GB2048875A - alpha -Halomethylaminoacids and Their Preparation - Google Patents

alpha -Halomethylaminoacids and Their Preparation Download PDF

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GB2048875A
GB2048875A GB8013818A GB8013818A GB2048875A GB 2048875 A GB2048875 A GB 2048875A GB 8013818 A GB8013818 A GB 8013818A GB 8013818 A GB8013818 A GB 8013818A GB 2048875 A GB2048875 A GB 2048875A
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methoxy
hydroxy
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Merrell Toraude et Cie
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Abstract

Compounds of formula I <IMAGE> wherein X1 and X2 are each hydrogen or fluorine; R1 is hydrogen, alkylcarbonyl, alkoxycarbonyl or aminoalkylcarbonyl, and three of R2, R3, R4, R5 and R6 are hydrogen, the others being selected from hydroxy, methyl and methoxy. Also disclosed is a process of preparing compounds of formula I in which R1 and X2 are hydrogen and X1 is fluorine and R2, R3, R4, R5 and R6 are various combinations of hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, hydroxy, methoxy and methylene dioxy by reacting a corresponding benzyl magnesium halide with fluoroacetonitrile and reducing the resultant ketimine salt.

Description

SPECIFICATION -Halomethylaminoacids and their Preparation This invention relates to novel a-halomethylaminoacid derivatives and to a process for preparing the novel compounds and the related compounds disclosed in British Patent publication No. 2,003,871 A. The known and the novel compounds can have utility as inhibitors of aromatic aminoacid decarboxylase. The mode of action of this enzyme, and the desirability of providing an inhibitor thereof, are discussed in British Patent Publication No. 2,003,871A.
The related known compounds are of formula I
wherein X1 and X2 are independently selected from hydrogen and fluorine; R1 is hydrogen, (C, 4 alkyl)carbonyl, (cm 4 alkoxy)carbonyl or -CO CHR7-NH2 in which R7 is hydrogen, Ca 4 alkyl, benzylorp-hydroxybenzyl;andR2, R3, R4, R5 and R6 are one of various specified combinations of hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, hydroxy, C18 alkoxy, C2.7 alkanoyloxy, benzoyloxy and phenyl (C2.7 alkanoyloxy), and include the pharmaceutically acceptable salts thereof.
The novel compounds of this invention are of formula I, Y, R and R, being as defined above, in which R2, R3, R4, R5 and R6 are one of the ten combinations defined in the following Table: R2 R3 R4 R5 R6 OH CH3 H H H H OH CH3 H H OH H CH3 H H OH OCH3 H H H OH H OH H H OH H H H CH3 OH H OCH3 H H OH H H OH H OH CH3 OH H H OH H H H OH and include the pharmaceutically acceptable salts, as well as the individual optical isomers, thereof.
The novel compounds of this invention are useful pharmacological agents in that they are inhibitors of aromatic aminoacid decarboxylase, and are useful as intermediates in the preparation of other useful pharmacological agents.
Illustrative of C1.4 alkyl and Ca 4 alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, methoxy, ethoxy, ispropoxy, n-butoxy and tert-butoxy.
Illustrative examples of pharmaceutically acceptable salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids such as methanesulfonic, salicylic, maleic, malonic, tartaric, citric and ascorbic acids.
The salts are prepared by conventional means.
Preferred compounds of this invention are those wherein R1 is hydrogen or (C1.4 alkyl)carbonyl, most preferably hydrogen. It is also preferred that two of R2, R3, R4, R5 and R6 should be hydroxy or methoxy, the others being hydrogen; more preferably, R2 is hydroxy, R3 is hydrogen, one of R4, R5 and R6 is hydroxy and the others are hydrogen. X2 is preferably hydrogen; it is particularly preferred that X, should be fluorine and X2 hydrogen.
The novel compounds of this invention in which Rr and X2 are each hydrogen may be prepared by a method wholiy analogous to that described in British Patent Publication No.
2,003,871A. Accordingly, the starting material is a compound of formula II
wherein R2, R13, Err4, Rr5 and R,6 correspond to R2, R3, R4, R5 and R6 as defined above, respectively, provided that hydroxy groups in the absence of methoxy groups are protected as methoxy and hydroxy groups in the presence of methoxy groups are protected as benzyloxy, and X, is as defined above, i.e. hydrogen or fluorine. The ketone of formula II is reduced chemically using a metal hydride or catalytically to the corresponding alcohol which is then converted to the desired amine. Suitable reagents and conditions are as disclosed in British Patent Publication No.
2,003,871 A.
The novel compounds of this invention in which R, and X, are hydrogen and X2 is fluorine may be prepared by treating a malonic acid di(C, 4 alkyl) ester with a strong base to generate a carbanion which is then treated with an alkyiating reagent of formula Ill
wherein R,2, R,3, R 4, R15 and R,6 are as defined above and X is a good leaving group. The alkylated malonic acid ester is then treated with a base, followed by treatment with a difluoromethylhaloalkylating reagent. The difluoromethylmalonic acid monoester is then decarboxylated by treatment with an organic acid, and the free acid converted to the corresponding amine by the Schmidt or Curtius reaction.
Suitable reagents and conditions for this sequence of reactions are described in British Patent Publication No. 2,003,871A.
The novel compounds of this invention in which R, is hydrogen and X, and X2 are each fluorine may be prepared by treating a ketone of formula IV
wherein Era2, Err3, Err4, Rr5 and R,6 are as defined above, with a hydroxylamine salt in the presence of a base to give the corresponding oxime which is then reduced to the amine. The ketone of formula IV may also be converted to the corresponding amine by reductive alkylation or amination. Suitable reagents and conditions are described in British Patent Publication No.
2,003,871 A.
The compounds prepared by the methods disclosed herein, in which R1 is hydrogen, may be converted into compounds of formula I in which R, is any of the other given values, by the methods, and under the conditions described, for the analagous conversions in British Patent Publication No. 2,003,871A. Salts of the invention may also be prepared by process analagous to those described in that publication.
An alternative process for the preparation of the novel compounds of this invention is nonanalagous to those described in the given publication and can be used for the preparation of all compounds of formula I in which Rr, X and X2 are hydrogen and R2, R3, R4, R5 and R6 are any combination of hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, hydroxy and methoxy, provided that at least two are hydrogen. This process involves three stages, and provides a further aspect of this invention.
The first stage comprises adding very slowly a benzyl halide of formula V
wherein R,2, Err3, R4, Ra5 and R,6 are as defined above to magnesium turnings in a suitable ether solvent such as tetrahydrofuran or ethyl ether, and allowing the reaction to proceed for T to 24 hours at from -20 to 700C, preferably from 250C to the boiling point of the solvent. At the beginning of the reaction, a trace of methyl iodide is added. Further, if any of R2, Rr4 and R,6 is methoxy, the reaction is initiated in tetrahydrofuran.
In the second stage of the reaction sequence, the Grignard reagent formed in the preceding stage is reacted with fluoroacetonitrile in a ratio of from 0.5:1 to 3:1. The reaction is conducted in an aprotic solvent such as tetrahydrofuran, ethyl ether, dioxane, benzene, dimethoxyethane or dimethoxymethane. The temperature of the reaction during the addition of fluroacetonitrile may vary from -20 to -70, and preferably from -20 to -250C and the reaction time may be from 10 minutes to 12 hours, and preferablyfrom 10 minutes to 1 hour. The product is a ketimine salt of formula VI
wherein Err2, Err3, R,4, R15 a.nd R,6 and Z are as defined above.In the final stage of the reaction sequence, the ketimine salt is reduced by pouring it into a solution of, for example, sodium potassium or lithium borohydride or sodium cyanoborohydride, in a protic solvent such as a Cut~4 alcohol, e.g. methanol or ethanol, optionally in admixture with water. Alternatively, the reducing agent can be lithium aluminium hydride, in which case the reaction is conducted in an aprotic solvent such as ethyl ether, tetrahydrofuran, benzene, pentane, hexane, dimethoxyethane or dimethyl sulfoxide. The reducing agent is preferably a borohydride. The reaction is conducted at from -20 to 250C for from 1 to 20 hours.
The novel compounds of this invention can be compounded, with a suitable physiologically acceptable excipient, into pharmaceutical compositions which can be used for the same purposes and in the same dosages as the compounds and compositions described in British Patent Publication No. 2,003,871A.
Further, the novel compounds are useful in the preparation of cephalosporin derivatives analagous to those which can be prepared from the known compound of formula I (see formula II in British Patent Publication No. 2,O03,871A).
The cephalosporin derivatives, which can have antibiotic activity, can be prepared from the compounds of this invention in which R, is hydrogen using the same reaction conditions and the same coupling reagent as described in British Patent Publication No. 2,005,659A (the coupling reagent is formula lil in that publication).
The individual optical isomers of the compounds of the invention may be prepared by conventional methods, e.g. as described in British Patent Publication No. 2,003,871A.
The following Example illustrates the novel process of this invention.
Example 1 -FEuoromethyl-2-(4- methoxyphenyl)ethylamine Under an atmosphere of nitrogen, and under magnetic stirring, a solution of p-methoxybenzyl chloride (0.1 mole) in tetrahydrofuran (130 ml) is added slowly (20 drops/min) to magnesium turnings (4.8- g) in tetrahydrofuran (90 ml). The formation of the Grignard reagent- is initiated by the addition of 2 drops of methyl iodide. During the reaction, the flask is immersed in a bath containing water at room temperature. Stirring is continued for an additional 30 minutes and then the Grignard reagent is separated from the excess magnesium, transferred to a second flask and cooled to -200C (internal temperature).
Fluoroacetonitrile (6.35 g) in tetrahydrofuran (45 ml) is added slowly, at such a rate that the internal temperature is kept at -200C.
After the addition, the mixture is poured into a solution of sodium borohydride (4.16 g) in aqueous methanol (350 ml MeOH, 7 ml H2O) and kept at -200C for 90 minutes, acidified with concentrated HCI to about pH2, and most of the solvent is removed under reduced pressure. 3 N HCI (235 ml) is added, and the mixture extracted twice with ethyl ether (2x200 ml), then made strongly alkaline (NaOH) and again extracted with ether (4x200 ml). After drying (Na2SO4) and removal of the solvent, 1-fluoromethyl-2-(4- methoxyphenyl)ethylamine is obtained.
When in the above procedure an appropriate amount of 3,4-dimethoxybenzyl chloride is substituted forp-methoxybenzyl chloride, 1flubromethyl-2-(3,4-dimethoxyphenyl)ethylamine is obtained.

Claims (12)

Claims
1. A process for preparing a compound of the formula
wherein R2, R3, R4, R5 and R6 are independently selected from hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, hydroxy and methoxy or two of R2, R3, R4, R5 and R6 are methylenedioxy, provided that at least two of R2, R3, R4, R5 and R6 are hydrogen, which comprises adding very slowly a benzyl halide of the formula
wherein R,2, R13, R,4, R,5 and Rl8 are as defined above for R2, R3, R4, R5 and R8, respectively, provided that hydroxy groups in the absence of methoxy groups are protected as methoxy and hydroxy groups in the presence of methoxy groups are protected as benzyloxy, and Z is chlorine or bromine, to magnesium turnings in an ether solvent, adding a catalytic amount of methyl iodide and allowing the reaction to proceed for T to 24 hours at -20 to 700C; adding fluoroacetonitrile to the resultant Grignard reagent in a ratio of 0.5:1 to 3:1 in an aprotic solvent at -20 to -700C and allowing the reaction to proceed for from 10 minutes to 12 hours, and reducing the resultant ketimine salt by reaction with a reducing agent in a solvent for 1 to 20 hours at -20 to 250C.
2. A process according to claim 1 in which R2, R3, R4, R5 and R6 are as defined in claim 1 of British Patent Publication No. 2,003,871A.
3. A process according to claim 1 in which R2, R3, R4, R5 and R6 are one of the ten combinations defined in the following Table: R2 R3 R4 R5 R8 OH CH3 H H H H OH CH3 H H OH H CH, H H OH LOCHS H H H OH H OH H H OH H H H CH3 OH H OCH3 H H OH H H OH H OH CH3 OH H H OH H H H OH
4. A process according to claim 1 substantially as described in the Example.
5. A compound of the formula
wherein X1 and X2 are independently selected from hydrogen and fluorine; R1 is hydrogen, (C1-4 alkyl)carbonyl, (C1-4 alkoxy)carbonyl or -CO CHR7-NH2 in which R7 is hydrogen, C 1-4 alkyl, benzyl orp-hydroxybenzyl; and R2, R3, R4, R5 and R8 are as defined in claim 3.
6. A compound as claimed in claim 5 wherein R1 is hydrogen or (C 4 alkyl)carbonyl.
7. A compound as claimed in claim 5 wherein R1 is hydrogen.
8. A compound as claimed in any of claims 5 to 7 wherein Y is -CH2F or-CHF2.
9. A compound as claimed in claim 8 wherein Yis-CHF2.
10. A compound as claimed in any of claims 5 to 9 wherein two of R2, R3, R4, R5 and R6 are hydroxy or methoxy and the others are hydrogen.
11. A compound as claimed in claim 10 wherein R2 and one of R4, R5 and R6 are hydroxy.
12. A pharmaceutical composition comprising a compound as claimed in any of claims 5 to 11 in association with a physiologically acceptable excipient.
GB8013818A 1979-04-26 1980-04-25 alpha -Halomethylaminoacids and Their Preparation Withdrawn GB2048875A (en)

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EP1078632A1 (en) * 1999-08-16 2001-02-28 Sanofi-Synthelabo Use of monoamine oxydase inhibitors for the manufacture of drugs intended for the treatment of obesity
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CN113302176A (en) * 2018-12-06 2021-08-24 先达生物科技公司 Decarboxylase inhibitors for the treatment of parkinson's disease
US20220048849A1 (en) * 2018-12-06 2022-02-17 Senda Biosciences, Inc. Decarboxylase inhibitors for treating parkinson's disease
EP3891122A4 (en) * 2018-12-06 2022-10-05 Senda Biosciences, Inc. Decarboxylase inhibitors for treating parkinson's disease

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DK180980A (en) 1980-10-27
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AU5550780A (en) 1980-10-30
SE8003117L (en) 1980-10-27
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FR2457277A2 (en) 1980-12-19
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DE3015373A1 (en) 1980-11-06
BE882104R (en) 1980-07-01

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