GB2375108A

GB2375108A - Production of a bicycloheptanone

Info

Publication number: GB2375108A
Application number: GB0110884A
Authority: GB
Inventors: Justin Stephen Bryans; David Clive Blakemore
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2001-05-04
Filing date: 2001-05-04
Publication date: 2002-11-06
Also published as: GB0110884D0; AR033304A1; WO2002090306A1

Abstract

This invention relates to a process for the production of (1R,5S)-bicyclo[3.2.0]heptan-3-one. This compound is useful <I>inter alia</I> as an intermediate for the synthesis of analogues of gabapentin (Neurontin¹). The reaction process is illustrated by the following scheme: <EMI ID=1.1 HE=83 WI=119 LX=511 LY=1006 TI=CF> <PC>wherein R is an alkyl or an aryl group; X is iodine or bromine; and R' is an alkyl group.

Description

PROCESS FOR PRODUCTION OF CYCLIC KETONE FIELD OF THE INVENTION This invention relates to a process for the production of the cyclic ketone

(lR, 5S)-bicyclo [3. 2. 0] heptan-3-one. This compound is useful inter alia as an t intermediate for the synthesis of analogues of gabapentin (Neurontin < S)).

BACKGROUND TO THE INVENTION Gabapentin (Neuronting) is an anticonvulsant agent that is useful in the treatment of epilepsy and that has recently been shown to be a potential treatment for neurogenic pain. It is (l-aminomethyl-cycIohexy1) -acetic acid of structural formula :

Gabapentin is one of a series of compounds of formula

in which R. is hydrogen or a lower alkyl radical and n is 4,5, or 6. These compounds are described US-A-4,024, 175 and its divisional US-A-4, 087,544.

Their disclosed uses are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients.

The disclosures of the above two patents are hereby incorporated by reference.

Patent Application No. US 60/160725 describes a series of novel bicyclic amino acids, their pharmaceutically acceptable salts, and their prodrugs of formula:

wherein n is an integer of from 1 to 4, where there are stereocenters, each center may be independently R or S, preferred compounds being those of Formulae I-IV above in which n is an integer of from 2 to 4. The compounds are disclosed as being useful in treating a variety of disorders including epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, and sleep disorders. Certain of the compounds disclosed in that patent have high activity as measured in a radioligand binding assay using [Hjgabapentin and the u20 subunit derived from porcine brain tissue (Gee N. S. , Brown J. P. , Dissanayake V. U. K., Offord J., Thurlow R. , Woodruff G. N., 1. Bio. Chem., 1996; 271: 5879-5776). Results for some of the compounds are set out in the following table:

TABLE 1 Compound Structure a25 binding affinity ( M) (la, 3a, 5a) (3-Aminomethyl- NH2 bicyclo[3.2.0]hept-3-yl)-acetic #OH 0.038 acid (+/-)- (la, 5p) (3-OOH" Aminomethylbicyclo[3.2.0]hept-3-yl)-acetic #NH acid ((1α,3ss,5α)(3-Aminomethyl- HO2C NH2 bicyclo[3.2.0]hept-3-yl)-acetic # 0.332 acid

Patent Application No. US 60/160725 discloses inter alia a route for the production of the active compound (la, 3a, 5a) (3-Aminomethylbicyclo[3. 2. 0]hept-3-y1) -acetic acid hydrochloride which proceeds via (lR, 5S)bicyclo [3. 2. 0] heptan-3-one. The present invention addresses the problem of producing this cyclic ketone from a readily available source, and with improved yield and improved ratio of stereoisomers.

Casadevall et al, Bull. Soc. Chim. France, 1968, 1514-24, disclose the conversion of tetrahydrophthalic anhydride to bicyclo- (4, 2, 0) octene-3 trans via di-iodomethyl cyclohexene. Although they disclose the use of butyl lithium in the final step, they comment that this does not give good results, and they prefer a method using magnesium. In the present invention we have found that the use of butyl lithium in this step gives superior yields to those disclosed by Casadevall et al.

Bailey et al, J Org. Chem., 1984, 49, 2098-2107, discloses the use of tbutyl lithium in the ring-closing reaction of a, co-diiodoalkanes. However, they do not disclose this reaction using the alkene substrate

as used in our process. Also in the present invention, we have found that n-butyl lithium can be used as well as t-butyl lithium, and the n-butyl lithium has significant safety advantages, especially when used on a large scale.

SUMMARY OF THE INVENTION The present invention thus provides a process for preparing (1R, 5S)- bicyclo [3. 2. 0] heptan-3-one, which comprises: (i) reducing cis-l, 2,3, 6-tetrahydrophthalic anhydride to form a diol (I) :

(ii) reacting the diol (1) with an alkyl-sulphonyl halide or an aryl-sulphonyl halide to form an alkyl-or aryl-sulphonyl derivative (2):

where R is an alkyl or aryl group;

(iii) reacting the alkyl-or aryl-sulphonyl derivative (2) with an alkali metal iodide or bromide to form a diiodo or dibromo derivative (3):

where X is iodine or bromine; (iv) reacting the diiodo or dibromo derivative (3) with an alkyl lithium compound to form the bicyclic alkene (4):

(v) ring-opening oxidation of the bicyclic alkene (4) to form the diacid (5):

(vi) reacting the diacid (5) with an alkanol to form a dialkyl ester (6):

where R'is an alkyl group;

(vii) reacting the dialkyl ester (6) with a strong base to form the ketoester (7):

and (viii) heating the ketoester (7) to convert it to (lR, 5S)-bicyclo [3. 2. 0] heptan-3- one (8):

DESCRIPTION OF PREFERRED FEATURES The starting cis-tetrahydrophthalic anhydride is readily available from commercial sources (or via Diels-Alder reaction).

In step (i) the reduction is preferably carried out using an organometallic hydride, such as lithium aluminium hydride.

The alkyl or aryl group R is preferably alkyl having I to 6 carbon atoms or aryl having 6 to 12 carbon atoms, optionally substituted by alkyl having I to 6 carbon atoms. The alkyl or aryl sulphonyl compound in step (ii) is preferably methyl sulphonyl chloride or toluene sulphonyl chloride, so as to produce the corresponding mesyl or tosyl derivative of formula (2).

The alkali metal iodide or bromide in step (iii) is preferably sodium iodide or sodium bromide. X is most preferably iodine.

The alkyl lithium compound in step (iv) is preferably t-butyl lithium or nbutyl lithium.

, The ring-opening oxidation in step (v) is preferably carried out using sodium periodate in the presence of ruthenium trichloride, or potassium permanganate in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide.

The reaction in step (vi) is preferably carried out with an aliphatic alkanol having 1 to 6 carbon atoms, in the presence of a concentrated acid, such as sulphuric acid or hydrochloric acid.

The strong base used in step (vii) is preferably sodium hydride or potassium t-butoxide, and is generally used in the presence of a solvent such as tetrahydrofuran.

The ketoester (7) is heated in step (viii) preferably in the presence of water and dimethylsulphoxide.

EXAMPLES Our preferred synthetic route to the ketone, (lR, 5S)-bicyclo [3. 2. 0] heptan-3-one, is illustrated in the following Examples, and summarised in the following reaction scheme:

EXAMPLE 1 Synthesis of :

cis-1, 2,3, 6-Tetrahydrophthalic anhydride (37.8 g, 248.4 mmol) in THF (200 ml) was added dropwise over 1 hour to a stirring solution of lithium aluminium hydride (300 ml of a 1M solution in THF, 300 mmol) at 0 C under nitrogen. The mixture was allowed to warm to room temperature and then refluxed for 5 h. The mixture was cooled to 0 oc and quenched by careful addition of water (11.4 ml), sodium hydroxide solution (11.4 ml of a 15% w/v solution) and water (34.2 ml).

The mixture was stirred for 15 min and the precipitate was removed by filtration.

The solvent was evaporated under reduced pressure to give the diol 1 as a colourless oil (35.0 g, 99%); vmax (film)/cm-1 3320 (OH); OH (400 MHz; CD13) 5.62 (2H, s), 3.73 (2H, dd, J 10.7, 6.6), 3.59 (2H, dd, J 10.8,

3. 5), 3. 04 (2H, s), 2. 17-2. 00 (4H, m) ; m/z (ES+) 125 (M-OH, 100%), 143 (M+H, 48%). i EXAMPLE 2 Synthesis of :

Two different methods have been used for the mesylation and both are detailed below: Method A Mesyl chloride (44.2 ml, 571.3 mmol) was added dropwise to a stirring solution of diol 1 (35.0 g, 246.1 mmol) in dichloromethane (500 ml) at - 40 C under argon.

Triethylamine (86.6 ml, 621.0 mmol) was then added dropwise over 1 h and the mixture was then allowed to warm to room temperature and stirred overnight (14 h). The mixture was acidified using dilute hydrochloric acid (150 ml) and the organic layer separated from the aqueous layer. The aqueous layer was further extracted with dichloromethane (2 x 100 ml) and the combined organic fractions were washed with brine, dried (MgS04) and the solvent was evaporated under reduced pressure to give a colourless oil. Drying of the oil at 40 C under vacuum

gave the dimesylate 2 as a white solid (45. 01 g, 61 %) ; vrnax (film)/cm-l 1651 (C=C), 1345, 1197, 1174 ;

OH (400 MHz; CDC13) 5.30 (2H, s), 4.29 (2H, dd, J9. 9,7. 2), 4.17 (2H, dd, J 10.0, 7.1), 3.04 (6H, s), 2.43 (2H, m), 2.25 (2H, dd, J 16.3, 4.4), 1.98 (2H, dd, J 15.8, 5.1) ; m/z (CI+) 299 (M+H, 55%).

Method B Mesyl chloride (20 ml, 258.4 mmol) was added dropwise to stirring pyridine (100 ml) at-20 C under argon taking care that the internal temperature never rose above-10 C. Diol 1 (11.5 g, 80.9 mmol) in pyridine (60 ml) was added dropwise again keeping the internal temperature below-10 C. The mixture was then stored in the fridge overnight (16 h). The mixture was poured onto ice (150 g) and then ice cold hydrochloric acid (500 ml of a 10% solution) was added. The solid formed was collected, washed with water, cold 2N hydrochloric acid, water and then dried in the vacuum oven overnight to give the dimesylate 2 (21.0 g, 87%).

EXAMPLE 3 Synthesis of :

Dimesylate 2 (45.01 g, 150.9 mmol) and sodium iodide (56.5 g, 377.1 mmol) were refluxed in acetone (1000 ml) for 48 h. The mixture was allowed to cool and the solvent was evaporated under reduced pressure. The residue was taken up in ether (400 ml), washed with water (300 ml), brine, dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was chromatographed (Si02, heptane-ethyl acetate, 95: 5) to give the diiodide 3 (38.2 g, 70%); Rf (heptane-ethyl acetate, 9: 1) 0.64 ;

Vmax (film)/cm-l 1651 (C=C), 1435,1192 ; 8H (400 MHz ; CD13) 5.59 (2H, s), 3.20 (2H, dd, J 9. 5,5. 2), 3.10 (2H, t, J 9. 5), 2.34-2. 20 (4H, m), 2.04 (2H, m).

EXAMPLE 4

I Synthesis of :

Tert-buty1-1ithium (200 ml of a 1.7 M solution in pentane, 340 mmol) was added dropwise over 30 min to a stirring mixture of diiodide 3 (58.6 g, 161.9 mmol) in ether (216 ml) and pentane (324 ml) at-30 to-25 C under argon. After 45 min, the mixture was quenched by addition of saturated ammonium chloride solution (50 ml). The mixture was allowed to warm to room temperature and dilute hydrochloric acid (150 ml) was added. The mixture was extracted with ether (3 x 200 ml) and the combined organic fractions were washed with brine, dried (MgS04) and the solvent removed carefully (due to volatility of product) under reduced pressure to give the alkene 4;

vmax (film)/cm-' 1642 (C=C), 1434, 1364, 1192 ; OH (400 MHz ; CDC13) 5. 31 (2H, s), 2. 56 (2H, br s), 2. 13-1. 86 (4H, m), 1. 87 (2H, m), 1.58-1. 55 (2H, m).

The above reaction can be carried out using n-BuLi instead oft-BuLi.

EXAMPLE 5 Synthesis of :

Method A Sodium periodate (83 g, 388.1 mmol) was added to a stirring mixture of alkene 4 (10 g, 92.4 mmol) in ethyl acetate (185 ml), acetonitrile (185 ml) and water (277.5 ml). The mixture was cooled to 0 C and ruthenium trichloride monohydrate (0.39 g, 1.85 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. Ether (100 ml) was added and the mixture was stirred for a further 15 min. Dilute hydrochloric acid (150 ml) was added and the

mixture was extracted with ethyl acetate (3 x 300 ml). The combined organic fractions were washed with brine, dried (MgS04) and the solvent was removed under reduced pressure to give crude diacid 5; vrnax (film)/cm-'2940 (OH), 1693 (C=O) ; 8H (400 MHz ; d6-DMSO) 12.0 (2H, s, 2 x C02H), 2.66 (2H, m), 2.36-2. 27 (4H, m), 2.00 (2H, m), 1.62 (2H, m); m/z (CI-) 171 (M-H, 73%).

Method B This is an alternative to the above Method A. Potassium permanganate (65.7 g, 416.0 mmol) was completely dissolved in water (500 ml) and then cooled to 0 C. Dichloromethan (80 ml) was added followed by tetrabutyl-ammonium bromide (0.9 g) and the mixture was stirred vigorously. Alkene 4 in dichloromethane (50 ml) was added dropwise over 20 min. The mixture was allowed to slowly warm to room temperature and stirred for 16 h. The mixture was cooled to 0 C and sulphur dioxide gas was bubbled into the mixture until the solution went

colourless/pink (and all the insoluble manganese dioxide was removed). The mixture was acidified to pH = 2 and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2 x 200 ml) and the combined organic fractions were washed with brine, dried (MgS04) and the solvent was removed under reduced pressure to give diacid 5 (17.15 g, 72%) as a white solid.

I EXAMPLE 6 Synthesis of :

Concentrated sulphuric acid (0.2 mi) was added to a stirring mixture of diacid 5 (approx 92.4 mmol) in methanol at 0 C. After 16 h, the mixture was neutralised with saturated sodium hydrogen carbonate solution (10 ml) and the solvent was removed under reduced pressure. The residue was taken up in ether (200 ml), washed with water, brine and dried (MgS04). The solvent was removed in vacuo and the residue was chromatographed (Si02, heptane-ethyl acetate, 95: 5) to give the diester 6 (11.4 g, 85% from diiodide 3); Rt (heptane-ethy1 acetate, 8: 2) 0.38 ; vrnax (fi1m)/cm-1 1737 (C=O) ; 8H (400 MHz; CDC13) 3.65 (6H, s, 2 x OMe), 2.86 (2H, m), 2.45 (2H, dd, J 15.5, 6.2), 2.37 (2H, dd, J 15.5, 8.6), 2.12 (2H, m), 1.67 (2H, m).

EXAMPLE ? Synthesis of :

Method A Diester 6 (46.0 g, 229.7 mmol) in THF (300 ml) was added dropwise to a refluxing suspension of sodium hydride (11.03 g, 275. 7mmol) in THF (400 ml) under argon. After 4 h, the mixture was allowed to cool and quenched with glacial acetic acid (7 ml). Water (150 ml) was added and the mixture was

extracted with ethyl acetate (3 x 200 ml). The combined organic fractions were washed with brine, dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was chromatographed (Si02, heptane-ethyl acetate, 95: 5) to give the ketoester 7 (28.1 g, 73%); Rt (heptane-ethy 1 acetate, 9: 1) 0. 38 ; vmax (film)/cm-' 1755, 1728,1660, 1616, 1446 ; bu (400 MHz; CDC13) 3.76 & 3.71 (3H, 2 x s, OMe), 3.42-3. 02,2. 98-2.82 & 2.78- 2.64 (4H, m), 2.46-2. 14 (3H, m), 1.84-1. 60 (2H, m) ; m/z (CI-) 167 (M-H, 100%).

Method B This is an alternative to the above Method A. Potassium ter-butoxid (13.9 g, 113.3 mmol) was added to a stirring solution of diester 6 (17.5 g, 87.2 mmol) in tetrahydrofuran (400 ml) at room temperature under nitrogen. The mixture was heated to reflux and this temperature was maintained for 3 h. The mixture was allowed to cool and acidified with dilute hydrochloric acid (100 ml). The mixture was extracted with diethyl ether (3 x 100ml) and the combined organic fractions were washed with brine, dried (MgS04) and the solvent removed under reduced pressure (this was done carefully due to volatility of 7) to give crude ketoester 7 (14.2 g, 97%).

EXAMPLE 8 Synthesis of :

Ketoester 7 (28.1 g, 167.1 mmol), water (17 ml) and DMSO (250 ml) were heated to 155 C for 6 h. The mixture was allowed to cool, diluted with water (600 ml) and extracted with ether (3 x 250 ml). The combined ether fractions were washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was chromatographed (Si02, pentane-ether, 95: 5) to give the ketone 8 (18.0 g, 98%); Rf (heptane-ethyl acetate, 8: 2) 0.26 ; vmax (film)/cm-1 1738 (C=O), 1399,1157 ; 8H (400 MHz; CDCIs) 3.02 (2H, m), 2.49 (2H, ddd, J 19.2, 7.4, 1.7), 2.34 (2H, m), 2.19 (2H, d, J 19. 2).

Claims

CLAIMS 1 A process for preparing (lR, 5S)-bicyclo [3. 2. 0] heptan-3-one, which comprises :

(i) reducing cis-1, 2, 3, 6-tetrahydrophthalic anhydride to form a diol (I) : i

(ii) reacting the diol (1) with an alkyl-sulphonyl halide or an aryl-sulphonyl halide to form an alkyl-or aryl-sulphonyl derivative (2):

where R is an alkyl or aryl group; (iii) reacting the alkyl-or aryl-sulphonyl derivative (2) with an alkali metal iodide or bromide to form a diiodo or dibromo derivative (3):

where X is iodine or bromine ; (iv) reacting the diiodo or dibromo derivative (3) with an alkyl lithium compound to form the bicyclic alkene (4):

<Desc/Clms Page number 17>

(v) ring-opening oxidation of the bicyclic alkene (4) to form the diacid (5):

(vi) reacting the diacid (5) with an alkanol to form a dialkyl ester (6):

where R'is an alkyl group; (vii) reacting the dialkyl ester (6) with a strong base to form the ketoester (7):

and

<Desc/Clms Page number 18>

(viii) heating the ketoester (7) to convert it to (lR, 5S)-bicyclo [3. 2. 0] heptan-3one (8):
2 A process according to Claim 1, in which the reduction in step (i) is carried out using an organometallic hydride.
3 A process according to Claim 2, in which the organometallic hydride is lithium aluminium hydride.
4 A process according to any of Claims 1 to 3, in which the alkyl or aryl sulphonyl compound in step (ii) is methyl sulphonyl chloride or toluene sulphonyl chloride.
5 A process according to any of Claims 1 to 4, in which the alkali metal iodide or bromide in step (iii) is sodium iodide or sodium bromide.
6 A process according to any of Claims 1 to 5, in which the alkyl lithium compound in step (iv) is t-butyl lithium or n-butyl lithium.
7 A process according to any of Claims I to 6, in which the ring-opening oxidation in step (v) is carried out using sodium periodate in the presence of ruthenium trichloride or potassium permanganate in the presence of a phase transfer catalyst.

<Desc/Clms Page number 19>
8 A process according to any of Claims 1 to 7, in which the reaction in step (vi) is carried out with an aliphatic alkanol having 1 to 6 carbon atoms, in the presence of a strong acid.
9 A process according to any of Claims 1 to 8, in which the strong base used

in step (vii) is sodium hydride or potassium t-butoxide.

I 10 A process according to any of Claims 1 to 9, in which the ketoester (7) is heated in step (viii) in the presence of water and dimethylsulphoxide.