GB2050356A - alpha -Halomethylamino compounds and their preparation - Google Patents

alpha -Halomethylamino compounds and their preparation Download PDF

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GB2050356A
GB2050356A GB8013819A GB8013819A GB2050356A GB 2050356 A GB2050356 A GB 2050356A GB 8013819 A GB8013819 A GB 8013819A GB 8013819 A GB8013819 A GB 8013819A GB 2050356 A GB2050356 A GB 2050356A
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Abstract

Compounds of formula I <IMAGE> wherein Y is -CH2F, -CHF2, -CH2Cl or -CHCl2; R is hydroxy, alkoxy, amino alkylamino, dialkylamino or carboxyalkylamino, R1 is hydrogen, alkylcarbonyl, alkoxycarbonyl or aminoalkylcarbonyl, and three of R2, R3, R4, R5 and R6 are hydrogen and the other two are selected from hydroxy, methyl and methoxy, and salts thereof. Also disclosed is a process of preparing compounds of formula I in which R is hydroxy, R1 is hydrogen, Y is -CH2F and R2, R3, R4, R5 and R6 are various combinations of hydrogen, methyl, ethyl, halogen, trifluoromethyl, hydroxy, methoxy and methylenedioxy by reacting a novel ketone of formula III <IMAGE> wherein R12 to R16 correspond to R2 to R6 provided that hydroxy groups are protected, with sodium cyanide and an ammonium salt, and hydrolysing the resulting aminonitrile. The novel ketones are prepared by reacting a suitable benzyl Grignard with fluoroacetonitrile and hydrolysing the resulting ketimine.

Description

SPECIFICATION &alpha;-Halomethylaminoacids and their preparation This invention relates to novel (l-halomethylaminoacid derivatives and to a process for preparing the novel compounds and the related compounds disclosed in British Patent Publication No. 2,005,659 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. 2,005,659 A.
The related known compounds are of formula I
wherein Y is -CH2F, -CHF2, CH2CI or -CHC2; R is hydroxy, C1-8 alkoxy, -NR7R8 in which R7 and R8 are each hydrogen or C1-4 alkyl, or -NH-CHR9-COOH in which Rg is hydrogen, C, 4 alkyl, benzyl orp-hydroxybenzyl, P is hydrogen, (C1-4 alkyl) carbonyl, (1-4 alkoxyl-carbonyl or -CO-CHR27-NH2 In which R7 is hydrogen, C1-4 alkyl, benzyl orp-hydroxybenzyl; and R2, R3, R4, Ps and R6 are one of various specified combinations of hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, hydroxy, C1 8 alkoxy, (C1.6 alkyl)carbonyloxy, benzoyioxy and phenyl (C1 6 alkyl)carbonyloxy, and include the pharmaceutically acceptable salts thereof.
The novel compounds of this invention are of formula I, Y, Rand R1 being as defined above, in which R?, R3, R4, R5 and R6 are one of the 10 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 OCH1 H H OH H H OH H OH CH3 OH H H OH H H H OH OH H H H CH, and Include the pharmaceutically acceptable salts, as weil as the individuai 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 Interme(ilates In the preparation of other useful pharmacological agents Illustrative examples of C,, alkyl and C q alkoxy groups are methyl. ethyl, n-propyl, isopronyl, n-outvl.
tert-butyl, methoxy, methoxy. isopropoxy, 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, hydrobrolnlc, sulfuric and phosphoric acid, and organic acids such as methanesulfonic. salicylic, maleic, malonic, tartaric, citric and ascorbic acids; and non-toxic salts formed with inorganic or organic bases such as those of alkali metais such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of Group IIIA such as aluminium, and organic amines such as primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, metnylaminoethaiol, ethanolamlne and piperazine The salts are prepared by conventional means.
Preferred compounds of this Invention are those wherein R, Is hydrogen nr (C. , alkylicarhonyl, most preferably hydrogen. Another preference is that R is hydroxy or C1.8 alkoxy, most preferably hydroxy.
Compounds wherein each of R2, R3, R4, R5 and R6 is hydrogen or hydroxy represent another preferred embodiment of this invention. Also, compounds wherein P2 is OH and one of R3, R4, R5 and P6 is OH, OCH3 or CH3 and compounds wherein P3 is OH and R4 is methyl are preferred embodiments of the present invention Compounds wherein Y is -CH2F or -CHF2, especially -CHF2 when R is hydroxy and R1 is hydrogen, are also preferred.
Illustrative examples of novel compounds of this invention are 2-fluoromethyl-2-amino-3-(3-hydroxy-p- tolyl)propionic acid and 2-difluoromethyl-2-amino-3-(2-hydroxy-p-tolyl)propionic acid.
The novel compounds of this invention in which R is hydroxy and R1 is hydrogen may be prepared by a method wholly analogous to that described in British Patent Publication No. 2,005,659 A. Accordingly, the starting material for use in this invention is a suitably protected compound of formula II
wherein Pa is Cox 8 alkoxy; either Rb is hydrogen, phenyl, C1 8 alkyl, methoxy or ethoxy and Rc is phenyl or C18 alkyl or Rb and Rc taken together form an alkylene group of the formula -(CH2)n- wherein n Is an integer of from five to seven; and Rl2, R,3, R14, R15 and R16 correspond to R2, R3, R4, R5 and R6, respectively, provided that adjacent hydroxy groups are protected as methoxy or -O-C(CH3)2-O-, hydroxy groups in the presence of methoxy groups are protected as benzyloxy, and single and non-adjacent hydroxy groups are protected as methoxy.
The suitably protected compound is reacted with a strong base to generate a carbanion which Is treated with a suitable halomethyl alkylating agent, followed by acid hydrolysis. Suitable reagents and conditions are as disclosed in British Patent Publication No. 2,005,659 A.
The compounds prepared by this method, in which R is hydroxy and R, Is hydrogen, may be converted into compounds of formula I in which R and R1 are any of the other given values, by the methods, and under the conditions described for the analogous conversions in British Patent Publication No. 2,005,659 A. Salts of the invention may also be prepared by analogous processes to those described In that publication.
An alternative process for the preparation of the novel compounds of this Invention is non-analogous to that described in the given publication and can be used for the preparation of all compounds of formula I, in which R2, R3, R4, R5 and R6 are any combination of hydrogen, methyl, ethyl, halogen, trifluoromethyl, hydroxy and methoxy or two thereof are methylenedioxy, provided that at least two are hydrogen, and R IS hydroxy, R1 is hydrogen and Y IS -CH,F. In this process, Ii) a ketone of the formula Ill
wherein R1, R,3, Pi, R,+ and R1, are as defined above, (#) 1 to 10 equivalents of sodium cyanide and iii 1 to 10 equivalents of an ammonium salt are reacted together In d basic 01 neutral medium to obtain the corresponding aminonitrile; and the nitrite then hydrolysed with acid or base The ketones of formula Ill are novel and form a further aspect of this invention. Thev may be prepared by adding very slowly to magnesium turnings a compound of formula IV
wherein Z Is chlorine or bromine and R12, R13, R14, R15 and Rl6 are as defined above, In an ether solvent at from -20 to 70C for from 1.2 to 24 flourS, to obtain the corresponding Grignard reagent, reacting fluoroacetonitrile with the Grignard reagent, in a ratio of 0.5:1 to 3:1 in an aprotic solvent at from -20 to 70C for from 10 minutes to 12 hours, to obtain a ketimine; and hydrolysing the ketimine with acid.
The formation of the Grignard reagent is conducted in an ether solvent such as tetrahydrofuran or ethyl ether, or a mixture thereof. The reaction is preferably conducted at from 253C to the boiling point of the solvent. At the beginning of the reaction, a trace of methyl iodide is added. If R12 or R14 is methoxy, the reaction is initiated in tetrahydrofuran.
The solvent in which the Grignard reagent is reacted with fluoroacetonitrile is aprotic. Examples of suitable such solvents are tetrahydrofuran, ethyl ether, dioxane, benzene, dimethoxyethane, dimethoxymethane and mixtures thereof. The temperature of the reaction is preferably from -20 C to -255C, and the reaction time Is preferably from 10 minutes to 1 hour. The thus formed ketimine salt is hydrolysed with acid to give the ketone. Acid hydrolysis may be achieved by pouring the ketimine salt onto water and concentrated HCI, maintaining a strongly acidic medium. The ketone of Formula Ill may be isolated by conventional means, for example, by extraction with petroleum ether or pentane or hexane and then with an ether such as ethyl ether.
The ketone is converted to an aminonitrile under the conditions of a Strecker reaction by treatment with 1 to 10 equivalents of sodium cyanide and 1 to 10 equivalents of an ammonium salt such as ammonium chloride in either a basic medium using aqueous ammonium hydroxide (1 molar to concentrated) in a C14 alcohol such as methanol or ethanol or a neutral medium using water and a C1.4 alcohol.
Hydrolysis of the aminonitrile to give the desired amino acid may be achieved In various ways. For example, hydrolysis may be carried out by treatment with hydrogen bromide at 25 to 100'C for 1/2 to 24 hours. However, when HBr is used, R2 to Rg will be hydroxy rather than methoxy. Hydrolysis may also be achieved using sulfuric acid by generally known procedures or by treatment with a C1.4 alcohol, such as methanol, saturated with anhydrous hydrogen chloride, for 1 to 24 hours, preferably 10 hours, at about 0 to 50"C, preferably about 25cC, to give the corresponding aminoamide which Is hydrolysed by treatment with aqueous hydrochloric acid or 50 ,h aqueous sulfuric acid for 2 to 6 hours at 60 to 100or, preferably 95 C, with subsequent neutralisation using barium hydroxide when sulfuric acid is employed.
The preparation of fluoromethyl m-tolyl ketone is described by E.O. Bergmann et al., J Chem. Soc. 1961, 3452. The method of this invention can be distinguished readily from the prior art, since the Grignard reagents are benzylic, the temperature of the reaction mixture during the Grignard addition must be maintained at a temperature of -20-C or below, and the fluoroacetonitrile reagent employed in the present process is much iess toxic than the monofluoroacetic acid derivatives which have been used in the prior art to prepare fluoromethyl benzyl ketone.
The novel compounds of this Invention can be compounded, with a suitable prysiologically 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. 2,005,659 A. The only, minor, difference is that it is now thought preferable that, when It Is desired to achieve a central irreversible Inhibition of an aromatic decarboxylase or 3,4-dlhydroxy-phenylalanine decarboxylase, the effective amount of compound administered may be from 25 to 500, and preferably from 50 to 300, mg kg of body weight of the patient per day. The desired central effect can be achieved by administration of a unit dosage form, e.g. a tablet, containing from 350 to 500 mg of a novel compound of this invention taken from to 10 times daily.
Further, the novel compounds are useful in the preparation of cephalosporin derivatives analogous to those which can be prepared from the known compounds of formula I isee formula II In British Patent Publication No. 2,005,659 Al. The cephalosporin derivatives, which can have antibiotic activity, can be prepared from the compounds of this invention in which R Is hydroxy using the same coupling reagent (7-aminocephalosporansc acid or Its acetyl ester, or a salt thereof and the same reaction conditions as described In British Patent Pubilcation No. 2,005,659 A.
The Individual optical isomers of the compounds of the Invention may be obtained by conventional methods, e.g. as described In British Patent Publication No. 2,005,659 A.
The following Examples illustrate the Invention Example 1 iilustrates the preparation of a novel ketone Intermediate of this Invention and Examples 2 and 3 lilustr3te the novel process for preparing -halomethyl-amino acids.
EXAMPLE 1 1 -Fluoro-3-/3, 4-dlmerhoxyphenyli-2-propanone Under an atmosphere of nitrogen,3,4-dimethoxybenzyl chloride 112.20 p: n tetrahycirofuran lTHF 80 mi Is added slowly (within one houri to magnesium turnings 13.0 gi In THE 150 ml in a flask, whereupon the flask IS Immersed In a bath containing water at room temperature. Stirring is continued for one hour. The Grignard reagent Is then separated from the excess Mg, transferred into a second flask (under nltrogen tind cooled to -20 C. CHrFCN (4.0 gi in THE t25 ml) Is added from a dropping funnel at such a rate that the internal temperature Is mantained between -25 and - 20 C. After the addiction Is complete, stirring Is continued for one hour at -20 C. The solution Is then poured onto a mixture of Ice i200gl. water i240 mi) an concentrated HCI t120 ml)and extracted with petroleum ether 12 x 100 mali and ethyl ether !4 x 100 mit.
Drying INa;,SO,) and evaporation of the ethereai extract yieids 4.53 g 133",i of pure ketone, b.p. 100 C 0.35 mm Hg.
By substituting an appropriate amount of p-methoxybenzyl bromide for the 3,4-dimethoxybenzyl chloride in the above Example, 1 -fluoro-3-(p-methoxyphenyl)-2-propanone is obtained.
EXAMPLE 2 2-Fluoromethyl-2-amino-3-{3,4-dihydroxyphenylJpropionic acid To a suspension of 1-fluoro-3-(3,4-dimethoxyphenyl)-2-propanone (31.5 g; 0.149 mole) and ammonium chloride (9 57 ; 0.179 mole) in a solution of 28% aqueous ammonia (170 ml), sodium cyanide (8.77 g 0 179 0.179 mole) is added. The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The solid which separates is filtered off on a sintered glass, and then washed with 28% aqueous ammonia (50 ml). The solid is dissolved in ethyl ether (1.3 litres) and the organic phase is washed with water and then with brine, and dried over MgSO4. Upon concentration of the solvent, 2-amino-2-fluoromethyl-3-(3,4-dimethoxy- phenyl)propionitrile crystallises (21.8 g), m.p. 76"C.
A solution of 2-amino-2-fluoromethyl-3-(3,4-dimethoxyphenyl)propionitrile (20.7 g or 0.086 mole) in 47% aqueous hydrobromic acid (300 ml) is heated under nitrogen at 100C for 32 hours. Concentration of the solvent under reduced pressure leaves a residue which is dissolved in isopropanol (300 ml). The solution is aged for 12 hours at 4"C. The ammonium bromide which separates is filtered off and washed with isopropanol (3 x 40 ml). The filtrate is neutralised with triethylamine (16 g) in isopropanol until the pH of the solution reaches 4.5-5. The precipitate which is formed is collected and washed extensively with chloroform.
The residue (19.4 g) is dissolved in water (500 ml) and treated with charcoal. Upon concentration, a-fluoromethyl DOPA crystallises (13 g). From the mother liquor, a second batch (1.2 g) of 2-fluoromethyl-2amino-3-(3,4-dihydroxyphenyl)propionic acid is obtained, m.p. 230 C.
When an appropriate amount of 1 -fluoro-3-(p-methoxyphenyl)-2-propanone is substituted for the 1-fluoro-3-(3,4-dimethoxypheny )-2-propanone in the above Example, 2-amino-2-fluoromethyl-3-(pmethoxyphenyl)-propionitrile is obtained.
EXAMPLE 3 2-Fluoromethyl-2-amino-3-(p-methoxyphenyl)propionic acid A solution of 2-amino-2-fluoromethyl-3-(p-methoxypheny )propionitrile hydrochloride (1.0 g) in anhyd rous methanol 40 ml) is saturated with dry HCI under ice cooling. The mixture is allowed to stand overnight at room temperature. Evaporation of the solvent gives the corresponding amide hydrochloride in quantitative yield. nmr (020) J ppm: 6.88 (4H, AB, JAB 9Hz). 4.76 (2H, 2AB, JAB = 1 1 11 Hz, JF = 46 Hz), 3.64 (3H, s), 3.08 (2H, AB, Jae = 14Hz).
The thus obtained amide hydrochloride (600 mg), dissolved in 3N NaOH (50 ml) and extracted with Et2O (3 x 50 ml), gives the free amide (420 mg), nmr (CDCI3) J ppm: 6.94 (4H, AB, JAB = 9 Hz); 4.56 (2H. 2AB, JAB = 9 Hz, JHF = 47 Hz); 3.80 (3H, s), 3.0 (2H, AB, JAB = 14 Hz),1 1.68 (2H, broad s).
The free amide (920 mg) and 50 vol. % aq. H2S04 (7 ml) are heated to 95 C for 2 hours. The mixture is diluted with water to a volume of 50 ml and neutralised with a Ba(OH)2 solution (total volume is then about 150 ml). An equal volume of 0.2 N H2 S04 is added, and the BaSO4 removed by filtration over Celite. The filtrate is passed on an Amberlite (registered Trade Mark) resin column (ca. 50 ml, H form), the resin washed to neutrality with water and eluted with 3 N NH40H (150 ml). On evaporation of the ommonio fraction, 2-f uoromethyl-2-amino-3-(p-methoxyphenyl)propionic acid is obtained 1390 mg); nmr (D2OJDCI) J ppm: 7.0 (4H, AB, JAB = 9Hz), 4.80 )2H. 2AB, JAB = 11 Hz, Jl1f = 46 Hz), 3.80 (3H, s),3.20 (2H, AB, JAB = 14 Hz).

Claims (18)

1. A process for preparing a compound of the formula
wherein R2, R3, R4, Rs and R6 are independently selected from hydrogen, methyl, ethyl, tert-butyl, halogen, trifluoromethyl, hydroxy and methoxy or two of R2, R3, P4, R5 and P6 are methylenedioxy, provided that at least two of R2, R3, R4, R5 and R6 are hydrogen, which comprises reacting (i) a ketone of the formula
wherein R12, Rl3, R14, R15 and R16 are as defined above for R2, R3, R4, R5 and R6, respectively, provided that adjacent hydroxy groups are protected as methoxy or -O-C(CH3)2-O-, hydroxy groups in the presence of methoxy groups are protected as benzyloxy, and single and non-adjacent hydroxy groups are protected as methoxy; (ii) 1 to 10 equivalents of sodium cyanide and (iii) 1 to 10 equivalents of an ammonium salt ion a basic or neutral medium, to obtain the corresponding aminonitrile; and hydrolysing the nitrile with acid or base.
2. A process according to claim 1 substantially as described in Example 2 or Example 3.
3. A process for preparing a ketone as defined in claim 1, which comprises adding very slowly to magnesium turnings a compound of the formula
wherein Z is chlorine or bromine and Rl2, R13, Rl4, R15 and R16 are as defined in claim 1, in an ether solvent at from -20 to 70"C for from to 24 hours, to obtain the corresponding Grignard reagent; reacting fluoroacetonitrile with the Grignard reagent, in a ratio of 0.5:1 to 3:1, in an aprotic solvent at from -20 to 70 Cforfrom 10 minutes to 12 hours, to obtain a ketimine; and hydrolysing the ketimine with acid.
4. A process according to claim 3 substantially as described in Example 1.
5. A process according to claim 1 in which the ketone is prepared by a process according to claim 3 or claim 4.
6. A ketone as defined in claim 1.
7. 1-Fluoro-3-(3,4-dimethoxyphenyl)-2-propanone.
8. A process or compound according to any preceding claim in which R2, R3, R4, R5 and Rg are as defined in claim 1 of British Patent Publication No. 2,005,659 A.
9. A process or compound according to any preceding claim in which R2, R3, R4, R5 and Rg are one of the
10 combinations defined in the following Table; R2 R3 P4 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 OCH3 H H OH H H OH H OH CH3 OH H H OH H H H OH OH H H H CH3 10. A compound of the formula
wherein Y is -CH2F, -CHF2, -CH2Cl or -CHCl2; R Is hydroxy, C1-8 alkoxy. -NP7P8 in which R7 and R8 are each hydrogen or C1 4 alkyl, or -NH-CHR9-COOH in which P8 is hydrogen, C1 4 alkyl, benzyl orp-hydroxybenzyl; R1 is hydrogen, (C1-4 alkyl)carbonyl, (C1.4 alkoxy)carbonyl or -CO-CHR27-NH2 in which R27 is hydrogen, C14 alkyl, benzyl orp-hydroxybenzyl; and R2, R, R4, R5 and P6 are as defined in claim 9; or a pharmaceutically acceptable salt thereof.
11. A compound as claimed in claim 10 wherein R1 is hydrogen or (C14 alkyl)carbonyl.
12. A compound as claimed in claim 10 or claim 11 wherein R is hydroxy or C1 8 alkoxy.
13. A compound as claimed in claim 10 wherein R1 is hydrogen and R is hydroxy.
14. A compound as claimed in any of claims 10 to 13 wherein Y is -CH2F or -CHF2.
15. A compound as claimed in claim 13 wherein Y is -CHF2.
16. A compound as claimed in any of claims 10 to 15 wherein two of R2, R3, R4, R5 and P6 are hydroxy or methoxy and the others are hydrogen.
17. A compound as claimed in claim 16 wherein R2 is hydroxy, R3 is hydrogen, one of R4, R5 and P6 is hydroxy and the others are hydrogen.
18. A pharmaceutical composition comprising a compound as claimed in any of claims 10 to 17 in association with a physiologically acceptable excipient.
GB8013819A 1979-04-26 1980-04-25 A-halomethylamino compounds and their preparation Expired GB2050356B (en)

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