EP-A-0 376 524 describes certain compounds of formula (A)

Rs R ₄

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein:

one of Ai or A2 represents hydrogen and the other represents a group CF3-Y- wherein Y represents -CF ₂ -, >C=O, or -CH(OH)-;

Yj represents -O-, -CH2- or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl;Rι and R2 independently represent hydrogen or alkyl; or Rl and R ₂ together represent a C2.7 polymethylene moiety; R3 represents hydrogen, hydroxy, alkoxy or acyloxy and R4 is hydrogen or R3 and R4 together represent a bond;

R5 represents either a moiety of formula (a):

Re

wherein A represents >C=X wherein X is O, S or NRg wherein Rg represents CN, NO ₂ . COR9 wherein R9 is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl or Rg is SO2R9 wherein R9 is as defined above, or A represents a bond; when A represents >C=X wherein X is O or S, then g is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide

thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or by an alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by alkyl, alkoxy or halogen; substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R7 represents hydrogen or alkyl; or Rg and R7 together represent a linking chain of formula -A3-A4-, A3 being attached to the nitrogen atom of the moiety -N-A- and A4 being attached to the group A on the said moiety, and wherein A3 represents a substituted or unsubstituted methylene group, A4 represents 2 or 3 linking members, one of the linking members optionally representing O, S or NR and the other linking members each independently representing a substituted or unsubstituted methylene group; R represents hydrogen, alkyl, alkanoyl, phenyl C1-.4- alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R is mono- or bi-cyclic- heteroarylcarbonyl; when A represents >C=X wherein X represents NRg, then Rg represents -NH.RlO wherein R o is hydrogen, alkyl, C3.6 cycloalkyl, alkenyl or alkynyl and R7 is hydrogen or alkyl; or R7 and Rio together represent C2- 4 polymethylene;

when A represents a bond, then Rg and R7 together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted;

or R5 represents a moiety of formula (b):

wherein T^ represents >C-OH or N(O) _n wherein n is zero or 1 and T2 together with C-Tχ, when T]_ is >C-OH, represents an optionally substituted aryl group or T2 together with CTi, when T^ is N(O) _n ,

represents an optionally substituted, N- heteroaryl group;

or R5 represents a moiety of formula (c):

wherein ^~ \ represents O or NRn wherein RJI represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L2 represents N or CL4 wherein L4 is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH2, O, S, >CHL.5 wherein L5 is halogen or NLg wherein Lg is hydrogen or alkyl and R12 and 13 each independently represent hydrogen or alkyl or 12 together with R13 represents oxo or thioxo; and p represents 1,2 or 3; which compounds are described as being useful as smooth muscle relaxants.

A useful intermediate in the preparation of compounds of formula (A) is an epoxide of formula (B):

wherein . and A2' are h.\ or A ₂ as defined in relation to formula (A), or groups convertible thereto and Rj, R2 and Yj are as defined in relation to formula (A).

The carbon atoms marked with an asterisk (*) on formula (B) are chiral carbon atoms.

Previously, chemical methods for preparing the epoxide of formula (B) resulted in the formation of a racemic mixture of the epoxide: Any compound of formula (A) produced from such an epoxide would also be

racemic and hence would need to be resolved to yield an optically pure product.

WO 91/14694 describes certain catalysts which may be used for enantioselectively epoxidizing prochiral olefins. However, there is no mention that such catalysts could be used to prepare substantially enantiomerically pure chiral epoxides of formula (B).

Surprisingly a new process has now been found which uses particular catalysts from WO 91/14694 to produce the chiral epoxide of formula (B) in substantially enantiomerically pure form thus obviating the need for any resolution when preparing compounds of formula (A).

Accordingly, the present invention provides a process for preparing compounds of formula (B) (hereinbefore described) which process comprises reacting a compound of formula (C):

wherein Ai', A2 ^* , Ri, R2 and Y]_ are as defined in relation to formula (B) in the presence of an oxygen source and a chiral catalyst as defined in WO/91/14694, especially those of formula (D):

in which

M is a transition metal ion, J is an anion, and n is either 0, 1 or 2; at least one of X or X ₂ is selected from the group consisting of silyls, aryls, secondary alkyls and tertiary alkyls; and at least one of X3 or X4 is selected from the same group, Z , Z ₂ , Z3, Z4, Z5 and Zg are independently selected from the group consisting of hydrogen, halides, alkyls, aryl groups, silyl groups, and alkyl groups bearing heteroatoms such as alkoxy and halide, also, at least one of Qi, Q ₂ , Q3 and Q4 is selected from a first group consisting of H, CH3, C H5 and primary alkyls, furthermore, if Qi is selected from said first group, then Q ₂ and Q3 are selected from a second group consisting of aryl groups, heteroatom-bearing aromatic groups, secondary alkyls and tertiary alkyls; if Q is selected from said first group, then Qi and Q4 are selected from said second group; if Q3 is selected from said first group, then Qj and Q4 are selected from said second group; if Q4 is selected from said first group, then Q and Q3 are selected from said second group, and thereafter when A and/or A ₂ ' are groups convertible to K and A2 respectively; converting K\ and A2' to K and A ₂ respectively.

It should be appreciated that the bond between M and J has varying degrees of ionic character depending on the anion used.

Preferred values for A , A ₂ ', Y , j and R in compounds of formula (C) are as defined in EP-A-0376 524.

Most preferably A-] is CF3CF2;, A ₂ ' is hydrogen, Y,ι is oxygen and Rj and R ₂ are both methyl.

Preferred values for M, J, n, X _x , X2, X3, X4, Z ^* ι, Z2, Z3, Z4, Z5, Zg, Qi, Q ₂ , Q3 and Q4 are as defined in WO/91/14694.

A preferred sub-group of catalysts of formula (D) are of formula (E):

in which Z and Z4 are the same and are selected from the group consisting of methyl, i-butyl or methoxy and Q ₂ and Q3 are either both phenyl or together with the carbon atoms to which they are attached form an hexyl ring.

Most preferably, in catalysts of formula (E), and Z4 are both ±-butyl and ₂ and Q3 together with the carbon atoms to which they are attached form an hexyl ring.

The reaction between the compound of formula (C) in the presence of an oxygen source and the chiral catalyst is suitably carried out using the procedures outlined in WO/91/14694 or procedures analogous thereto.

Suitably, the reaction is carried out as a two phase reaction with the compound of formula (C) and the chiral catalyst being disolved in an inert solvent such as dichloromethane and the other phase being water with sodiu hypochlorite added as the oxygen source, optionally in the presence of a buffer such as sodium dihydrogen phosphate, the pH being suitably adjusted to a pH of between 10 and 13, preferably between 10.5 and 12, most preferably between 11 and 11.5

The reaction is suitably carried out at reduced, ambient or elevated temperature, preferably at elevated temperature, such as greater than 30°C, preferably greater than 35°C, most preferably at 40°C to 45°C.

Suitably the mole ratio of chiral catalyst to compound of formula (C) is in the range of 0.01 to 10, preferably in the range of 1 to 5, most preferably in the range of l to 3.

Examples of groups and A2' convertible to A^ and A2 and methods for their conversion are described in EP-A-0376524.

Preferred catalysts include the specific examples mentioned in WO

91 14694. Most preferably the chiral catalyst is (S,S)-[l,2-bis(3,5-di-tert- butylsahcylideneamino) cyclohexane]manganese (HL) chloride as characterised on pages 33 and 34 of WO 91/14694.

It should be appreciated that the present invention specifically covers the preparation of all epoxide precursors to all specific examples in EP-A-0376 524 using the process hereinbefore described, especially the preparation of (3S,4S)-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H- 1-benzopyran.

Compounds of formula (C) are commercially available or may be prepared according to the procedures referred to or outlined in EP-A-0 376 524.

Chiral catalysts mentioned in WO/91/14694 may be prepared according to the procedures in WO 91/14694 or by procedures analogous to them.

The present invention also provides a process for preparing compounds of formula (A) (hereinbefore described) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof which comprises reacting a compound of formula (C) (hereinbefore described) in the presence of an oxygen source and a chiral catalyst as defined in WO/91/14694 and thereafter converting the resulting compound of formula (B) to a compound of formula (A) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

It should also be appreciated that the present process specifically encompasses the preparation of all the specific examples in EP-A-0376 524 by reacting appropriate compounds of formula (C) in the presence of an oxygen source and a chiral catalyst a defined in WO/91/14694 and thereafter converting the resulting compound of formula (B) to a compound of formula (A).

A preferred compound of formula (A) is (3S,4R)-3,4-dihydro-2,2-dimethyl- 4-(2-oxopiperidin-l-yl)-6-penta-fluoroethyl-2H-l-benzopyran- 3-ol, which is prepared by reacting (3S,4S)-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl- 2H-l-benzopyran in the presence of an oxygen source and a chiral catalyst as defined in WO/91/14694 and thereafter converting the resulting epoxide compound to the compound of formula (A) as above.

Suitable methods for converting compounds of formula (B) to compounds of formula (A) include those mentioned in EP-A-0 376 524.

The following example illustrates the present invention.

Example 1

Preparation of (3S,4S)-2^-DimethyI-3,4-epoxy-6-pentafluoroethyl- 2H-l-benzopyran

A titrated solution of sodium hypochlorite (2.5L) water (4.2L) and 0.05M sodium dihydrogen phosphate (16.0g) in 2.7L of deionised water was added to a 20L flanged flask and the mixture adjusted to pH 11.3 with a few drops of orthophosphoric acid. This solution was added to a solution of 2,2-dimethyl-6-pentafIuoroethyl-2H-l- benzopyran (0.75kg) (which maybe prepared according to the procedures outlined in EP-A-0376524) and (S,S)-[l,2-bis(3,5-di-tert-butylsahcyUdeneamino) cyclohexanejmanganese (HI) chloride (17. lg) (which may be prepared according to the procedures outlined in WO/91/14694 in dichloromethane (2.7L) in a 25L vessel and the mixture stirred at 42°C overnight. The solution was cooled to 20°C, dichloromethane (4.1L) was added, the mixture filtered through a bed of celite filter aid, washing the filter cake with dichloromethane (2.7L) and the phases separated. The aqueous phase was washed with dichloromethane (6.7L) and the combined organic phases were washed with brine (5.3L) and evaporated to dryness to give 800g of crude title product.

The crude epoxide was recrystallised from hot hexane (1.8L) to give a first crop of a white solid which was filtered off and washed with 3 x 0.5L portions of ice cold hexane. The solid was dried in vacuo at 50°C for 3 hours.

The mother liquors were concentrated to 1.1L and allowed to cool to 4°C for 3-4 hours. The second crop of solid was filtered off and the product washed with 2 X 0.3L of ice cold hexane. The solid was dried in vacuo at 50° for 3 hours.

Yield of first crop of title compound - 533g (67.2%).

Purity of first crop of title compound - 98.7% (determined by quantitative

HPLC).

Enantiomeric excess of first crop of title compound - 99.7% (determined by quantitative chiral HPLC).

Yield of second crop of title compound - 36.5g (4.6%). Purity of second crop of title compound - 97.1% (determined by quantitative HPLC.

Enantiomeric excess of second crop of title compound - 96.9% (determined by quantitative chiral HPLC).