WO1991001317A1

WO1991001317A1 - Synthesis of cyclopentene derivatives

Info

Publication number: WO1991001317A1
Application number: PCT/EP1990/001198
Authority: WO
Inventors: Peter Leslie Myers; Richard Storer; Christopher Williamson
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1989-07-19
Filing date: 1990-07-18
Publication date: 1991-02-07
Anticipated expiration: 1992-01-19
Also published as: GB8916477D0

Abstract

A process is described for the preparation of the 1R-cis isomer of carbovir, [1'R,4'R]-2-amino-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-1,9-dihydro-6H-purin-6-one from carbocyclic guanosine via a cyclic orthoester of formula (III) (where R is a protecting group and R1 is a C¿1-6? alkyl group). The 1R-cis isomer of carbovir is an antiviral agent with potent activity against human immunodeficiency virus (HIV).

Description

SYNTHESIS OF CYCLOPENTENE DERIVATIVES

This invention relates to a new process for the preparation of certain optically active purine substituted cyclopentene derivatives and novel intermediates used in this process. In particular, the invention describes the synthesis of the IR-cis isomer of carbovir, [1 'R,4'S]-2-amino-9-[4-(hydroxymethyl)-2-cyclopenten-l-yl]-l,9- dihydro-6H-purin-6-one, an antiviral agent.

GB-A-2217320 discloses a group of antiviral purine substituted cyclopentene derivatives including the IR-cis isomer of carbovir, [l 'R,4'R]-2-amino-9-[4- (hydroxymethyl)-2-cyclopenten-l-yl]-l,9- dihydro-6H-purin-6-one, a compound of 0 the formula (I)

together with processes for their preparation. o The compound of formula (I) (also referred to hereinafter as (-)-carbovir) has been found to have potent activity against human immunodeficiency virus (HIV) associated with acquired immune deficiency syndrome (AIDS) [see Vince, R., ______ al., Biochem. Biophys. Res. Commun., 156 (2), 1046 (1988)]. There is however a need for improved synthetic routes to (-)-carbovir from relatively inexpensive starting materials.

We have now found a novel, efficient process for preparing the compound of formula (I) from carbocyclic guanosine. Thus, according to one aspect of the invention, we provide a process for the preparation of the compound of formula (I) and physiologically acceptable salts thereof, which comprises reacting a compound of formula (II)

(wherein R is a suitable hydroxyl protecting group) to convert the 2'- and 3'- hydroxyl groups therein to a 2',3'-ene group and thereafter removing the protecting group, together with N-deacylation (e.g. N- deacetylation) where appropriate, followed, if desired by salt formation.

In a particularly convenient embodiment of the above process the introduction of the double bond may be effected by first reacting a compound of formula (II) with an orthoester CH(OR )_j (where R is an alkyl group, for example a C-μgalkyl group such as methyl) in a solvent such as an ether (e.g. tetrahydrofuran or diisopropyl ether) or a mixture of ethers and in the presence of a suitable acid (e.g. p-toluenesulphonic acid) or pyridinium p-toluenesulphonate and at a convenient temperature (e.g. ambient to reflux) to provide a compound of formula (III) as a mixture of diasteroisomers

(where R and R are as defined previously), and then treating the compound (III) with an acidic reagent such as a carboxylic acid (e.g. benzoic acid) or more preferably a carboxylic acid anhydride (e.g. acetic anhydride) at elevated temperature (e.g. reflux) to provide a compound of formula (IV)

(where R is as defined previously and R is a hydrogen atom or an acyl, e.g. acetyl, group).

R represents any suitable hydroxyl protecting group which can be introduced and removed without affecting the rest of the molecule. Suitable hydroxyl protecting groups will be familiar to those skilled in the art and may include groups disclosed in 'Protective Groups in Organic Chemistry', Ed. J. F. W. McOmie (Plenum Press, 1973) and 'Protective Groups in Organic Synthesis' by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitable hydroxyl protecting groups include silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl or thexyldimethylsilyl). The hydroxyl protecting group may be removed by conventional techniques.

Thus, for example, when R is a silyl group such as t-butyldimethylsilyl or thexyldimethylsilyl this may conveniently be removed by adding hydrochloric acid at about ambient temperature to Intermediate (IV) in a suitable solvent such as an alcohol (e.g. ethanol or n-propanol). Alternatively, silyl groups may be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.

When the compound of formula (III) is treated with a carboxylic acid anhydride (such as acetic anhydride) as described above, the compound of formula (IV) formed is an N-acylated product (i.e. a compound of formula (IV) in which R² represents an acyl group such as acetyl). Removal of the acyl (e.g. acetyl) function may be effected, for example, using an ammonia/methanol mixture. Removal of the protecting group R from a compound of formula (IV) preceded by or followed by N-deacylation (e.g. N-deacetylation) where appropriate provides the desired compound of formula (I) or the hydrochloride salt thereof.

The compound of formula (I) may be prepared from its hydrochloride salt by addition of a base such as an alkali metal hydroxide (e.g. sodium hydroxide) in the presence of a suitable solvent such as an alcohol (e.g. n-propanol) optionally containing some water.

Salts (e.g. physiologically acceptable salts) of the compound of formula (I) may be prepared from the corresponding free base according to the methods described in GB-A-2217320.

Compounds of formula (II) may be prepared from carbocyclic guanosine, a compound of formula (V)

by reacting a compound of formula (V) with a reagent capable of introducing a suitable hydroxyl protecting group R. Suitable reagents include silyl halides such as trialkylsilyl halides (e.g. t-butyldimethylsilyl halides or thexyldimethylsilyl halides) and the reaction may be effected in a suitable solvent such as an aprotic dipolar solvent (e.g. dimethylformamide) conveniently in the presence of a suitable base such as an organic base (e.g. imidazole). The reaction may conveniently be carried out at ambient temperature.

The compound of formula (V) is known in the art [cf. Y. F. Shealy and J. D. Clayton, J. Pharm. Sci., 62, 1432 (1973) and K. Biggadike et. al., J. Chem. Soc. Chem. Commun.. 14, 1083 (1987)].

Compounds of formula (III) are novel intermediates and form a further feature of the present invention. It is to be understood that individual steps in the process described hereinabove and sequential combinations of such steps represent further aspects of the present invention.

The following exemplification illustrates the present invention but should not be construed as in any way limiting the invention. All temperatures are in °C.

Intermediate 1 π^,R,2^,S,3'R,4^,R1-2-Amino-9-r2,3-dihvdroxy-4-((((l,l- 0 dimethylethyl)dimethylsilyl)oxy)methyl)cyclopentyπ - 1 ,9-dihydro-όH- purin-6-one

To a stirred suspension of [1 'R,2'S,3'R,4'R]-2-amino-9-[2,3- dihydroxy-4- (hydroxymethyl)cyclopentyl]-l,9-dihydro-6H-purin- 6-one (carbocyclic guanosine; 1.35g) in N,N-dimethylformamide (10ml), tertiary butyldimethylsilyl chloride (0.98g) and imidazole (1.34g) were added. After stirring the mixture at 20^ for 1 5 hour the resulting solution was added dropwise to water (100ml). The precipitated solid was collected by filtration, washed with water and sucked dry. The filter cake was crystallised from absolute alcohol (50ml) to give crystalline title product (1.03g); m.p. > 305°; ^!H nmr (DMSO-d⁶) 10.54 (1H), 7.74 (1H), 6.37 (2H), 4.98 0 (1H), 4.63 (1H), 4.53 (1H), 4.17 (1H), 3.77 (1H), 3.62 (2H), 2.18 (1H), 2.01 (1H), 1.43 (1H), 0.88 (9H), 0.05 (6H).

Intermediate 2 5 ( + ) |3aS.4R.6R.6aR1-2-Amino-9-r6-((((l,l-dimethylethvn dimethylsilvDoxy)methyl)-4,5,6,6a-tetrahvdro-2-methoxy-3aH- cyclopenta- 1 ,3-dioxol-4-vπ- 1 ,9-dihvdro-6H-purin-6-one

To a hazy suspension of Intermediate 1 (375mg) in tetrahydrofuran (37.5ml), 0 distilled trimethyl orthoformate (2.5ml) and p-toluenesulphonic acid monohydrate

(6.23g) were added. After stirring the reaction mixture at 20 , under nitrogen for 15 hours, solvents were evaporated under reduced pressure. The resulting residue was subjected to column chromatography on Merck Kieselgel 60 Art 9385 (250g) r using chloroform-methanol mixtures as the eluant. Combination of the appropriate fractions gave, after evaporation of the solvents in vacuo, the title product (0.270g), m.p. 252° (dec); ^!H n.m.r. (DMSO-d₆) 10.55 (1H), 7.70 (1H), 6.35 (2H), 5.88 (1H), 4.94 (1H), 3.52 (2H), 3.24-3.10 (3H), 0.82 (9H), 0.01 (6H).

Intermediate 3 ri 'R,4'S1-2-Amino-9-r4-((((lJ-dimethvIethyl)dimethylsilyl) oxy)methyl)-2- cvclopenten- 1 -yl]- 1 ,9-dihydro-6H-purin-6-one

Intermediate 2 (255mg) was suspended in distilled acetic anhydride (12.5ml) and the mixture heated under reflux for 1.5 hours to give a clear solution. The reaction mixture was evaporated in vacuo and then co-evaporated with methanol (10ml) and toluene (10ml) to remove small amounts of residual acetic anhydride to give a pale pink solid. This was then dissolved in methanol (75ml), saturated with ammonia gas and left to stand at 20 for 15 hours. The methanol/ ammonia mixture was then evaporated in vacuo to give an off-white solid residue which was subjected to column chromatography on Merck Kieselgel 60 Art 9385 (75g) using chloroform - methanol mixtures as the eluant. Combination of the appropriate fractions gave, after evaporation of the solvents in vacuo, the title product (144mg), m.p. 235", darkened; ^!H n.m.r. (DMSO-d₆) 10.51 (1H), 7.5 (1H), 6.4 (2H), 6.07 (1H), 5.88 (1H), 5.31 (1H), 3.6 (2H), 2.89 (1H), 2.56 (1H), 1.53 (1H), 0.83 (9H), 0.01 (6H).

Intermediate 4 r rR_2'S,3 'R,4'R]-2-Amino-9-r2,3-dihvdroxy-4-(((thexyldimethylsilyl) oxy)methyl)cvclopentvn - 1 ,9-dihydro-6H-purin-6-one

Imidazole (9.25g) was added to a slurry of [l'R,2'S,3'R,4'R]-2- amino-9-[2,3- dihydroxy-4-(hydroxymethyl)cyclopentyl]-l,9-dihydro-6H- purin-6-one (19.2g) in N,N-dimethylfoιτnamide (192ml). The mixture was treated with thexyldimethylsilyl chloride (13.4ml) added drop wise. After 3 hours and then after an additional 40 minutes more imidazole and dimethylthexylsilyl chloride were added (2.3g and 3.3ml in total respectively). The mixture was left at room temperature for 48 hours and then treated with methyl isobutyl ketone (50ml) and water (384ml) added over 1 hour. After cooling in an ice bath for 45 minutes the precipitated solid was collected by filtration, washed with water, methyl isobutyl ketone and diisopropyl ether and dried in vacuo at 60° to give the title product (24.0g); m.p. 323-324°; H n.m.r. (DMSO-d₆) 10.64 (1H), 7.70 (1H), 6.26 (2H), 4.83 (1H), 4.56 (1H), 4.44 (1H), 4.20 ( 1 H ) , 3 . 83 ( 1 H ) , 3 .75 -_3 .55 ( 2 H ) , 2.24 ( 1 H ) , 2.07 ( 1 H ) , 1 .6 (2H), 0.89 (6H) , 0.85 (6H) , 0. 12 (6H); λ_{m aχ} (methanol) 255 nm (EJ 305).

Intermediate 5 rrR,4^,S]-2-Acetamido-9-r4-(((thexyIdimethylsilyl)oxy)methyl)-2- cyclopenten-1- yl]-l ,9-dihydro-6H-purin-6-one

(i) (±)r3aS .4R.6R,6aR1-2-Amino-9-r6-(((thexyldimethylsilyl)oxy methyl)-

4,5,6,6a-tetrahvdro-2-methoxy-3aH-cyclopenta-l,3-dioxol-4- yl1-l,9-dihydro-6H- purin-6-one Intermediate 4 (116.3g) was slurried in a mixture of tetrahydrofuran (600ml) and diisopropyl ether (1.2L). Pyridinium p-toluenesulphonate (13.5g) was added followed by trimethyl orthoformate (240ml). The mixture was heated at reflux for I 2 hours, cooled to 15° and treated with water (600ml). The organic layer was separated and washed with 8% sodium bicarbonate solution and 30% sodium chloride solution. The aqueous layer was washed with tetrahydrofuran, diisopropyl ether and ethyl acetate. The organic layers were combined and evaporated to give the title product as a foam (158g).

(ii) [1 'R,4'Sl-2-Acetamido-9-[4-(((thexyIdimethylsilyl)oxy)methyl)-2- cyclopenten- l-yll-l,9-dihydro-6H-purin-6-one

The product from part (i) above (158g) was dissolved in acetic anhydride (1.2L) with heating at 90° for 30 minutes. The solution was then heated at 130 C for 30 minutes and ca. 100ml of solvent removed by distillation over 2¹/-_? hours. The solution was then allowed to cool and reduced to low volume by vacuum distillation. The resulting thick suspension was cooled and treated with diisopropyl ether (1.4L). The mixture was left in a cold room overnight and the resulting dense solid filtered off, washed with diisopropyl ether and dried in vacuo at 60° to give the title product (72.9g); m.p. 216-219°; ^!H n.m.r. (DMSO-d₆) 7.82 (1H), 6.16 (1H), 5.98 (1H), 5.45 (1H), 3.63 (2H), 2.96 (1H), 2.66 (1H), 2.20 (3H), 1.6 (2H), 0.88 (6H), 0.82 (6H), 0.07 (6H), 0.07 (6H); _maχ

(methanol) 26lnm (E j 377).

Intermediate 6 r R,4'S]-2-Amino-9-r4-(((thexyldimethylsilyl)oxy)methyl)-2- cyclopenten-l-yn- 1 -9-dihydro-6H-puiin-6-one

Intermediate 5 (72.7g) was partially dissolved in methanol (725ml) and water (120ml) was added. 0.880 ammonium solution (120ml) was added and the mixture was stirred at ca. 65° for 75 minutes and then cooled in ice for 1 hours. The resulting solid was filtered off, washed with methanol- water (3:1) and dried in vacuo at 55° to give the title product (56.9g); m.p. 280-281°; n.mr. (DMSO-d₆) 10.53 (1H), 7.52 (1H), 6.41 (2H), 6.13 (1H), 5.93 (1H), 5.36 (1H), 3.62 (2H), 2.93 (1H), 2.61 (1H), 1.6 (2H), 0.87 (6H), 0.83 (6H), 0.07 (6H); λ_maχ (methanol) 255nm (E [ 373).

Intermediate 7 r R,4^,S]-2-Acetamido-9-r4-(hvdroxymethyl)-2-cyclopenten-l-vn-1.9- dihvdro-6H- purin-6-one Intermediate 5 (1.0g) was added to a stirred mixture of n-propanol (10ml) and distilled water (1ml). The mixture was treated with concentrated hydrochloric acid (0.32ml), stirred for 5 /2 hours and allowed to stand overnight. To the solution was added diisopropyl ether (20ml) over 15 minutes and the resulting suspension was cooled to ca. 5° and stirred for 30 minutes. The solid was then filtered off, washed with the reaction liquors and with cold diisopropyl ether and dried in vacuo at room temperature to give the title product (0.70g); m.p. 208-212° (dec); H n.m.r. (DMSO-d₆) 12.30 (1H), 11.91 (1H), 8.58 (1H), 6.82 (1H), 6.24 (1H), 5.97 (1H), 5.50 (1H), 3.47 (2H), 2.94 (1H), 2.68 (1H), 2.23 (3H), 1.76 (1H); λ_maχ (methanol) 261nm (E,507).

Example 1 rrR,4'Sl-2-Amino-9-r4-(hvdroxymethyl)-2-cyclopenten-l-yl]- 1,9-dihydro-

6H-purin-6-one [i.e. (-)Carbovir], hydrochloride monohydrate

Intermediate 3 (130mg) was suspended in absolute ethanol (5ml) and slightly warmed to give a clear solution. After allowing the solution to cool to 20° 1.0M hydrochloric acid (1.12ml) was added. The mixture was stirred for 1.5 hours after which the crystalline precipitate was collected by filtration and washed with absolute alcohol (10ml). The solid was dried in vacuo to give the title product as a white crystalline solid (72.2mg), m.p. 192-195° (dec); ^!H n.m.r. (DMSO-d₆) 11.6 (1H), 8.78 (1H), 7.21 (2H), 6.23 (1H), 5.91 (1H), 5.44 (1H), 3.44 (2H), 2.90 (1H), 2.64 (1H), 1.71 (1H).

Example 2

[rR,4'Sl-2-Amino-9-[4-(hvdroxymethyl)-2-cvclopenten-l-vn-l ,9- dihydro-6H- purin-6-one, hydrochloride monohydrate

Intermediate 6 (56.8g) was added to a stirred mixture of n-propanol (500ml) and water (50ml). The mixture was treated with more n-propanol (70ml) and concentrated hydrochloric acid (22ml). After 6 hours the crystals formed were harvested, washed with n-propanol and diisopropyl ether and dried to give the title product (40.2g); m.p. 192° (dec); *H n.m.r. (DMSO-d₆) 11.83 (1H), 8.89 (1H), 7.36 (2H), 6.24 (1H), 5.94 (1H), 5.47 (1H), 3.6-3.35 (2H), 2.93

(1H), 2.67 (1H), 1.76 (1H); λ_maχ (methanol) 255nm (E',449).

Example 3

[l 'R,4'S1-2-Amino-9-[4-(hvdroxymethyl)-2-cyclopenten-l-yl1-l,9- dihvdro-6H- purin-6-one The product of Example 2 (40.0g) in water (300ml) and n-propanol (150ml) was stirred with charcoal (lg) for 20 minutes. The mixture was filtered and the filter washed with water-n-propanol (2:1, 20ml). The combined filtrates were stirred with more charcoal (3g) and treated as above. The combined filtrates were stirred and 1.5M sodium hydroxide (ca. 50ml) was added. After 20 minutes more 1.5M sodium hydroxide (ca. 45ml) was added, and the resulting suspension evaporated to a thick slurry (ca. 200ml) and chilled in an ice bath for 2 hours. The product was harvested, washed with chilled water, dried at 50° overnight and re-equilibrated with air to give the title product (33.6g); ^lH n.m.r. (DMSO-d₆) 11.55 (1H), 7.61 (1H), 6.42 (2H), 6.13 (1H), 5.89 (1H), 5.37 (1H), 4.70 (1H), 3.46 (2H), 2.88 (1H), 2.61 (1H), 1.60 (1H); λ_maχ (methanol) 254nm E',564).

Example 4

[!' R 'SI^-Amino-g-^-ftvdroxymethvP-Σ-cvclopenten-l-vn-l ,9- dihvdro-6H- purin-6-one

Intermediate 7 (3.25g) was dissolved in methanol (32.5ml) and 0.880 ammonia (6.5ml) in distilled water (6.5ml) was added. The mixture was heated with stirring at ca. 60° for 2 Λ> hours, allowed to cool to room temperature and stirred for a further 2 hours. The solid was filtered off, washed with chilled methanol-water (2:1) and dried in vacuo at 60° overnight to give the title product (1.62g); H n.m.r. (DMSO-d₆) 10.55 (1H), 7.41 (1H), 6.42 (2H), 6.13 (1H), 5.88 (1H), 5.36 (1H), 4.69 (1H), 3.46 (2H), 2.88 (1H), 2.61 (1H),

1.60 (1H); λ_maχ (methanol) 254nm (E1537).

The liquors were evaporated to 22ml and the resulting suspension stirred at room temperature whilst water (15ml) was added over 15 minutes. Stirring was continued for 30 minutes and the solid was filtered off, washed with methanol-water (2: 1 ) and dried in vacuo at 60° overnight to give a further crop of the title product (0.59g).

Claims

1. A process for the preparation of a compound of formula (IV)

₀ (wherein R represents a hydroxyl protecting group and R represents a hydrogen atom or an acyl group), which comprises reacting a compound of formula (II)

with an orthoester CH(OR )^ (wherein R¹ is a C-μ^alkyl group) to provide a o compound of formula (III)

5 and thereafter treating a compound of formula (III) with an acid or carboxylic acid anhydride as appropriate to provide the desired compound of formula (IV).

2. A proces ^'according to Claim 1 wherein the compound of formula (IV) prepared according to the method of Claim 1 is deprotected, and N-deacylated where necessary, to provide the compound of formula (I)

with salt formation as an optional subsequent step. 5

3. A process according to Claim 1 or Claim 2 wherein R represents a silyl group.

4. A process according to Claim 1 or Claim 2 wherein R represents a trialkylsilyl group. 0

5. A process according to any preceding claim wherein the compound of formula (III) is treated with a carboxylic acid anhydride at an elevated temperature to provide o the compound of formula (IV) in which R is an acyl group.

c 6. A process according to any preceding claim wherein the compound of formula

1 1

(II) is reacted with an orthoester CHfOR¹^ (wherein R¹ is a C- ^alkyl group) in a solvent and in the presence of an acid or pyridinium p-toluenesulphonate to provide the compound of formula (III).

7. A process according to Claim 6 wherein the compound of formula (II) is reacted with an orthoester CHCOR¹)^ (wherein R^ is a C-_j^alkyl group) in an ether solvent and in the presence of p-toluenesulphonic acid.

8. Compounds of formula (III) - 1 A -

wherein R represents a hydroxyl protecting group and R¹ represents a

group.

9. Compounds of formula (III) (as depicted in Claim 8) wherein R represents a silyl group and R represents a C- ^alkyl group.