JP2922220B2 - Penem recipe - Google Patents

Description

The present invention relates to a method for producing 6-[(1R) -hydroxyethyl] penem useful for synthesizing an antibacterial agent, an intermediate used in the method, and production of the intermediate.

More specifically, the present invention provides a compound of formula (I): (In wherein: R is a) alkanoyl moiety is a linear or branched C ₂ -C ₁₀ alkanoyl or C ₄ -C ₈ white alkanoyloxymethyl an alkanoyl group or a 1- (alkanoyloxy) ethyl; b) benzoyl oxymethyl or 1- (benzoyloxy) ethyl; c) alkoxycarbonyl oxymethyl or 1- (alkoxycarbonyloxy) ethyl; d) 3- phthalidyl; e) or 5-position is substituted by C ₁ -C ₄ alkyl group Or unsubstituted 2-oxo-1,3-dioxolan-4-
Yl; it is or a substituted or g) 4-position is substituted by C ₁ -C ₄ alkyl group; f) R 'is -CH ₂ COOR a C ₁ -C ₄ straight or branched chain alkyl or benzyl' R ₁ is a tetrahydrofuranyl group, or an unsubstituted or substituted C ₁ -C ₄ alkyl group, a methylphenyl group or a methylphenoxymethyl group, wherein the substituent is Selected from the following groups: (i) carbamoyloxy, C ₁ -C ₁₈ alkoxy, carboxy, or free or protected hydroxy, and (ii) unsubstituted or substituted and / or fused (fuse
d) pyridinium, a N- methyl pyrrolidinium or piperidinium, C ₁ -C its substituent is not or is substituted is substituted by a group in which one or a sulfonyloxy group or carboxy group of the (i) _Four
An alkyl group, and R ₂ represents a hydrogen atom or a hydroxy protecting group). (Wherein R, R ₁ and R ₂ have the meanings given above).

The alkoxy moiety preferably contains 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. The hydroxy-protecting moiety of R ₂ or R ₁ includes, for example, p-nitrobenzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, p-bromophenacyl, It may be a triphenylmethyl group or a tetrahydropyranyl group.

Pyridinium groups, examples of which can be fused to N- methyl-pyrrolidinium group and piperidinium group, phenyl, and C ₅ -C ₇ is saturated or unsaturated cycloaliphatic radical, or a heterocyclic group. The heterocyclic group may contain, for example, 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Preferred groups which can be fused with the pyridinium, N-methylpyrrolidinium and piperidinium groups are: It is.

Examples of compounds of formula (I) are described in European Patent Application No. 88305277.1
No., UK Patent Application No. 2,133,010 and UK Patent Application No. 2,0
No. 97,786.

The present invention also provides a compound of formula (II), and further provides a method for preparing a compound of formula (II), wherein the method comprises formula (V): (Wherein R, R ₁ and R ₂ have the meanings given above).

Formula (III): The compound of formula (V) may be prepared by ozonolysis of a compound of formula (where R, R ₁ and R ₂ have the meanings given above).

The process of the present invention provides penems of formula (I) in good yield and of high optical purity. This method differs from the prior art in that bromine atoms are maintained on the β-lactam nucleus until the final stage.

The replacement of the bromine atom by a hydrogen atom proceeds with a higher stereoselectivity on the compounds of formula (II) than other intermediates in the earlier stages of the process. Further, the intermediates involved in the process of the present invention are more stable and easier to handle than previously reported, and therefore can be stored without degradation.

To obtain the preferred final [5R, 6S, (1R)] stereochemistry of the penem nucleus, the configuration of the compound of formula (II) is [5R, 6
S, (1R)]. The starting materials of the formula (III) can be conveniently prepared from 6-aminopenicillanic acids as described in European Patent Application 0188247. Thus, the present invention allows the synthesis of compounds of formula (I) directly from 6-aminopenicillanic acid, as summarized in the following reaction scheme.

In general, the compound of formula (V) in the scheme is prepared by ozonolysis of compound (III) at low temperature and further treated with triethyl phosphite or trimethyl phosphite dissolved in an inert organic solvent such as chloroform, benzene, toluene or xylene. The compound is generally cyclized to a compound (II) by treatment.

Examples of the above cyclization conditions are described in C. Battistini et al., Tetrahedron.
Lett. 25 , 2595, (1984); A. Yoshida et al., Chem. Pharm.
l. 31 , 768, (1983), and references therein, as well as U.S. Patent Application No. 4,631,150.

The compound of formula (II) is reduced to compound (I) by any suitable method, such as catalytic hydrogenation or treatment with a reducing metal. Preferably, treatment with zinc or an alloy of zinc with another metal, such as copper or silver, yields penem (I) from (II). Preferably, the reaction is carried out in an organic solvent such as acetonitrile, ethyl ether, t-butyl methyl ether, ethyl acetate, teorahydrofuran, acetone, chloroform or methylene chloride in the presence of an aqueous solution of ammonium or zinc carboxylate or halide. Perform

The reaction temperature is generally between -20 ° C and + 80 ° C. At the end of the reaction, the penem of formula (I) is taken up by conventional procedures.
If necessary, the reaction crude is deprotected and purified by column chromatography.

The penems of the formula (I) are antimicrobial agents. Thus, they may be formulated as pharmaceutical compositions and may include a pharmaceutically acceptable carrier or diluent.

 The following examples illustrate the invention in more detail.

Example 1 Preparation of bromopenem (II) (general method) (3S, 4R) -1- (1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl) -4-acylthio-3-bromo-3- [ 1- (R) -Hydroxyethyl] -azetidin-2-one (III, R = CH ₂ OCOCH ₃ , R ₂ =
H) was converted to Alpegiani et al., J. Am. Chem. Soc., 107 , 6398, (198
As described in 5), (3S, 5R, 6S) -6-bromo-6-
Prepared from [1- (R) -hydroxyethyl] -acetoxymethyl penicillanate (IV, R = CH ₂ OCOCH ₃ ).

Crude (III) was converted to its trimethylsilyl (TMS) derivative according to conventional procedures. The protected azetidinone (III) (20 mmol) was dried at -78 ° C with methylene chloride (300
ml).

Ozone was bubbled through the solution at the same temperature for 4-6 hours.

At the end of the reaction, excess ozone was removed by passing nitrogen through the solution and the mixture was brought to 0 ° C. This solution was washed with sodium bisulfite (0.2 M, 2 × 100 ml) and dried over sodium sulfate. Evaporation of the solvent gave oxoamide (V), which could be stored for several days without any decomposition.

_{Va (R = CH 2 OCOCH 3} , R 1 = CH 2 OCONH 2, R 2 = TMS): white foam; yield _{80%; 1H-NMRδ (CDCl 3)} : 0.2 (9H, s, OTMS), 1.55 (3H, d, CH ₃
-CH), 2.15 (3H, s , OCOCH 3), 4.18 (1H, m, H-8), 4.82
(2H, AB, SCOCH ₂ ), 5.1 (2H, br, NH ₂ ), 5.9 (2H, AB, C
_{H 2 OCOCH 3), 6.23 (} 1H, s, H-5).

_{Vb (R = CH 2 OCOOH 3} , R 1 = CH 2 OCH 3, R 2 = TMS), oil;
1H-NMR δ (CDCl ₃ ): 0.2 (9H, s, OTMS), 1.55 (3H, d, CH ₃₎
CH), 2.15 (3H, s , OCOCH 3), 3.5 (3H, s, OCH 3), 4.13-4.
22 (3H: SCOCH ₂ and H-8), 5.9 (2H, AB system, CH ₂ OCOC
_{H 3), 6.22 (1H,} s, H = 5).

_{Vc (R = CH 2 OCOCH 3} , R 1 = CH 3, R 2 = TMS), oil; yield 7
5%; 1H = NMRδ (CDCl ₃ ): 0.2 (9H, s, OTMS), 1.55 (3H,
d, CH ₃ -CH), 2.15 (3H, s, OCOCH ₃ ), 2.35 (3H, s, SOCO
H ₃ ), 4.12 (1H, m, H-8), 5.85 (2H, AB system, CH ₂ OCOCH ₃ ),
6.02 (1H, s, H-5).

Crude (V) was dissolved in dry toluene or xylene (70 ml). Triethyl phosphite (8.7 ml, 50 mmol) was added and the solution was refluxed for 1-6 hours. At the end of the reaction, cool the mixture to 20 ° C. and add phosphate buffer (pH = 7.3 × 2
0 ml) and dried over sodium sulfate. Evaporation of the solvent gave an oil which was purified by column chromatography to give 80-protected bromopenem (II).

_{IIa (R = CH 2 OCOCH 3} , R 1 = CH 2 OCONH 2, R 2 = TMS): yellow oil; 50% _{yield; 1H-NMRδ (CDCl 3)} : 0.13 (9H, s, OTMS), 1.28 (3H, d, CH
_{3 CH), 2.1 (3H,} s, OCOCH 3), 4.33 (1H, m, H-8), 5.0-
5.5 (2H, AB _{system, CH 2 OCONH 2), 4.95} (2H, br, OCONH 2), 5.75
(1H, s, H-5 ), 5.85 (2H, AB system, CH ₂ OCOCH _3).

IIb (R = CH ₂ OCOCH ₃ , R ₁ CHCH ₂ OCH ₃ , R ₂ TMTMS): yellow oil; yield 57%; 1 H-NMR δ (CDCl ₃ ): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH ₃
CH), 2.13 (3H, s , OCOCH 3), 3.4 (3H, s, OCH 3), 4.37 (1
H, m, H-8) , 4.64 (2H, AB _{system, CH 2 OCH 3), 5.24} (1H, s, H-
5), 5.58 (2H, AB system, CH ₂ OCOCH _3).

IIc (R = CH ₂ OCOCH ₃ , R ₁ = CH ₃ , R ₂ = TMS): yellow oil;
1H-NMRδ (CDCl ₃ ): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH ₃₎
CH), 2.12 (3H, s , OCOCH 3), 2.4 (3H, s, 2-CH 3), 4.35
(1H, m, H-8), 5.71 (1H, s, H-5), 5.85 (2H, AB system, CH
₂ OCOCH ₃ ).

The protected (II), obtained as described above, is deprotected according to conventional methods and the corresponding 8-OH bromopenem (II)
I got

IIe (R = CH ₂ OCOCH ₃ , R ₁ 2CH ₂ OCONH ₂ , R ₂ ＨH): yellow oil; 1 H-NMR δ (CDCl ₃ ): 1.3 (3H, d, CH ₃ CH), 2.13 (3
H, s, OCOCH ₃ ), 2.7 (1H, br, OH), 4.38 (1H, m, H-8), 5.
05−5.47 (2H, AB system, CH ₂ OCONH ₂ ), 4.98 (2H, br, OCON
_{H 2), 5.81 (1H,} s, H-5), 5.87 (2H, AB system, CH ₂ OCOC
H _3).

IIf (R = CH ₂ OCOCH ₃ , R ₁ CHCH ₂ OCH ₃ , R ₂ ＨH): yellow oil; 1H-NMR δ (CDCl ₃ ): 1.3 (3H, d, CH ₃ CH), 2.13 (3H,
s, OCOCH ₃ ), 2.6 (1H, br, OH), 3.4 (3H, s, OCH ₃ ), 4.40
(1H, m, H-8 ), 4.64 (2H, AB _{system, CH 2 OCH 3), 5.76} (1H, s,
H-5), 5.85 (2H , AB system, CH ₂ OCOCH _3).

_{IIg (R = CH 2 OCOCH 3} , R 1 = CH 3 R 2 = H): yellow oil; 1
H-NMR δ (CDCl ₃ ): 1.3 (3H, d, CH ₃ CH), 2.12 (3H, s, OCO
CH ₃ ), 2.4 (3H, s, 2-CH ₃ ), 2.9 (1H, br, OH), 4.35 (1H,
m, H-8), 5.75 (1H, s, H-5), 5.79 (2H, AB system, CH ₂ OCOC
H _3).

Example 2 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H] (88
(0 mg, 2 mmol) was dissolved in acetonitrile (40 ml). 1
M ammonium acetate (10 ml, 10 mmol) and a silver / zinc couple (520 mg, 0.4% Ag) are added and the mixture is cooled at 20 ° C. to 75 ° C.
Stirred for minutes. At the end of the reaction, the mixture was filtered, diluted with ethyl acetate and washed with brine. The solvent was evaporated and column chromatography (silica gel, ethyl ether /
Purification by ethyl acetate 60:40 v / v) gave a white solid (5
R, 6S) -2-carbamoyloxymethyl-6- [1-
(R) -Hydroxyethyl] -penem- ₃ -acetoxymethyl carboxylate [(Ie): R = CH ₂ OCOCH ₃ ; R ₁ = CH ₂ COCNH
₂ ; R ₂ = H]. Yield 252 mg (35%).

1H-NMR (CDCl ₃ ): δ 1.35 (3H, d, CH ₃ CH), 1.5-1.8 (1
H, br, OH), 2.13 (3H, s, OCOCH 3), 3.77 (1H, dd, H-6),
4.22 (1H, m, H- 8), 4.82 (2H, br, NH 2), 5.27 (2H, AB
_{System, CH 2 OCONH 2), 5.65} (1H, d, H-5), 5.85 (2H, AB system, CH
₂ OCOCH ₃ ).

Example 3 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H] (92
4 mg, 2.1 mmol) was dissolved in 95% ethanol (18 ml).

Calcium carbonate (420 mg, 4.2 mmol) and 10% palladium supported on calcium carbonate (40 mg, 0.228 mmol P
d) was added and the mixture was stirred under a hydrogen atmosphere for 1 hour in a room. The catalyst was removed and the alcohol solution was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. Evaporate the solvent and column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v)
And purified by (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate acetoxymethyl [(Ie): R = C
_{H 2 OCOCH 3; R 1 =} CH 2 OCONH 2; the R ₂ = H] was obtained as a white solid. Yield 258 mg (34%).

Example 4 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -trimethylsilyloxyethyl] -penem-3-carboxylate acetoxymethyl [(II
a) R: = CH ₂ OCOCH ₃ ; R ₁ = CH ₂ OCONH ₂ ; R ₂ = TMS] (1.02 g, 2 mmol) was dissolved in acetonitrile (40 ml). 1M ammonium formate (10ml, 1
0 mmol) and activated zinc (260 mg, 4 mmol) were added and the mixture was stirred at 20 ° C. for 30 minutes. At the end of the reaction, the mixture was filtered, diluted with ethyl acetate, and washed with brine. The solvent was evaporated and purified by column chromatography (silica gel, ethyl ether / ethyl acetate 2: 1 v / v),
(5R, 6S) -2-carbamoyloxymethyl-6- [1
-(R) -trimethylsilyloxyethyl] -penem-
Acetoxymethyl 3-carboxylate [(Ia): R = CH ₂ OCOC
H ₃ ; R ₁ = CH ₂ OCONH ₂ ; R ₂ = TMS]. Yellow oil. yield
260 mg (30%).

1H-NMR (CDCl ₃ ): δ 0.13 (9H, s, TMS), 1.24 (3H, d, CH
_{3 CH), 2.12 (3H,} s, OCOCH 3), 3.70 (1H, dd, H-6), 4.18
(1H, m, H-8 ), 4.95 (2H, br, NH 2), 5.27 (2H, AB system, CH ₂
OCONH ₂ ), 5.35 (1H, d, H-5), 5.83 (2H, AB system, CH ₂ OCOCH)
₃ ).

Example 5 (5R, 6S) -2-methoxymethyl-6-bromo-6
[1- (R) -hydroxylethyl] -penem-3-acetoxymethyl carboxylate [(IIf): R = CH ₂ OCOCH ₃ , R ₁
= Dissolved _{CH 2 OCH 3, R 2 =} H] (820mg, 2mmol) in ethyl ether (40 ml). 1M ammonium acetate (10ml, 10mmo
l) and 85% zinc (615 mg, 8 mmol) were added and the mixture was stirred at room temperature for 2 hours. At the end of the reaction, the mixture was filtered, washed with brine, and dried over sodium sulfate. The solvent was evaporated and column chromatography (silica gel,
(5R, 6S) -2-
Acetoxymethyl methoxymethyl-6- [1- (R) -hydroxylethyl] -penem-3-carboxylate [(I
f): R = CH ₂ OCOCH ₃ , R ₁ = CH ₂ OCH ₃ , R ₂ = H]. Oil. Yield 250 mg (38%).

1H-NMR (CDCl ₃ ): δ 1.33 (3H, d, CH ₃ CH), 2.13 (3H, s,
OCOCH ₃ ), 3.42 (3H, s, OCH ₃ ), 3.72 (1H, dd, H-6), 4.2
2 (1H, m, H-8), 4.61 (2H, AB system, CH ₂ OCH ₃ ), 5.62 (1H,
d, H-5), 5.83 (2H, AB system, CH ₂ OCOCH _3).

Example 6 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
Acetoxymethyl 3-carboxylate [(II e): = R = CH
₂ OCOCH ₃ ; R ₁ CHCH ₂ OCONH ₂ ; R ₂ ＨH] (880 mg, 2 mmol) was dissolved in acetonitrile (40 ml). 1M zinc acetate (10ml, 1
0 mmol) and a silver-zinc couple (520 mg. 0.4% silver) were added and the mixture was stirred at 20 ° C. for 40 minutes. After completion of the reaction, the mixture was passed through, diluted with ethyl acetate, and washed with brine. Evaporate the solvent and column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v)
And purified by acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ie): =
_{R = CH 2 OCOCH 3; R} 1 = CH 2 OCONH 2; to give the R ₂ = H] as a white solid. Yield 215 mg (30%).

Example 7 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): = R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H]
(880 mg, 2 mmol) was dissolved in acetonitrile (40 ml).

1M ammonium chloride (10 ml, 10 mmol) and a silver / zinc couple (520 mg, 0.4% silver) were added and the mixture was added for 20 minutes.
Stirred at C for 20 minutes. After completion of the reaction, the mixture was passed, diluted with ethyl acetate, and washed with brine. The solvent was evaporated and purified by column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v) to give (5
R, 6S) -2-carbamoyloxymethyl-6- [1-
(R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl [(I e): = R = CH 2 OCOCH 3; R 1 = CH 2
OCONH ₂ ; R ₂ = H] was obtained as a white solid. Yield 180mg (28
%).

Example 8 (5R, 6S) -2-methyl-6-bromo-6- [1-
(R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl _{[IIg): R = CH 2} OCOCH 3, R 1 = CH 3, R 2 =
H] (760 mg, 2 mmol) was dissolved in ethyl acetate (40 ml). 1 M ammonium acetate (10 ml, 10 mmol) and 85% zinc (6
15 mg, 8 mmol) and the mixture was stirred at 20 ° C. for 3 hours. At the end of the reaction, the mixture was filtered, washed with brine and dried over sodium sulfate. Evaporate the solvent and column chromatography (silica gel, ethyl ether)
And purified by (5R, 6S) -2-methyl-6- [1
- (R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl _{[I g: R = CH 2} OCOCH 3, R 1 = CH 3, R 2 =
H]. Yellow oil. Yield 110 mg (18%).

1H-NMR (CDCl ₃ ): δ1.3 (3H, d, CH ₃ CH), 2.13 (3H, s, O
_{COCH 3), 2.38 (3H,} s, 2-CH 3), 2.80 (1H, br, OH), 3.80
(1H, dd, H-6), 4.20 (1H, m, H-8), 5.65 (1H, d, H-
5), 5.85 (2H, AB system, CH ₂ OCOCH _3).

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-56-65892 (JP, A) JP-A-61-180766 (JP, A) JP-A-63-316784 (JP, A) JP-A-57-658 99589 (JP, A) Am. Chem. Soc. (1985), 107, pages 6398-6399 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 499/00-499/82 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] (1) Formula (I): (Wherein R a) alkanoyl moiety is a linear or branched C ₂ -C ₁₀ alkanoyl or C ₄ -C ₈ cycloalkanoyl alkanoyloxymethyl a group or a 1- (alkanoyloxy) ethyl; b) benzoyloxy methyl or 1- (benzoyloxy) ethyl; c) alkoxycarbonyloxymethyl or 1- (alkoxycarbonyloxy) ethyl; d) 3- phthalidyl; e) or 5-position is substituted by C ₁ -C ₄ alkyl or Unsubstituted 2-oxo-1,3-dioxolan-4-
Yl; it is or a substituted or g) 4-position is substituted by C ₁ -C ₄ alkyl group; f) R 'is -CH ₂ COOR a C ₁ -C ₄ straight or branched chain alkyl or benzyl' R ₁ is a tetrahydrofuranyl group, or a substituted or unsubstituted C ₁ -C ₄ alkyl group, methylphenyl group or methylphenoxymethyl group; ,
The substituents are selected from: (i) carbamoyloxy, C ₁ -C ₁₈ alkoxy, carboxy, or free or protected hydroxy, and (ii) substituted or unsubstituted pyridinium, N - a methyl pyrrolidinium or piperidinium, these phenyl, a saturated or C ₅ ~ unsaturated
C ₇ may be condensed with an alicyclic group or a heterocyclic group, and the substituent thereof is the group of the above (i), or is substituted or unsubstituted by a sulfonyloxy group or a carboxy group. ₁ -C is ₄ alkyl group; and to a process for the preparation of compounds of R ₂ represents a hydrogen atom or a hydroxy protecting group), the formula (II) Wherein R, R ₁ and R ₂ have the above-mentioned meanings. 2. The method according to claim 1, wherein the reduction is carried out by catalytic hydrogenation. 3. The method according to claim 1, wherein the reduction is performed by a treatment using a reducing metal. 4. The method according to claim 3, wherein the reducing metal is zinc or an alloy of zinc and another metal. 5. The method according to claim 4, wherein the reducing metal is an alloy of zinc and copper or silver. 6. The method according to claim ₁ , wherein the hydroxy-protecting moiety of R ₂ or R ₁ is p-nitrobenzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, p-nitrobenzyl. The method according to any one of claims 1 to 5, wherein the method is a bromophenacyl group, a triphenylmethyl group, or a tetrahydropyranyl group. 7. The method according to claim 1, wherein the reduction is carried out in an organic solvent at a temperature of -20.degree. C. to + 80.degree. C. in the presence of an aqueous solution of ammonium or zinc carboxylate or a halide. A method according to claim 1. 8. A compound of formula (II) as defined in any one of claims 1 and 6. 9. A process for preparing a compound of formula (II) as defined in claim 8, comprising cyclizing the compound of formula (V). (Wherein R, R ₁ and R ₂ have the meanings described in claims 1 or 6) 10. The process according to claim 9, wherein the cyclization is carried out using triethyl phosphite or trimethyl phosphite in an inert organic solvent. 11. Formula (III): (Wherein R, R ₁ and R ₂ means has according to paragraph 9 claims) Claims 9 or paragraph 10 for preparing a compound of formula (V) by ozonolysis of a compound of The method described in the section. 12. A compound of formula (II) as defined in claim 1 as specified herein.