WO1993022321A1

WO1993022321A1 - Phosphorus containing alkynyl derivatives

Info

Publication number: WO1993022321A1
Application number: PCT/GB1993/000837
Authority: WO
Inventors: Richard Simon Todd; Maxwell Reeve; Alan Hornsby Davidson
Original assignee: British Bio Technology Ltd
Current assignee: Vernalis R&D Ltd
Priority date: 1992-04-23
Filing date: 1993-04-22
Publication date: 1993-11-11
Anticipated expiration: 1994-10-23
Also published as: AU4265593A; GB9208790D0

Abstract

Compounds of general formula (I), wherein n is 0 or 1; R?1 and R2¿ each independently represents a group R, OR, NHR or NR¿2? in which the two R groups may be the same or different and wherein: R is -C1-8 alkyl optionally substituted with one or more halogen atoms, -C2-8 alkenyl, -C3-8 cycloalkyl, C1-6 alkyl-O-C1-6 alkyl, -C1-8 alkyl(C3-8 cycloalkyl), phenyl, -C1-C6alkylphenyl, -C2-C6-alkenylphenyl, or R?1 and R2¿ together for a C¿2?-C6 alkyl bridge which may optionally be substituted at any position with a C1-4alkyl group; Y is CHOH, CHOQ where Q is a suitable protecting group or C=O; X represents any group which does not interact chemically or sterically with the group Y; are useful intermediates in the preparation of ketophosphonates and their derivatives and these, in turn, are useful synthetic intermediates for a variety of compounds, for example mevinic acid derivatives.

Description

PHOSPHORUS CONTAINING ALKYNYL DERIVATIVES

This invention relates to novel compounds which are useful intermediates in the synthesis of a range of mevinic acids and other HMGCoA reductase inhibitors, to a process for the synthesis of these compounds and to their use in the synthesis of mevinic acids. A number of mevinic acids have been reported to be potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.

Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin, having the structure:

EP-A-0251625 (Inamine) discloses compounds of structure:

where R is similar to the corresponding group in the compounds described above, R1 is a group of formula CH₂OH, CH₂OCOR3 , CO₂R4 or CONR6R7 wherein R3, R4, R6, and R7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.

The compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost. Accordingly, Heathcock and Rosen disclosed in US 4,950,775 the total synthesis of compactin, which also possesses HMG-CoA reductase inhibitory activity, and which has the structure:

The synthetic procedure disclosed therein involved a key step involving a Homer Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:

and a ketophosphonate reagent that is the precursor to the substituted ethyl tetrahydropyran moiety:

Similarly, WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. In particular the document describes the synthesis of (1S, 2S,4aR,6S,8S,8aS,4'R,6aR')-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one which has the structure:

The synthetic procedure disclosed in WO-A-9100280 also utilised as a key step a Homer Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:

and a ketophosphonate:

Because of the problems associated with this reaction, a new process for the coupling of the two reagents was developed and is disclosed in our copending British application No 9115773.5. However, in all of the processes which have so far been described, the use of a ketophosphonate is necessary and this presents problems because of the difficulties in synthesising these compounds. Methods for the preparation of ketophosphonates have been described in US 4950775 and by Karanewsky (J. Org. Chem., 56, 3744, (1991)). However, both of these syntheses involve a large number of steps, for example, nine steps are involved in the process of US 4950075, and this makes the procedures unsuitable for the production of ketophosphonates on a large scale since the overall yield of the process is low and the product may be contaminated with one or more of the intermediates. Therefore, it would be particularly advantageous to develop a process for the synthesis of ketophosphonates in which fewer steps are used.

Accordingly, in a first aspect of the present invention there is provided a compound of general formula I:

wherein: n is 0 or 1; R¹ and R² each independently represents a group R, OR, NHR or NR₂ in which the two R groups may be the same or different and wherein:

R is -C_1-8 alkyl optionally substituted with one or more halogen atoms, -C_2-8 alkenyl, -C_3-8 cycloalkyl, C_1-6 alkyl-O-C_1-6 alkyl, -C_1-8 alkyl (C_3-8 cycloalkyl), phenyl, -C₁-C₆alkylphenyl, -C₂-C₆alkenylphenyl, or R¹ and R² together form a C₂-C₆ alkyl bridge which may optionally be substituted at any position with a C_1-4 alkyl group;

Y is CHOH, CHOQ where Q is a suitable protecting group or C=0; X represents any group which does not interact chemically or sterically with the group Y.

When Y is CHOH or CHOQ, the compounds of general formula I have a chiral centre and can therefore adopt either the R or the S stereoisomeric configuration. Compounds having the S configuration are preferred.

As used herein the term "C₁-C₈ alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to eight carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.

As used herein the term "hydroxy C₁-C₈ alkyl" refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxy-n-propyl.

As used herein, the term "C₃-C₈ cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C₄-C₈ cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.

As used herein the term "substituted alkyl" refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl. As used herein the term "suitable protecting group" refers to a group temporarily attached to a reactive centre in a multi-functional molecule. Such protecting groups are well known to those skilled in the art. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see "Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981.

Compounds of general formula I are useful intermediates in the synthesis of ketophosphonates which, in turn, are useful intermediates in the synthesis of many useful compounds, for example, mevinic acids.

The nature of the group X will depend on the nature of the target compound to be synthesised, however, it is preferred that:

X represents C_1-8 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, any of which may be substituted with one or more halogen atoms, optionally protected hydroxy, C_1-6 alkoxy, C_1-6 alkyl-OH, a nitrile, C_1-6 alkyl nitrile, a halogen, a CO₂R³, CONR³ ₂, -C(OR⁴)₃, C_1-6 alkyl CO₂R³, C_1-6 alkyl CONR³ ₂, C_1-8 alkyl-C(OR⁴)₃, or optionally protected CHO or C_1-6 alkyl CHO;

R³ is H, C_1-6 alkyl or a suitable acid protecting group;

R⁴ is C_1-8 alkyl, or the three R⁴ groups together with the carbon atom and the oxygen atoms to which they are attached form a tricyclic ortho-ester.

In compounds of general formula I, particularly preferred protecting groups for the hydroxy functions are alkylsiloxy groups such as trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy. Preferred protecting groups for the aldehyde functions are acetals.

Other preferred compounds of general formula I include those in which, independently or in any compatible combination:

R¹ and R² each represent a group OR;

R represents a C_1-6 alkyl group; R³ is C_1-6 alkyl. n = 1

X is more preferably optionally protected hydroxy, C_1-6 alkoxy, a nitrile, halogen, CO₂R³ CONR³ ₂ or -C(OR⁴)₃ group and in the most preferred compounds of general formula I, X is CO₂R³.

A particularly preferred compound is methyl 6- (diethylphosphono)-3(S)-hydroxyhex-5-ynoate.

In a second aspect of the invention, there is provided a process for the preparation of a compound of general formula I, the process comprising

(a) reacting a compound of general formula II R¹R²P(O)_n -C≡C-R⁵ II

wherein: n, R¹ and R² are as defined in general formula I;

R⁵ is hydrogen or a protecting group which can easily be removed in situ to expose the acetylene carbanion;

with a compound of general formula III:

wherein:

Y and X are as defined for general formula I; A is a leaving group; or

Y and A together form a -CH-O- or -CH-O-SO₂-O- bridge in which the CH moiety is at the Y group end of the bridge; under basic conditions; (b) optionally after step (a), converting a compound of general formula I to another compound of general formula I. Preferably, the protecting group R⁵ in general formula II is a tri(C_1-6)alkylsilyl group, for example a trimethylsilyl group.

The group A in general formula III may be a halogen atom, a C_1-6 alkyl sulphonate or an aryl sulphonate.

The reaction is preferably carried out in a polar aprotic solvent such as tetrahydrofuran, dimethylsulphoxide or dimethylformamide. The base is a strong base which is preferably derived from lithium. n-Butyl lithium has been found to be particularly suitable but lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LHMDS) may also be used. It is also possible to use potassium t-butoxide but a base which is weaker than this will usually not be effective.

A Lewis acid such as boron trifluoride etherate may also be present, especially in cases when, in general formula III, Y and A form a -CH-O- or -CH-O-SO₂-O- bridge.

A compound of general formula I in which n is 0 can readily be converted into a compound of general formula I in which n is 1 by oxidation. Compounds of general formula II are available in the art or may be prepared by methods known to those skilled in the art, for example, see Burt et al, J. Chem. Soc., 2, 2273-76 (1969). Compounds of general formula III are also available in the art or may be prepared by methods analogous to those described in the art, for example, by Larcheveque et al, Tetrahedron. 46, (12), 4277-4282 (1990) and Seiki et al, Chem. Letters, 8, 1389-1392 (1984).

The compounds of general formula I are valuable intermediates in the synthesis of ketophosphonates and related compounds and therefore, according to a third aspect of the invention, there is provided a process for the preparation of a compound of general formula IV:

wherein:

R¹, R², n, Y and X are as defined for general formula I; the process comprising reacting a compound of general formula I with an aqueous acid under catalytic conditions in an alcoholic solvent.

The acid will preferably be a strong non-oxidising acid, with sulphuric acid being the most preferred. The alcoholic solvent should preferably be at least partially miscible with water and methanol is a particularly, suitable solvent. Mercury (II) salts are the most preferred catalysts for the reaction. The compounds of general formula I are useful intermediates in the synthesis of a wide variety of compounds, particularly intermediates of various active mevinic acid derivatives.

Therefore, in a further aspect of the invention, there is provided a process for the preparation of a compound of general formula VI

wherein X and Y are as defined above and Z is a bulky organic substituent. the process comprising the preparation of a compound of general formula IV by a process as described above, followed by the conversion of a compound of general formula IV to a compound of general formula VI by any suitable method. One such suitable method is described in our copending British patent application No 9115773.5, in which a compound of general formula VI may be obtained by reacting a compound of general formula IV with a compound of general formula V

wherein:

Z is a bulky organic substituent.

This reaction is particularly suitable for the production of mevinic acid precursors in which Z is a group of general formula VII

wherein:

R⁷ represents a hydrogen atom, COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COO_1- ₆ alkyl substituted phenyl group, or a suitable protecting group;

R⁸ represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl, C_2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C_1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group; R⁹ represents a hydrogen atom or a C_1-8 alkyl group;

R¹⁰ represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond. From these compounds of formula VI, a range of mevinic acid derivatives can be prepared which are active as HMG-CoA reductase inhibitors.

In particular, in a further aspect of the invention, there is provided a process for the preparation of a compound of general formula VIII or general formula IX

wherein:

R³, R⁷, R⁸, R⁹, R¹⁰, a, b and c are as defined above and d is a single or a double bond; the process comprising converting a compound of general formula I in which X is CO₂R³ to a compound of general formula IV in which X is CO₂R³ and subsequently converting the compound of general formula IV to a compound of general formula VIII or IX by any suitable process.

In one such process, the compound of general formula IV may be reacted with a compound of general formula V wherein Z is a group of general formula VII as described above to form a compound of general formula VI. This compound may then be converted to compounds of general formulae VIII and IX by the process described in WO-A-9100280.

The invention will be now be further described with reference to the following examples, of which Example 1 gives a method for the preparation of a compound of general formula I and Example 2 gives a method for the conversion of a compound of general formula I to a compound of general formula IV.

In the examples, the following abbreviations have been used:

THF - tetrahydrofuran

EtOAc - ethylacetate

Example 1

Methyl 6-(diethylphosphono)-3 (S)-hydroxyhex-5-ynoate n-Butyl lithium (1.6M in hexane; 272 μmol) was added slowly to a stirred solution of diethylacetylene phosphonate (40 mg, 247 μmol) in THF (300 μL) at -78°. After 10 min., boron trifluoride etherate (33 μL, 272 μmol) was added and after a further 15 min., a solution of methyl (S) - 3,4 -epoxybutanoate (29mg, 247μmol) in THF (100μL) was added and stirring continued for 0.5 hours. Saturated aqueous NH₄Cl (lmL) was added, the mixture extracted with EtOAc (2 × 2 mL) and the combined organic extracts dried (MgSO₄) and evaporated in vacuo. Column chromatography (SiO₂, gradient eluting with 7:3 EtOAc / hexane to neat EtOAc) gave the starting material (7mg) and the title compound (17mg, 25%).

1H nmr (250 MHz) (CDCl₃) : 4.35-4.20, (1H, br. m, 3-H); 4.15, (4H, dq, J = 8.3, 7.4 Hz, 2 x CH₂CH₃); 3.73, (3H, s, CO₂Me); 3.52-3.0, (1H, m, OH); 2.72-2.52, (4H, m, 2 × 2-H + 2 × 4-H); 1.36, (6H, t, J = 7.4 Hz, 2 × CH₂CH₃).

Example 2

Methyl 6-(diethylphosphono)-3 (S)-hydroxy-5-oxo hexanoate

A mixture of the product from example 1 (17 mg, 61.2 μmol), HgSO₄ (4.5 mg, 15.3μmol), and H₂SO₄ (10% aqueous) in MeOH (200μL) was stirred at room temperature for 44h, then the solvents evaporated under a stream of argon and the residue partitioned between saturated aqueous NaHCO₃ (1mL) and EtOAc (3 × 5 mL). The combined organic extracts were dried (MgSO₄) and evaporated in vacuo to leave the title compound (15 mg, 83%).

¹H nmr (400 MHz) (CDCl₃) : 4.54-4.45, (1H, m, 3-H); 4.19-4.10, (4H, m, 2 × CH₂CH₃); 3.71, (3H, s, CO₂Me); 3.14, (2H, d, J = 22.8 Hz and 3.13, d, J = 22.8 Hz, P(O)CH₂C(O)); 2.842, (1H, d, J = 7.0 Hz), and 2.84, (1H, d, J = 5.2 HZ, C(O)CH₂CH); 2.51, (2H, J = 6.3 Hz, CHCH₂CO₂Me), 1.324, (3H, t, J = 6.9 Hz, CH₂CH₃), 1.323, (3H, t, J = 6.9 Hz, CH₂CH₃).

¹³C nmr (100 MHz) : 202.2, 202.1, 172.8, 65.0, 63.53, 63.51, 63.47, 63.44, 52.5, 50.6, 44.5, 43.2, 41.2, 17.0, and 16.94 ppm.

Example 3

Methyl 7-{ 1-[1R, 2R, 4aR, 6R, 8S, 8aS)-8-[(2,2-dimethyl-1-oxobutyi)oxy]-1, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-methylnaphthalenyl]}-3(R)-hydroxy-5-oxohepten-6-oate.

A mixture of (1S, 3S, 4aR, 7S, 8S, 8aS)-1, 2, 3, 4, 4a, 7, 8, 8a-octahydro-8-formyl-7-methyl-3-[(E)-prop-1-enyl]-1-naphthalenyl 2,2-dimethylbutyrate (59 mg, 0.18 mmol), methyl 6-(diethylphosphono)-3(S)-hydroxy-5-oxohexanoate (79 mg, 0.27 mmol) and caesium carbonate (87 mg, 0.27 mmol) were stirred in propan-2-ol (0.75 ml), under an atmosphere of argon, for 42h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (2 × 5 ml) and saturated aqueous ammonium chloride (5 ml). The organic phase was washed with brine (5 ml), dried (MgSO₄) and evaporated in vacuo to leave a yellow oil (84 mg). Chromatography (SiO₂, eluting with 7:3 hexane ethyl acetate -> dichloromethane -> 9:1 dichloromethane:methanol) gave the title compound (24 mg, 28%) together with unreacted aldehyde (21 mg, 30%). ¹H nmr (400MHz; CDCl₃) 6.79 (1H, dd, J 14, 11 Hz); 6.00 (1H, d, J 14 Hz); 5.79-5.70 (1H, m); 5.65-5.59 (1H, m); 5.45-5.33 (2H, m); 5.00-4.95 (1H, m); 4.50-4.43 (1H, m); 3.70 (3H, s); 2.83 (1H, dd, J 15, 8 Hz); 2.70 (1H, dd, J 15, 5 Hz); 2.60-2.45 (4H, m); 2.35-2.25 (1H, m); 1.93-1.85 (1H, m); 1.83-1.70 (2H, m); 1.60 (3H, d, J 9 Hz); 1.68-1.45 (3H, m); 1.37 (1H, dt, J 13, 6 Hz); 1.14 (3H, s); 1.00 (3H, s); 0.95 (3H, d, J 8 Hz); 0.80 (3H, t, J 8 Hz).

Claims

1. A compound of general formula (I):

wherein: n is 0 or 1;

R¹ and R² each independently represents a group R, OR, NHR or NR₂ in which the two R groups may be the same or different and wherein:

Y is CHOH, CHOQ where Q is a suitable protecting group or C=0;

X represents any group which does not interact chemically or sterically with the group Y.

2. A compound as claimed in claim 1 wherein X represents C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, any of which may be substituted with one or more halogen atoms, optionally protected hydroxy, C_1-6 alkoxy, C_1-6 alkyl-OH, a nitrile, C_1-6 alkyl nitrile, a halogen, a CO₂R³, CONR³ ₂ or -C(OR⁴)₃, C_1-6 alkyl CO₂R³, C_1-6 alkyl CONR³ ₂, C_1-6 alkyl-C(OR⁴)₃ or optionally protected CHO or C_1-6 alkyl CHO;

R³ is H, C_1-6 alkyl or a suitable acid protecting group;

R⁴ is C_1-8alkyl, or the three R⁴ groups together with the carbon atom and the oxygen atoms to which they are attached form a tricyclic ortho-ester.

3. A compound as claimed in claim 2 wherein X represents optionally protected hydroxy, C_1-6 alkoxy, a nitrile, halogen, CO₂R³, CONR³ ₂ or -C(OR⁴)₃ group.

4. A compound as claimed in claim 3 wherein X is CO₂R³.

5. A compound as claimed in claim 4 wherein R³ is C_1-6 alkyl.

6. A compound as claimed in any one of claims 1 to 5 wherein R¹ and R² each represent -O(C_1-6 alkyl).

7. A compound as claimed in any one of claims 1 to 6 wherein n is 1.

8. A process for the preparation of a compound of general formula I, the process comprising

(a) reacting a compound of general formula IX R¹R²P(O)_n -C≡C-R⁵ II wherein: n, R¹ and R² are as defined in general formula I; and R⁵ is H or a protecting group which can easily be removed in situ to expose the acetylene carbanion; with a compound of general formula III

wherein:

X and Y are as defined in general formula I; and

A is a leaving group; or

Y and A together form a -CH-O- or -CH-O-SO₂-O- bridge in which the -CH moiety is at the Y group end of the bridge; under basic conditions;

(b) optionally, after step (a), converting a compound of general formula I to another compound of general formula I.

9. A process as claimed in claim 8, wherein A is a halogen atom, a C_1-6 alkyl sulphonate or an aryl sulphonate.

10. A process as claimed in claim 8 or claim 9 wherein R⁵ is a tri(C_1-6 alkyl) silyl group.

11. A process as claimed in any one of claims 8 to 10 wherein the base is n-butyl lithium.

12. A process as claimed in any one of claims 8 to 11 wherein the reaction is carried out in the presence of a Lewis acid.

13. A process for the preparation of a compound of general formula IV

wherein:

R¹, R², X and Y are as defined in general formula I;

the process comprising reacting a compound of general formula I with an aqueous acid under catalytic conditions in an alcoholic solvent.

14. A process as claimed in claim 13, wherein the solvent is methanol.

15. A process as claimed in claim 13 or claim 14 wherein the catalyst is a mercury (II) salt.

16. A process for the preparation of a compound of general formula VI

wherein X and Y are as defined above and Z is a bulky organic substituent; the process comprising the preparation of a compound of general formula IV by a process as claimed in any one of claims 13 to 15, followed by the conversion of a compound of general formula IV to a compound of general formula VI by any suitable method.

17. A process for the preparation of a compound of general formula VIII or formula IX

wherein:

R⁷ represents a hydrogen atom, COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COC_1- ₆ alkyl substituted phenyl group, or a suitable protecting group; R⁸ represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl, C_2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C_1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;

R⁹ represents a hydrogen atom or a C_1-8 alkyl group;

R¹⁰ represents a hydrogen atom, or a methyl or ethyl group; each of a, b, c and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula IV by a process as claimed in any one of claims 13 to 15, followed by the conversion of a compound of general formula IV to a compound of general formula VIII or IX by any suitable method.