optionally alkyl, alkoxy or halogen-substituted or substituted with a nitro group or -B (OH) ₂ , tert. -Alkoxy with a tertiary carbon atom which is bonded to the oxygen atom, adamantyloxycarbonyl, diphenylisopropyloxycarbonyl, fluorenyl-9-methyloxycarbonyl, methylsulfonylethy-loxycarbonyl, 3,5-dimethoxyphenylisopropyloxycarbonyl, isobornyloxycarbonyl, nitrophenylsulfenyl, diphenyl, dibyl, tosyl, dibylphenyl, tosyl, dibyl, tosyl, dibyl, tosyl, dibyl, tosyl, dibyl.

The optically active compounds of the formula mentioned are used as starting material for the production of semisynthetic antibiotics of the cephalosporin or penicillin type, for example ampicillin or amoxycillin. The invention relates to a new process for the preparation of the optically active compounds of the above formula using optically active 2-aminobutanol.

In a known process for separating compounds into optical isomers of the above formula, optically active natural amines, such as cinchonidine or dehydroabiethylamine, have been used. However, these natural amines are very expensive and the separation yields are low. In addition, there is the further disadvantage that recovery of these natural amines for further use is limited because some of these amines are destroyed during the separation process, which is carried out at high temperatures.

According to the invention, the amino group of the amino acid or one of its derivatives is substituted for acidity

to increase the amino acid. These derivatives of the amino acids form the corresponding salts more easily with 2-aminobutanol than the amino acids themselves. The salts are generally prepared in water or a lower alkanol, preferably methanol, ethanol or isopropanol, one of the two salts precipitating out, starting from a racemi see compound of formula I and optically active 2-aminobutanol can be formed.

The process according to the invention is superior to known processes in that the optical purity is higher than 99% and higher yields are obtained.

If appropriate, the amino acid derivatives are converted into the amino acids or into an amino acid which is either still substituted on the amino group or on the phenyl ring. The invention is illustrated by the following examples.

example 1

Salt of 1-N, O-diacetyl-4-hydroxy-phenylglycine and 1-2-aminobutanol.

To a suspension of dl-diacetyl-4-hydroxy-phenylglycine (47.5 g) in 400 ml of ethanol was added 1-2-aminobutanol (18 g) with stirring. The reaction mixture was slowly warmed to dissolution, then cooled to room temperature and allowed to stand for 2 hours to complete the precipitation of the salt. The salt was separated by filtration and gave a crude product (30 g). The pure salt of 1-N, O-diacetyl-4-hydroxy-phenylglycine and 1-2-aminobutanol was obtained by recrystallization from 80 ml of ethanol.

Mp 168-170 ° C and (α) _D ²⁵ = 126 ° (C = 2, H ₂ O).

1-4-hydroxyphenylglycine

The salt obtained according to the above procedure was treated in a known manner in order to obtain ^1- 4-hydroxyphenylglycine with an optical purity ([α] ²⁵ _D = -159 ° (C = 2, N-HCl) of more than 99%.

Example 2

Salt of 1N-acetyl-4-methoxy-phenylglycine with 1-2-amino butanol.

To a suspension of dl-N-acetyl-4-methoxy-phenylglycine (4.46 g) in 15 ml abs. Methanol was added to 1-2-aminobutanol (1.8 g). The procedure was as in Example 1 and a crude salt (3.1 g) of 1-N-acetyl-4-methoxy-phenylglycine with 1-2-aminobutanol was obtained. The pure salt was recrystallized from 5 ml abs. Get methanol. 2.5 g (80%); [α] ²⁵ _D = -107 ° (C = 2, H ₂ O).

Claims (2)

1. Salt consisting of an optical isomer of a compound of formula I.

wherein XH, OH, C ₁ -C ₄ alkoxy, aryloxy, C ₁ -C ₄ acyloxy, aralkyloxy, which is optionally substituted with at most 3 halogen atoms or nitro groups and contains at most 4 carbon atoms in the alkyl radical, tert-alkoxy with a tertiary carbon atom bonded to the oxygen atom, alkoxycarbonyloxy or ^p icolyloxycarbonyloxy and Y denotes aliphatic acyl which may optionally be substituted by up to 3 halogen atoms or which may contain further carbonyl groups, optionally halogen-substituted aroyl, or alkyl, alkoxy, nitro, phthalyl, trityl, optionally alkyl-, alkoxy- or halogen-substituted benzylidene, acetylisopropylidene, benzoylisopropylidene, 5,5-dimethyl-3-oxo-cyclohexan-1-yl, trichloroethyloxycarbonyl, benzyloxycarbonyl optionally alkyl-, alkoxy-, halogen-substituted or substituted with a nitro group or - B (OH) ₂ , tert-alkoxy with a tertiary carbon atom which is bonded to the oxygen atom, adamantyloxycarbonyl, Di phenylisopropyloxycarbonyl, fluorenyl-9-methyloxycarbonyl, methylsulfonylethyloxycarbonyl, 3,5-dimethoxyphenylisopropyloxycarbonyl, isobornyloxycarbonyl, nitrophenylsulfenyl, tcsyl, dibenzylphosphoryl, diphenylphosphine or trimethylsilyl and an optical isomer of 2-amine. 2. A method for producing a salt according to claim 1, characterized in that a salt of a racemic A compound of formula I in claim 1 is formed with an optical isomer of 2-aminobutanol and the salt of an optical isomer of a compound of formula I with the optical isomer of a compound of formula I with the optical isomer of 2-aminobutanol is separated.