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

Salt of an optically active isomer of phenylglycine and an optically active isomer of 2-amino butanol and process for its preparation Download PDF

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Publication number
EP0000745A1
EP0000745A1 EP7878100531A EP78100531A EP0000745A1 EP 0000745 A1 EP0000745 A1 EP 0000745A1 EP 7878100531 A EP7878100531 A EP 7878100531A EP 78100531 A EP78100531 A EP 78100531A EP 0000745 A1 EP0000745 A1 EP 0000745A1
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alkoxy
substituted
optical isomer
salt
formula
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French (fr)
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EP0000745B1 (en
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Yung Bog Dr. Chae
Dae Whang Kim
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

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  • 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, acetylisoprop
  • 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.
  • optically active natural amines such as cinchonidine or dehydroabiethylamine
  • these natural amines are very expensive and the separation yields are low.
  • 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.
  • amino group of the amino acid or one of its derivatives is substituted for acidity
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Trennung von Aminosäuren in optische Antipoden. Die vorliegende Anmeldung betrifft Salze, bestehend aus einem optischen Isomeren einer Verbindung der Formel <IMAGE> worin X ein Wasserstofatom oder eine gegebenenfalls verätherte oder veresterte Hydroxygruppe bedeutet und Y unter anderen eine Acylgruppe ist, und einem optischen Isomeren von 2-Aminobutanol sowie ein Verfahren zur Herstellung von solchen Salzen. Die optisch aktiven Verbindungen der genannten Formel werden als Ausgangsmaterial für die Produktion von halbsynthetischen Antibiotika des Cephalosporinoder Penicillin-Typs eingesetzt.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

Die vorliegende Erfindung betrifft die Trennung in optische Antipoden von Verbindungen der Formel I

Figure imgb0001
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.
Figure imgb0001
 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.

Die optisch aktiven Verbindungen der genannten Formel werden als Ausgangsmaterial für die Produktion von halbsynthetischen Antibiotika des CephalosporinoderPenicillin-Typs, beispielsweise Ampicillin oder Amoxycillin eingesetzt. Die Erfindung betrifft ein neues'Verfahren zur Herstellung der optisch aktiven Verbindungen der obigen Formel unter Einsatz von optisch aktivem 2-Aminobutanol.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 einem bekannten Verfahren zur Trennung von Verbindungen in optische Isomere der obigen Formel wurden optisch aktive natürliche Amine, wie Cinchonidin oder Dehydroabiethylamin, eingesetzt. Doch diese natürlichen Amine sind sehr teuer, und die Trennungsausbeuten sind niedrig. Hinzu kommtnoch der weitere Nachteil, daß eine Wiedergewinnung dieser natürlichen Amine zum'weiteren Gebrauch begrenzt ist, weil ein Teil dieser Amine während des Trennungsverfahrens, das mit hohen-Temperaturen durchgeführt wird, zerstört wird.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.

Gemäß der Erfindung wird die Aminogruppe der Aminosäure oder eines ihrer Derivate substituiert, um die AciditätAccording to the invention, the amino group of the amino acid or one of its derivatives is substituted for acidity

der Aminosäure zu erhöhen. Diese Derivate der Aminosäuren bilden mit 2-Aminobutanol leichter die entsprechenden Salze als die Aminosäuren selbst. Die Salze werden im allgemeinen in Wasser oder einem niederen Alkanol, vorzugsweise Methanol, Äthanol oder Isopropanol hergestellt, wobei eines der beiden Salze ausfällt, die ausgehend von einer racemisehen Verbindung der Formel I und optisch aktivem 2-Aminobutanol gebildet werden können.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.

Das erfindungsgemäße Verfahren ist bekannten Verfahren darin überlegen, daß die optische Reinheit höher als 99 % liegt und höhere Ausbeuten erhalten werden.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.

Gegebenenfalls werden die Aniinosäure-Derivate in die Aminosäuren umgewandelt oder in eine Aminosäure, die entweder noch an der Aminogruppe oder am Phenylring substituiert ist. Die Erfindung wird durch die folgenden Beispiele erläutert.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.

Beispiel 1example 1

Salz von 1-N,O-Diacetyl-4-hydroxy-phenylglycin und 1-2-Aminobutanol.Salt of 1-N, O-diacetyl-4-hydroxy-phenylglycine and 1-2-aminobutanol.

Zu einer Suspension von dl-Diacetyl-4-hydroxy-phenylglycin (47,5 g) in 400 ml Äthanol, wurde 1-2-Aminobutanol (18 g) unter Rühren gegeben. Die Reaktionsmischung wurde langsam bis zur Auflösung erwärmt, worauf auf Raumtemperatur abgekühlt und 2 Stunden stehengelassen wurde, um die Ausfällung des Salzes zu vervollständigen. Das Salz wurde durch Filtrieren abgetrennt und ergab ein Rohprodukt (30 g). Durch Umkristallisieren aus 80 ml Äthanol wurde das reine Salz aus 1-N,O-Diacetyl-4-hydroxy-phenylglycin und 1-2-Aminobutanol erhalten.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.

Fp. 168-170° C und (α)D 25 = 126° (C=2, H2O).Mp 168-170 ° C and (α) D 25 = 126 ° (C = 2, H 2 O).

1-4-Hydroxyphenylglycin1-4-hydroxyphenylglycine

Das gemäß obiger Arbeitsweise erhaltene Salz wurde in bekannter Weise behandelt, um 1-4-Hydroxyphenylglycin mit einer optischen Reinheit ([α]25 D = -159° (C=2, N-HCl) von mehr als 99 % zu erhalten.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%.

Beispiel 2Example 2

Salz von l-N-Acetyl-4-methoxy-phenylglycin mit 1-2-Aminobutanol.Salt of 1N-acetyl-4-methoxy-phenylglycine with 1-2-amino butanol.

Zu einer Suspension von dl-N-Acetyl-4-methoxy-phenylglycin (4,46 g) in 15 ml abs. Methanol wurde 1-2-Aminobutanol (1,8g) gegeben. Es wurde wie in Beispiel 1 verfahren und ein rohes Salz (3,1 g) von 1-N-Acetyl-4-methoxy-phenylglycin mit 1-2-Aminobutanol erhalten. Das reine Salz wurde durch Umkristallisieren aus 5 ml abs. Methanol erhalten. 2,5 g (80 %); [α]25 D =-107° (C=2, H2O).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. Salz, bestehend aus einem optischen isomeren einer Verbindung der Formel I
Figure imgb0002
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 Kohlenstoffatom, Alkoxycarbonyloxy oder picolyloxycar- bonyloxy bedeutet und Y aliphatisches Acyl, das gegebenenfalls substituiert sein kann mit bis zu 3 Halogenatomen oder das weitere Carbonylgruppen enthalten kann, gegebenenfalls halogensubstituiertes Aroyl, oder Alkyl, Alkoxy, Nitro, Phthalyl, Trityl, gegebenenfalls alkyl-, alkoxy- oder halogen-substituiertes Benzyliden, Acetylisopropyliden, Benzoylisopropyliden, 5,5-Dimethyl-3-oxo-cyclohexan-1-yl, Trichlorethyloxycarbonyl, Benzyloxycarbonyl gegebenenfalls alkyl-, alkoxy-, halogensubstituiert oder substituiert mit einer Nitrogruppe oder -B(OH)2, tert.-Alkoxy mit einem tertiären Kohlenstoffatom, das an das Sauerstoffatom gebunden ist, Adamantyloxycarbonyl, Diphenylisopropyloxycarbonyl, Fluore- nyl-9-methyloxycarbonyl, Methylsulfonylethyloxycarbonyl, 3,5-Dimethoxyphenylisopropyloxycarbonyl, Isobornyloxycarbonyl, Nitrophenylsulfenyl, Tcsyl, Dibenzylphosphoryl, Diphenylphosphin oder Trimethylsilyl und einem optischen Isomeren von 2-Aminobutanol.1. Salt consisting of an optical isomer of a compound of formula I.
Figure imgb0002
 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. Verfahren zur Herstellung eines Salzes gemäß Anspruch 1, gekennzeichnet dadurch, daß ein Salz einer racemischen Verbindung der Formel I in Anspruch 1 mit einem optischen Isomeren von 2-Aminobutanol gebildet und das Salz eines optischen Isomeren einer Verbindung der Formel I mit dem optischen Isomeren einer Verbindung der Formel I mit dem optischen Isomeren von 2-Aminobutanol abgetrennt wird.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.
EP78100531A 1977-08-09 1978-07-28 Salt of an optically active isomer of phenylglycine and an optically active isomer of 2-amino butanol and process for its preparation Expired EP0000745B1 (en)

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DE19772735834 DE2735834A1 (en) 1977-08-09 1977-08-09 SEPARATION OF AMINO ACIDS INTO OPTICAL ANTIPODES
DE2735834 1977-08-09

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JP (1) JPS5430132A (en)
AT (1) AT359997B (en)
BG (1) BG35593A3 (en)
CA (1) CA1110653A (en)
CS (1) CS203200B2 (en)
DD (1) DD137580A5 (en)
DE (2) DE2735834A1 (en)
HU (1) HU178248B (en)
IE (1) IE47236B1 (en)
IL (1) IL55293A (en)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5041637A (en) * 1988-07-12 1991-08-20 Presidenza Del Consiglio Del Ministri-Ufficio Del Ministro Per Il Coordinamento Delle Iniziatjvo Per La Ricerca Scientifica E. Technologica Process for the synthesis of optically active aminoacids
FR2672593A1 (en) * 1991-02-08 1992-08-14 Beecham Sa Laboratoires NEW COMPOUNDS USEFUL FOR THE RESOLUTION OF DL-N-ACETYL OR DL-N-HALOACETYL-HYDROXYPHENYLGLYCINE.
US5583259A (en) * 1991-02-08 1996-12-10 Les Laboratoires Beecham S.A. 2-(RO)-1-(R) ethylamines
CN102887836A (en) * 2011-07-18 2013-01-23 西南大学 L-phenylglycine derivative and application thereof

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US4642205A (en) * 1984-03-01 1987-02-10 Alkaloida Vegyeszeti Gyar Diastereomer salts of phenylalanine and N-acyl derivatives thereof and process for the separation of optically active phenylalanine and N-acyl derivatives thereof
HU193199B (en) * 1984-03-01 1987-08-28 Budapesti Mueszaki Egyetem Process for preparing optically active alpha-amino-beta-phenyl-propionic acids
JPH01155119A (en) * 1987-12-14 1989-06-19 Rinnai Corp Combustion control device

Citations (2)

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FR2107926A1 (en) * 1970-09-24 1972-05-12 Beecham Group Ltd
AT334345B (en) * 1973-06-07 1976-01-10 Pliva Pharm & Chem Works PROCESS FOR THE PRODUCTION OF L- (-) -ALPHA- METHYL -BETA- (3,4-DIHYDROXYPHENYL) -ALANINE

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NL129419C (en) * 1960-08-19
US3904681A (en) * 1971-03-30 1975-09-09 Ciba Geigy Corp Propionic acid
US3796748A (en) * 1972-08-16 1974-03-12 Bristol Myers Co Dehydroabietylammonium d-(-)-2-chloroacetylamino-2-(p-hydroxyphenyl)-acetate
JPS5069039A (en) * 1973-10-23 1975-06-09
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JPS5152154A (en) * 1974-10-26 1976-05-08 Sankyo Co nn karubometokishifuenirugurishinno kogakubunkatsuho

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2107926A1 (en) * 1970-09-24 1972-05-12 Beecham Group Ltd
AT334345B (en) * 1973-06-07 1976-01-10 Pliva Pharm & Chem Works PROCESS FOR THE PRODUCTION OF L- (-) -ALPHA- METHYL -BETA- (3,4-DIHYDROXYPHENYL) -ALANINE

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5041637A (en) * 1988-07-12 1991-08-20 Presidenza Del Consiglio Del Ministri-Ufficio Del Ministro Per Il Coordinamento Delle Iniziatjvo Per La Ricerca Scientifica E. Technologica Process for the synthesis of optically active aminoacids
FR2672593A1 (en) * 1991-02-08 1992-08-14 Beecham Sa Laboratoires NEW COMPOUNDS USEFUL FOR THE RESOLUTION OF DL-N-ACETYL OR DL-N-HALOACETYL-HYDROXYPHENYLGLYCINE.
WO1992013823A1 (en) * 1991-02-08 1992-08-20 Les Laboratoires Beecham S.A. Aminoalcohols useful as optical resolving agents
US5583259A (en) * 1991-02-08 1996-12-10 Les Laboratoires Beecham S.A. 2-(RO)-1-(R) ethylamines
CN102887836A (en) * 2011-07-18 2013-01-23 西南大学 L-phenylglycine derivative and application thereof
CN102887836B (en) * 2011-07-18 2014-03-26 西南大学 L-phenylglycine derivative and application thereof

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US4182899A (en) 1980-01-08
CS203200B2 (en) 1981-02-27
IT1098014B (en) 1985-08-31
BG35593A3 (en) 1984-05-15
HU178248B (en) 1982-04-28
ATA577278A (en) 1980-05-15
AT359997B (en) 1980-12-10
DE2735834A1 (en) 1979-02-22
EP0000745B1 (en) 1981-07-15
IL55293A0 (en) 1978-10-31
SU913937A3 (en) 1982-03-15
IL55293A (en) 1982-09-30
JPS5430132A (en) 1979-03-06
IT7826559A0 (en) 1978-08-07
DD137580A5 (en) 1979-09-12
CA1110653A (en) 1981-10-13
IE47236B1 (en) 1984-01-25
DE2860839D1 (en) 1981-10-22
IE781611L (en) 1979-02-09

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