GB2051806A

GB2051806A - Hexahydrazepine piperidine and pyrrolidine derivatives

Info

Publication number: GB2051806A
Application number: GB8019748A
Authority: GB
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1979-07-03
Filing date: 1980-06-17
Publication date: 1981-01-21
Also published as: IE801249L; EP0021772B1; DE3069897D1; JPS5625155A; US4296029A; EP0021772A1; JPH0120149B2; IE49912B1; GB2051806B; ATE11046T1

Abstract

2-Oxo-hexahydroazepine, -piperidine or pyrrolidines of formula <IMAGE> wherein n is 2,3 or 4, R is hydrogen, lower alkyl, aryl(lower)alkyl, loweralkenylmethyl or cycloalkylmethyl, R1 is hydrogen or lower alkyl and R2 is hydrogen, lower alkyl or aryl(lower)alkyl are prepared by a novel process involving reaction of an anion of a lactam of formula <IMAGE> where R3 is lower alkyl, aryl(lower)alkyl, trialkyl-, triaryl- or triarylalkyl-silyl with a benzyne of formula <IMAGE> where R4 is lower alkyl, aryl(lower)alkyl or trialkyl-, triaryl- or triarylalkyl-silyl. The products are useful as intermediates for preparing pharmacologically active 2-unsubstituted -hexahydroazepine, -piperidine and pyrrolidine derivatives.

Description

2 051 806 A (12)UK Patent Application.)GB (ii) (21) Application No 8019748

(22) Date of filing 17 Jun 1980 (30) Priority data (31) 7923123 (32) 3 Jul 1979 (33) United Kingdom (GB) (43) Application published 21 Jan 1981 (51) INT CL3 C07D 207112 (52) Domestic classification C2C 13411532 1731215 220 226 22Y 250 251 25Y 30Y 351352 364 365 36Y 388 43X 623 624 625 662 699 761762 AB TT (56) Documents cited None (58) Field of search C2C (71) Applicants John Wyeth and Brother Limited, Huntercombe Lane South, Taplow, Maidenhead, Berkshire (72) Inventors (54) Hexahydroazepine, piperidine and pyrrolidine derivatives.

(57) 2-Oxo-hexahydroazepine, -piperidine or pyrrolidines of formula /,--,-c 2 (CH) OR 3 n 1 N 0 1 H RI wherein n is 2,3 or 4, R is hydrogen, lower alky], aryl(lower)alkyl, loweralkenyImethyl or cycl oalkyl methyl, R' is hydrogen or lower alkyl and R 2 is hydrogen, lower alkyl or aryf(fower)afkyl are prepared by a novel process involving reaction of an anion of a lactam of formula 1 (CH2) C 'n 1 ERRATUM SPECIFICATION NO 2051806A 1,

Page 5, lines 36 to 45, delete existing formula. insert R5 OR2 c (CH2)n -. \"'N- _j -. d. - - c) m 1 R N) C11 (J1 Bas 86984110 ---1 THE PATENT OFFICE 2.4 November 1981 - C0 C) a) 1 The chemical formulae appearing inthe printed specification weresubmitted afterthedate of filing. the formulae originally submitted being incapable of being satisfactorily reproduced.

C.t.e ' -, - -;. 1-. t,.

1 GB 2 051806 A 1 SPECIFICATION

Hexahydroazepine, piperidine and pyrrolidine derivatives This invention relates to hexahydroazepine, piperidine and pyrrolidine derivatives. More particularly the 5 invention relates to a novel process for preparing 2-oxo-hexahydroazepine, -piperidine and -pyrrolidine derivatives.

The 2-oxo-hexahydroazepine, -piperidine and pyrrolidine derivatives prepared by the novel process of the present invention have the general formula (1) R1 10 (C H 2),, OR N 0 15 1 wherein n is 2,3 or 4, R is hydrogen, lower alkyl aryl (lower) alky, loweralkeny1methyl or cycloal kyl m ethyl, R1 is hydrogen or lower alkyl and R 2 is hydrogen, lower alkyl or aryl (lower) alkyl.

These derivatives may be converted to the pharmacologically active 2unsubstituted -hexahydroazepine, -piperidine and pyrrolidine derivatives of general formula (11) 11- "-- R 5 2 (CH2), C OF? 11 11-i N 1 R (11) where n, R and R2 have the meanings given above and R' is lower alkyl. Compounds of general formula (1) in which R' is hydrogen may be C-alkylated (e.g. by reaction with an alkyl halide in presence of a strong base) to compounds of general formula (1) in which R, is lower alkyl. Compounds of general formula (1) in which R' 35 is lower alkyl may be reduced (e.g. with a hydride transfer agent such as lithium aluminium hydride) to the compounds of general formula 11. Compounds of general formula (11) in which R 2iS lower alkyl or aryl (lower) alkyl may be ether cleaved (e.g. with hydrogen bromide or boron tribromide(to compounds in which R' is hydrogen. The use of the compounds of formula (11) and their preparation from compounds of formula (1) is further exemplified in, for example, U.K. Patent Specification No. 1,285, 025 and European Patent Application 40

Publication No. 0 003 253. The present invention provides a novel process for preparing the intermediates of general formula (1).

According to the present invention there is provided a process for preparing a compound of general formula (1) which comprises reacting an anion of a lactam derivative of general formula (111) 1 45 (CH2) C \,, n ->H N 0 50 1 R3 w 1) k v where n and R' are as defined above and R' is lower alkyl, aryl (lower) alkyl, trialkyl-, triaryl- or triarylalkylsilyl, loweralkenymethyl or cycloalkyl methyl with a benzyne of general formula OV) 0 R 6 (IV) 4 2 GB 2 051806 A 2 where R' is lower alky], aryl or trial kyl-triaryl- or triaryalkyl-silyl to give an anion of the compound of general formula 1 where R' is lower alkyl or a dianion of the compound of general formula 1 where R' is hydrogen (if desired reacting the dianion where R' is hydrogen with a (lower) alkylating agent to give an anion of the compound of general formula 1 where R' is lower alkyl) and protonating the anion or dianion of the 5 compound of general formula 1 to give a compound of general formula 1.

The term "lower" as used herein means thatthe radical referred to contains 1 to 6 carbon atoms. The radical preferably contains 1 to 4 carbon atoms. For example when R or R' is lower alkyl, the radical may be, for example, methyl, ethyl, propyl or butyl. Similarly R' may be, for example, methyl, ethyl, propyl or butyl. When R, R 2, R 3 orR 4 is aryl (lower) alkyl, the radical is preferably a phenyl (lower) alkyl radical such as phenethyl or benzyi; the phenyl group maybe substituted by, for example, substituents such as alkyl or alkoxy. When R or R 3 is loweral kenym ethyl the radical is preferably allyl. When R or R' is cycloalkylmethyl the radical is preferably cyclopropyl methyl or cyclobutyl methyl.

The anion of the lactam of general formula (111) may be formed in situ by reacting the lactam with an alkyl lithium (e.g. tertiary butyl lithium) or with a compound of general formula MA where M is sodium, potassium or lithium and A is a secondary amine radical. The compound MA is a metal amide and is itself preferably 15 formed in situ by reacting a metal compound MR5 (where M is sodium, potassium or lithium and R 5 is alkyl, aryl or aralkyl) with a secondary amine. The secondary amine may be a dialkylamine, e.g. diethylamine, di- isopropyl-amine, di-tertiarybutylamine, di-cyclohexylamine, t-butyl- cyclohexylamine, N-t-amy]-N-tbutylamine, N-isopropyl-N-cyclohexylarnine or N-W-ethylcyclohexyl) -1,1,3 3-tetra methyl butyl am ine or a cyclic compound, e.g. piperidine or 2,2,6,6-tetra methyl pi peridi ne. Preferably the anion of the lactam is formed by reacting the lactam with lithium 2,2,6,6,-tetra methyl p iperid ide (which may be prepared in situ from 2,2,6,6-tetra methyl pi perid i ne and, for example, butyl lithium).

The benzyne of general formula (R) is formed in situ by, for example, reaction of a substituted halobenzene of general formula (V) 1 OR c::) Hol (V) where R 4 is as defined above and Hal is chlorine, bromine or iodine (preferably chlorine) with a strong base, such as an agent mentioned above for the formation of the anion of the lactam of formula (IV). Preferably the strong base is lithium 2,2,6,6-tetram ethyl pi peridide (which as mentioned above may be formed in situ).

In an especially preferred process the formation of the anion of the lactam (111) and the formation of the benzyne is carried out in the same reaction vessel to give the anion or dianion of the compound (1). For example, a base such as lithium 2,2,6,6-tetramethylpiperidide (formed in situ) may be reacted with a lactam of formula (111) to give the anion of the lactam and further lithium 2,2, 6,6-tetra m ethyl p i peri d ide may be generated in situ (by for example adding an alkyl lithium such as butyl lithium) and the substituted halobenzene (V) then added. The addition of the required quantity of substituted halobenzene (V), together 40 with the further generation of the lithium 2,2,6,6-tetram ethyl pi peridide or other base, may be carried out in two or more separate additions.

The anion or dianion of the compound (1) may be protonated without isolation. For example it may be protonated by reaction with water or dilute aqueous mineral acid (e.g. dilute hydrochloric acid) e.g. an excess of water may be added to the reaction vessel orthe reaction mixture may be added to the water. If desired the dianion of the compound in which R' is hydrogen may be reacted with a (lower) alkylating agent, for example a lower alkyl halide (preferably a lower alkyl iodide(, to give an anion of formula (1) in which RI is lower alkyl. This anion may then be protonated, e.g. by reaction with water.

When R 3 and/or R 4 is trialkyl-, triaryl- or triaryalkylsilyl the hydroylsis of the product gives a compound of formula I in which R and/or R' is hydrogen. The hydrolysis may occur during protonation of the anion or 50 dianion of compound (1) by reaction with water.

The lactams of general formula (111) are known compounds or can be prepared by known methods, e.g. by N-"alkylation" of corresponding lactams in which R 3 is hydrogen.

EXAMPLE 1 3-Ethylhexahydro-3-(3-methoxyphenyl)- 1-methyl-2H-azepin-2-one A solution of butyl lithium (0.05 mole) in hexane (31.25 mi) was treated with 2,2,6,6-tetra methyl pi peridi ne (8.5 mi) followed by dry tetrahydrofuran C71-IF"; 100 mi) under an inert atmosphere at O'C. The mixture was treated with a solution of N-methylcaprolactarn (6.25 mi, 50 mM) in THF (20 mi) and stirred for 30 minutes. A solution of butyl lithium (0.05 mole) in hexane (31.25 ml), was added and the mixture stirred for 15 minutes. 60 A solution of o-chloroanisole (6.2 mi) in THF (20 mi) was added slowly, the mixture stirred for 1.5 hours and treated with ethyl iodide (5.15 mi). After one hour, the reaction was quenched with water (100 mi) and the solvents removed under reduced pressure. The residue was partitioned between 2N HCI (200 mi) and toluene (250 m]). The organic layer was washed with brine, dried and the solvents removed under reduced pressure, to give 3-ethyihexahydro-3-(3-methoxphenyi)-1-methyi-2H-azepin2-one (5.5 9) b.p. 14C0.1 mm.65 j Q 3 GB 2 051806 A 3 Recrystallisation from diisopropyl ether gave pure title compound (5.0 9) m.p. 68-690C, identical with authentic material.

EXAMPLE 2

Hexahydro-3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one A solution of butyl lithium (0.05 mole) in hexane (34.4 ml), was treated with 2,2,6,6-tetramethyl-piperidine (9.3 m]) followed by dry THF (100 mi) under an inert atmosphere at O'C. The mixture was treated with Wmethyicaprolactam (6.9 mi, 55 mM) and stirred for 30 minutes. A solution of butyl lithium (0.05 mole) in hexane (34.4 mi) was added, the reaction mixture stirred 15 minutes then treated with o-chloroanisole (3.1 mi). After 30 minutes a solution of butyl lithium (0.05 moles) in hexane (31.25 mi) was added, the mixture 10 stirred for 15 minutes and treated with o-chloroanisole (3.1 mi). After a further 30 minutes, the reaction was quenched with water (100 mi) and the solvents removed under reduced pressure. The residue was partitioned between 5N HCI (100 mi) and toluene (250 mi). The organic phase was washed with brine, dried and the solvents removed under reduced pressure.

Distillation of the residue gave crude title compound (5.4 g) b.p. 150'/0. 5 mm. Recrystallisation from 15 diisopropyl ether gave pure material (4.2 g), m.p. 74-750C identical with authentic material.

EXAMPLE 3 Hexahydro-3-(3-methoxyphenyl)- 1-methyl-2H-azepin-2-one A solution of butyl lithium (0.05 moles) in hexane (31.25 m[), was treated with 2,2,6,6 tetramethylpiperidine (8.5 m[), followed by THF (100 mi) under an inert atmosphere at O'C. A solution of N-methylcaprolactam (6.25 m], 50 mM) in THF (20 mi) was added, the mixture stirred for 30 minutes and treated with a solution of butyl lithium (0.05 mole) in hexane (31.25 mi) After 15 minutes, o-chloroanisole (6.2 mi) was added and the mixture stirred forfifteen hours at ambient temperature.

The reaction was quenched with water (100 mi), the solvents removed in vacuo and the residue partitioned 25 between 5N HCl (100 mO and toluene (250 ml). The organic phase was washed with brine, dried and the solvents removed under reduced pressure. Distillation of the residue gave crude title compound (40%) b.p.

about 140010.05 mm. Recrystallisation from isopropyl ether gave ptre material (31%), m.p. 74-75'C, identical with authentic material.

EXAMPLE4

3-Ethylhexahydro-3-(3-methoxyphenyl)- 1-methyl-2H-azepin-2-one 2,2,6,6-tetramethylpiperidine (8.48 g) was added dropwise with cooling and stirring under nitrogen to a solution of butyl lithium (0.05 mole) in hexane (31.25 mi) and tetrahydrofuran (15 m]). 3-Ethylhexahydro-1 methyl-2H-azepin-2-one (7.75 g) in dry tetrahydrofuran (20 mi) was added. On completion of this addition a 35 further portion of butyl lithium (0.06 mole) in hexane (37.5 ml)was added with cooling. After ten minutes o-chloroanisole (8.54 g) was added dropwise in tetrahydrofuran (20 ml). The reaction was then stirred at ambient temperature for c.a. 20 hours. The reaction mixture was poured into water, and the tetrahydrofuran removed under reduced pressure. After acidifying with 5M hydrochloric acid the mixture was extracted with toluene. Toluene extracts were washed with water, dried (M9S04) and after removal of the solvent the product distilled affording 2.37 g, b.p. 150- 170'C atO.6 mm. Corrected for purity by g.i.c. assay, the yield of the title compound was 15.8%.

EXAMPLE 5

Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one Hexahydro-1 -trimethyisilyi-2H-azepin-2-one (9.2 g) in dry tetrahydrofu ran (20mi) was added dropwise with cooling and stirring under a nitrogen atmosphere to a solution of 1 ith i u m-2,2,6,6-tetra methyl pi peridide (prepared from 2,2,6,6-tetra methyl pi peridi ne (8.48 g) and butyl lithium (0.06 mole) in hexane tetrahydrofuran (38mi; 10 mO. A further portion of butyl lithium (0.06 mole) in hexane (38 mi) was then added, followed by o-chloroanisole (8.54 9) keeping the reaction temperature between - 10' and 5' C. After 50 allowing to warm to room temperature the reaction was stirred for 1.5 hours then decomposed by the addition of water (100 mi). The solvents were removed under reduced pressure, the resulting product partitioned between toluene and 5M hydrochloric acid. The toluene extracts were dried (M9S04), the solvent removed and the product distilled affording 2.7 g b.p. 160-170'C at 0.1 mm, which yielded 2.6 9 of the K 55 crystalline title compound from ethyl acetate.

EXAMPLE 6

1-Benzylhexahydro-3-(3-methoxyphenyl) 2H-azepin-2-one 1 -Benzy[hexahydro-2H-azepi n-2-one (10.2 g) in tetrahydrof u ran (100 m[) was added dropwise to a stirred, cooled solution of lithium-2,2,6,6-tetramethylpiperidide [prepared by the addition of 2,2,6,6 tetra methyl pi peridi ne (8.5 g) to butyl lithium (0.05 mole) in hexane (32 mi)l under nitrogen. When the addition was completed a further portion of butyl lithium (0.05 mole) in hexane (32 m[) was added. The solution was cooled to O'C and o-chloroanisole (6.2 ml) added dropwise. After stirring at room temperature for four hours the reaction was decomposed with water and the solvents removed under reduced pressure.

The resulting oil was partitioned between 5M hydrochloric acid and toluene. After drying (M9S04) the 65 4 GB 2 051 806 A toluene was removed to leave an oil which was distilled affording 5.02 9 b.p. 180-2200C at 0.2 mm. The oil was crystallised from methanol, affording 3.15 g m.p. 120-122'C. Analysis: Found C,77.6; H7.7; W, 4.6. C20H23NO2 requires C,77.6; H,7.5; N4.5%.

EXAMPLE 7

Hexahydro-3-(3-methoxyphenyl)- 1-methyl-2H-azepin-2-one Diisopropylamine (152 9) in tetrahydrofuran (150 mi) was added over 30 minutes to 15% butyl lithium in hexane (641 g, 1.50 mole) under nitrogen at 20-250C with cooling and the mixture stirred 30 minutes at room temperature. N-methylcaprolactam (63.6 g) in tetrahydrofuran (60 mi) was added over 5 minutes below 250C with cooling, the mixture was stirred for one hour at room temperature and then o-chloroanisole (71.3 g) was added over 20 minutes keeping the temperature below WC. The reaction mixture was stirred for two hours, water (2.l.) was added, the product was extracted into ethyl acetate (2 x 11.), the extracts were combined, washed with 2N hydrochloric acid (V.) and water (500 mi) and evaporated under reduced pressure to give 27.1 g oil.

The crude product was purified by column chromotography by eluting through a basic alumina column with toluene and concentrating the fractions to yield 8.7 g of title compound with melting point 74-760C.

EXAMPLE 8

3-(3-Hydroxyphenyl)-1-methyl-2-pyrrolidone Following the procedure of Example 3, reaction of the lithium anion of 1- methyl-2-pyrrolidone with m-methoxybenzyne (from lithium 2,2,6,6-tetra methyl pi peridide and o-chloroanisole) followed by aqueous workup gives 3-(3-methoxyphenyi)-1-methyi-2-pyrrolidone. Removal of the protecting group using iodotrimethylsilane gives the title compound m.p. 1134C (ethyl acetate-hexa ne).

4 101 EXAMPLE 9

3-(3-Hydroxyphenyl)- 1-methyl-2-piperidone Following the procedure of Example 3, reaction of the lithium anion of 1 - methyl-2-piperidine with m-benzyloxybenzyne (from lithium 2,2,6,6-tetra methyl pi peridide and obenzyioxychlorobenzene) followed by aqueous work up gives 3-(3-benzyioxyphenyi)-1-methyi-2-piperidone. Removal of the protecting group 30 by hydrogenolysis over palladium on carbon gives the title compound) as the quarter hydrate m.p. 11 1-40C (hexane).

EXAMPLE 10

Hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one Following the procedure of Example 3, reaction of the lithium anion of Nmethylcaprolactam with m-triphenyisilyloxybenzyne (from ochlorotriphenyisilyloxy-benzene and lithium tetra methyl pi peridide) followed by workup with aqueous acid gives the title compound m.p. 1923'C (ethylacetate).

Claims

1. A method of preparing a 2-oxo-hexahydroazepine, 2-oxo-piperidine or2oxo-pyrrolidine of general formula (1) ",."c R] P2 45 (C Hg) n 50 1 R wherein n is 2,3 or 4, R is hydrogen, lower alkyl aryl(lower)alkyl lower alkenyimethyl or cycloalkyl methyl, R, is hydrogen or lower alkyl and R2 is hydrogen, lower alkyl or aryl(lower)alkyl which comprises reacting an 55 anion of a lactam derivative of general formula (111) 1 (C H 2), C \, n -,:C-H N 0 1 3 P, (111) -45 GB 2 051806 A 5 where n and R' are as defined above and R 3 is lower alkyl, aryl(lower)alkyl, trial kyl-,triaryl-or triary)- alkylsilyljoweralkenylmethyl or cycloalkylmethyl with a benzyne of general formula (IV) (6 (IV) 5 where R' is lower alkyl, aryl(lower)alkyl ortrialkyl-, triaryl- ortriarylalkyl-silyl to give an anion of the compound of general formula 1 where R' is lower alkyl or a dianion of the compound of general formula 1 where R' is hydrogen (if desired reacting the dianion where R' is hydrogen with a (lower)alkylating agent to give an anion of the compound of general formula 1 where R' is lower alkyl) and protonating the anion or dianion of the compound of general formula 1 to give a compound of general formula 1.

2. A method as claimed in claim 1 wherein the anion of the lactam derivative of general formula Ill is 15 formed in situ by reacting the lactam derivative of general formula (ill) with an alkyl lithium or with a compound of general formula MA where M is sodium, potassium or lithium and A is a secondary amine radical.

3. A method as claimed in claim 2 wherein the anion of the lactam derivative is formed by reacting the lactam derivative with lithium 2,2,6,6-tetra methyl pi peridi de.

4. A method as claimed in anyone of claims 1 to 3 wherein the benzyne of general formula (IV) is formed in situ by reacting a substituted halobenzene of general formula (V) f' 1, OR 1 Ha M where R 4 is as defined in claim 1 and Hal is chlorine, bromine or iodine with a strong base.

5. A method as claimed in claim 4 wherein the strong base is lithium 2,2, 6,6-tetramethylpiperidide. 30

6. A method as claimed in anyone of claims 1 to 5 wherein the anion of dianion of the compound of general formula (1) is protonated in situ by reaction with water or dilute aqueous mineral acid.

7. Amethod asclaimed in anyone of claims 1 to 6wherein n is4and R1 is ethyl.

8. A method of preparing a 2-unsubstituted-hexahydroazepine, -piperidine or-pyrrolidine derivative of general formula (11) R1 1 c,-' p2 (C H -)) n 40 A - N 0 (1) 1 (where n, R and R 2 are as defined in claim 1 and R 5 is lower alkyl) which comprises preparing a 2-oxo-hexahydroazepine, -piperidine or;. pyrrolidine of general formula R, /1_---1 C.1 P2 50 (C H) N 0 (1) 1 55 A R (where n, R, R' and R' are as defined in claim 1 by the method claimed in any one of claims 1 to 7, where R' in the compound of general formula (1) is hydrogen C-alkylating the compound to give a compound of general formula (i) in which R' is lower alkyl, and reducing the compound of general formula (1) in which R' is lower 60 alkyl to give a compound of general formula (11) and, if desired, where in the compound of formula 11 R 2 is lower alkyl or aryi(lower)alkyl ether cleaving the compound to give a compound in which R2 is hydrogen.

9. A method as claimed in claim 8 wherein in general formula (11) n is 4, R is methyl, R 2 is hydrogen and R5 is ethyl

10. A method of preparing a 2-oxo-hexahydroazepine, 2-oxo-piperidine or2- oxo-pyrrolidine substantial65 6 GB 2 051 806 A 6 ly as hereinbefore described with reference to any one of the Examples.

11. A 2-oxo-hexahydroazepine, 2-oxo-piperidine or 2-oxo-pyrrolidine whenever prepared by the process claimed in any one of claims 1 to 7 and 10.

12. A 2-unsubstituted-hexahydroazepine, -piperidine or -pyrrolidine whenever prepared by the process 5 claimed in claim 8 or 9.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.

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