CS207573B2 - Method of preparatiob of 3-hydroxymethylenchromanone - Google Patents

Description

The present invention relates to a process for the preparation of 3-hydroxymethylenehromanone of the formula I

where

R ₄ and R ₅ are hydrogen, methyl or ethyl,

Z is (C 1 -C 9) alkylene or - (alk (X) - (alk ₂ ) _n - wherein each of (alk,) and (alk ₂ ) contains from 1 to 9 carbon atoms, the sum of the carbon atoms v (alkj) and (alk ₂ ) is at most 9, m and n are 0 or 1,

X is O, S, SO or SO _2; and

W is methyl, phenyl, p-chlorophenyl, β-fluorophenyl, pyrldyl, piperidyl, cycloalkyl of 3 to 7 carbon atoms which is optionally immonosubstituted and wherein the substituents are phenyl, p-chlorophenyl or p-fluorophenyl, wherein W is methyl, is Z - (allq) _m - X - (alk ₂ ) _n , characterized in that the compound of formula II

where

R ₁ , R ₄ , R ₅ , Z and W are as defined above, reacted with ethyl formate ®.

The compounds of formula I are novel compounds which are intermediates for the preparation of analgesic compounds.

The reaction is carried out by dropwise addition of the reactants to the sodium hydride suspension, after which dilution with ether is complete by boiling.

The desired starting compounds of formula II are prepared from 3,5-dihydroxybenzoic acid by the following reaction sequence:

II

The starting material 3,5-dihydroxybenzoic acid (V) is converted to a compound of formula VI, wherein Y ₂ is alkoxy, suitably methoxy or eithoxyl for ease of preparation, or amino and Y ₁ is a protected hydroxyl group, by methods commonly known in the literature.

When Z is alkylene, _Y;) is alkyl having 1 to 4 carbon atoms or benzyl. The function Y _t are protected hydroxy groups during subsequent reactions. More important is their specific function, that is the protection of the hydroxyl group and not their structure. Selection and identification of appropriate protecting groups can be readily accomplished by one skilled in the art. The suitability and efficacy of the groups as hydroxy protecting groups is determined by the utility of these groups in the above reaction sequence. It is therefore to be a group that is easily removed to restore hydroxyl groups. Methyl is preferred as a protective alkyl group since it is readily removed by reaction with pyridine hydrochloride. The benzyl group used to protect the hydroxyl group is removed by catalytic hydrogenolysis or acid hydrolysis.

If Z is - (alk _t J _{m -} X - (alk ₂ J _n) , Y _{: 1} is preferably benzyl or substituted benzyl, since they can be easily removed without affecting the Z group.

The double protected benzoic acid derivative (VIJ is then converted to the compound of formula VIII in a known manner. In one method, the compound of formula VI is hydrolyzed to the corresponding acid (Y ₂ = OH) or lithium salt and then reacted with the appropriate alkyl lithium to form an alkyl disubstituted phenyl ketone (Y ₂ = - alkyl). When used methyllithium, allowed the resulting acetophenone derivative with a Grignard reagent (W-Z'-MgBr). the intermediate is hydrolyzed to the corresponding alcohol which is then hydrogenolysuje to replace the hydroxyl group with This procedure is particularly useful for those compounds wherein Z is alkylene.

The ether groups are removed in a suitable manner: by reaction with pyridine hydrochloride (Y = methyl) or catalytic hydrogenolysis (Y _d = benzyl) or by treatment with an acid such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid or sulfuric acid or pyridine hydrochloride. Of course, acid debenzylation is used when the —Z — W group contains sulfur.

Another method for converting compounds of Formula VI to compounds of Formula VIII involves reacting a ketone of Formula VI (Y ₂ -alkyl) with an appropriate triphenylphosphonium-bromide derivative of formula [(C ₆ H ₅ ) ₃ P ⁺ -Z-W ₃ Br ^- in the presence of a base (e.g. sodium hydride). The reaction proceeds through an alkene which is then catalytically hydrogenated to the corresponding alkane (Z-WJ and then deprotected and the dihydroxy compound of formula VIII is prepared. If -Z- is (alkim-X-) (alk ₂ J _n and Y _x is benzyl) , catalytic hydrogenation also leads to the cleavage of benzyl ethers.

Alternatively, the conversion of compounds of formula VI to compounds of formula VIII can be carried out by the following sequence VI->VII-> VIII. In this sequence, the double-protected benzamide (VI, Y ₂ = NH ₂ ) is converted to the ketone (VII, Z '= Z without one CH ₂ -group) by reaction with the appropriate Grignard reagent (BrMg-Z'-Wj and then reaction with methyl Dehydration of the carbinol with, for example, p-toluenesulfonic acid leads to the corresponding alkene, which is then catalytically hydrogenated (Pd / C) to the alkane (VIII), and the ether groups are removed (converted to hydroxy groups as described above).

Conversion of the compound of formula VIII to 4-chromanone (IX) is accomplished by reacting the compound of formula VIII with crotonic acid or an acid of formula R ₄ R ₅ -C-CH-COOH in the presence of boron trifluoride etherate at a temperature of about 20 to about 125 ° C. Krol compound of formula IX to obtain a second product, the isomeric compound of Formula IX (7-hydroxy-2,2-R _{4 R)} -5-ZW-4-chromanone).

The present invention is illustrated by the following examples.

Example 1 dl-5-Hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromanone

A mixture of 2- (3,5-dihydroxyphenyl) -5-phenylpentane (9.6 g) and 3-methylcrotonic acid (5.6 g) was heated to 125 ° C under a nitrogen atmosphere and boron trifluoride etherate (8.7 g) was added. ml). After heating to boiling for 1 h, the reaction mixture was cooled, water (10 mL) was added, followed by 6N sodium hydroxide (40 mL). The reaction mixture was heated on a steam bath for 5 minutes, cooled and acidified with 6 N hydrochloric acid. The aqueous phase was extracted with ether (3 x 100 mL) and the combined ether extracts were washed with 10% sodium bicarbonate solution (1 x 25 mL) and water (1 x 25 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to give 12.7 g of a crude oil which was purified by silica gel chromatography to give 5.0 g of dl-5-hydroxy-2,2-dimethyl-7- (1-methyl). -4-phenylbutyl) -4-chromanone as a colorless oil.

IR: (CHCl 3) U - O 1635 cm ^-1 .

NMR: 1 ™ with _J3

1 - 1.7 (M, 7, α-methyl, ethylene),

1.5 (S, 6, gem.dimethyl),

2.3-2.9 (M, 3, benzyl methylene, methinyl),

2.65 (S, 2 ', 05-methylene),

6.1-6.35 (M, 2, aromatic protons),

6.9-7.4 (M, 5, aromatic protons),

11.53, 11.63 (d, 1, hydroxyl).

Similarly, 2- (3,5-dihydroxyphenyl) -6-phenylhexane is converted to dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-5-phenylpentyl) -4-chromanone (oil):

1.2 (d, 3, N-methyl, J = 7 cps),

1.4 (S, 6, gem.dimethyl),

I, 0-1,9 [M, 6,0-CH ₂ - (CH ₂ ) ₃ -C (CH ₃ j-Ar),

2,3-2,8 (M, 3, benzyl methylene, methyl),

2.7 (S, 2, N-methylene),

6.2-6.4 (M, 2, aromatic protons),

7.1-7.3 (δ, aromatic protons),

II.6 (S, 1, hydroxyl),

1- (3,5-Dihydroxyphenyl) -2-phenylethane was converted to 5-hydroxy-2,2-d: Imethyl-7- (2-phenylethyl) -4-chromanone (oil):

IC: (CHCl ₃ ) C = O 1645 cm ^-1

1.45 (S, 6, g. Dimethyl),

2.65 (S, 2'-methylene),

2.85 (s, 4, ethylene),

6.25, 6.3 (2d, 2, aromatic protons),

7.2 (S, 5, aromatic protons),

11.6 (S, 1, hydroxyl-D ₂ O overlap).

MS: molecular ion 296.

2- (3,5-Dihydroxyphenyl) -4-phenylbutane was converted to dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-3-phenylpropyl) -4-chromanone (oil):

1.3 (d, 3, methyl),

1.45 (S, 6, g. Dimethyl),

I, 55-2.1 (M, 2, methylene),

2.25-2.75 (M, 3, benzyl methylene, methinyl),

6.15 (d, 2, aromatic protons),

7.1 (S, 5, aromatic protons),

II, 6 (S, 1, hydroxyl-D ₂ O overlay).

MS: molecular ion 324.

2- (3,5-Dihydroxyphenyl) -5-phenylpentane (5.27 g) was converted by reaction with boron trifluoride etherate (4.81 ml) and crotonic acid (2.08 g freshly distilled) instead of s

3-methylcrotonic acid to dl-5-hydroxy-2-ethyl-7- (1-methyl-4-phenylbutyl) -4-chromanone:

NMR: .delta

TMS

CDC13

1.1 (D, 3, α-methyl, J = 7Hz),

1.4 (D, 3,2-methyl, J = 7Hz)

I, 3-1.8 (M, 4-ethylene),

2.2-2.9 (M, 5'-methylene, benzyl methylene, methinyl),

4.5 (Μ, 1, methinyl ether)

6.1, 6.2 (2, D, aromatic protons, J = 1 Hz),

6.9-7.4 (M, 5, aromatic protons),

II, 7 (S, 1, phenolic OH).

4- (3,5-Dihydroxyphenyl) -1-phenoxypentane was converted to dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenoxybutyl) -4-chromanone, light yellow oil:

MS: molecular ion 354.

R _f = 0.61 (silica gel, benzene-ethyl acetate 18: 1)

Analysis for C22H26O4:

calculated:

74.55% C, 7.39% H;

found:

74.56% C, 7.36% H.

4- (3,5-Dihydroxyphenyl) -1- (4-pyridyl) pentane was converted to dl-5-hydroxy-2,2'-dimethyl-7- [1-methyl-4- (4-pyridyl) butyl] -4-chrclmamone oil:

R _f = 0.39 (silica gel, benzene-ethyl acetate 1: 1)

NMR: .delta

1 - 1.90 (Μ, 13-H, methylene, methyl doublet at 1.20, J = 7 Hz, and gem.dimethyl singlet at 1.5),

2.43-2.86 (Μ, 5-H, methylene, methinyl, including singlet (two C-3 H at 2.71),

6.26 (b.d. S, 1-H, aromatic proton), 6.33 (b.d S, 1H, aromatic proton), 7.00-7.20 (b. D. D, 2-H, pyridine aromatic protons),

7.25 (bd., 1,1-H-hydroxyl),

8.41-8.61 (b.d. D, 2-H-pyridine aromatic protons).

dl-5-Hydroxy-2,2-dimethyl-7- (1-methyl-3-phenoxypropyl) -4-chromanone was prepared from 3- (2,5-dihydroxyphenyl) -1-phenoxybutanol as an oil .

R _f = 0.7 (silica gel, benzene-ethyl acetate 18: 1).

MS: molecular ion 340.

Analysis for C21H24O4:

calculated:

% C, 74.09;% H, 7.11; found:

% C, 74.04;% H, 7.19.

dl-2- (3,5-Dihydroxyphenyl) -1- (2-phenylethoxy) propane was converted to dl-2,2-dimethyl-5-hydroxy-7- (1-methyl-2- (2-phenylethoxy) ethyl) -4-Chromanone (oil).

1.21 (d, J = 7 Hz, methyl), 1.48 (s, g-dimethyl),

2.73 (s, C-3 methylene),

2.86 (+, J = 7 Hz, CH ₂ Ph),

2.9 (m, miethin),

3.50 (d, J = 7Hz, -CH ₂ O-)

3.65 (t, J = 7Hz, -OCH2 -), 6.31 (d, J = 1Hz, ArH), 6.38 (d, J = 1Hz, ArH),

7.26 (s, Phj and 13.33 (s, phenol)).

Example 2 dl-5-Hydroxy-3-hydroxyraethylene-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromanone

A solution of dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) was added dropwise over 30 minutes to the sodium hydride prepared by washing the 50% sodium hydride in a mineral oil dispersion (6.67 g) with pentane. Of 4-chromanone (4.7 g) and ethyl formate (23.1 g), the reaction mixture was then cooled to room temperature and -ether (350 mL) was added and the mixture was heated at reflux for 18 hours. The ethereal phase was separated and the aqueous phase was extracted with ether (3 x 100 mL). The combined ethereal extracts were dried over sodium sulfate and concentrated in vacuo to give 5.7 g of dl-5-hydroxy-3. hydroxymethyl-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chloroanine as an oil.

1,05-1,8 (M, 13, g-dimethyl, α-methyl, ethylene),

2.45 (M, 3, benzyl methylene, methinyl),

6.2 - 6.5 (M, 2, ArH),

7.0-7.6 (M, 6, ArH, methinyl ether),

11.3, 11.36 (2 d.d. of S, 1, phenolic hydroxyl),

13.3, 13.5, (2 d.d. of S, 1, hydroxyl).

IR: (CHCl 3) C = O 1625 cm ^-1 .

In the same manner, the products of Example 1 were converted to dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-5-phenylpentyl) -4-chromanone:

1.2 (D, 3, N-methyl, J = 7 cps),

1.6 (S, 6, gem.diethyl),

1.0-2.0 [M, 6, 0CH2- (CH2) 3-CH _(CH3) Ar]

2,3-2,8 (Μ, 3, benzyl methylene, methinyl},

6.2-6.4 (M, 2, Ar H),

7.1-7.4 (M, 6, ArH, vinyl proton),

11.4 (bdS, 1, phenolic hydroxyl),

5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-phenylphenyl) -4-chromanone (oil):

IC: (CHCl 3) C = O 1625 cm ^-1 .

1.5 (S, 6, gem.dimethyl),

2.85 (s, 4, ethylene),

6.2, 6.3 (d, 2, ArH),

7.0-7.5 (M, 6, ArH, methinyl),

11.35 (S, 1, hydroxyl-DgO overlay),

13.4, 13.6 (d, 1, hydroxyl-D ₂ O overlap).

MS: molecular ion 324.

dl-5-Hydroxy-3-hydroxymethylene-2,2-diethyl-7- (1-methyl-3-phenylpropyl) -4-chroimanoin (oil):

1.15 (d, 3, methyl),

1.5 (S, 6, gem.dimethyl),

I, 65-2.1 (M, 2, methylene),

2.25-2.75 (M, 3, benzyl methylene, methinyl),

6.15, 6.3 (2d, 2, ArH),

7.1 (M, 6, ArH, olefinic proton),

II, 3 (S, 1, hydroxyl-D ₂₀ overlap),

13.3, 13.8 (d, 1, hydroxyl-D ₂ O overlap). MS: molecular ion 352.

dl-5-Hydroxy-3-hydroxymethylene-2-methyl-7- (1-methyl-4-phenylbutyl) -4-chromanone:

1.1 (D, 3'-methyl, J = 7 Hz),

1.5 (D, 3.2-methyl, J = 7 Hz),

1.3-1.8 (M, 4-ethylene),

2.3-2.9 (M, 3, benzylic protons),

4.9 (Μ, 1, methynyl ether, J = 5 Hz),

6.2, 6.3 (2D, 2, ArH, J = 1Hz),

6.9-7.4 (M, 6, ArH, vinyl proton),

11.2 (b.d. S, 1, feholic OH).

dl-5-Hydroxy-2,2-dimethyl-7- (1-methyl-4-phenoxybutyl) -4-chromanone was converted to dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- ( 1-Methyl-4-phenoxybutyl) -4-chromonanone:

^Rf = 0.44 [silica gel, benzene-ethyl acetate 18:

: 1].

MS: molecular ion 382.

dl-5-Hydroxy-2,2-dimethyl-7- [1-methyl-4- (4-pyridyl) blutyl] -4-chromanone was converted to dl-5-hydroxy-3-hydroxymethylene-2,2- dimethyl 7- [1-methyl-4- (4-pyridyl) butyl] -4-chromanone, viscous oil.

R _f = 0.15 (silica gel, benzene-ethyl acetate 1: 1).

dl-2,2-Dimethyl-5-hydroxy-7- [1-methyl-2- (2-phenylethoxy) ethyl] -4-chromanoin is converted to dl-2,2-dimethyl-3-hydroxymethylene-5- hydroxy-7- [1-methyl-2- (2-phenylethyl) ethyl] -4-chromanone (oil).

Rf ₌ 0.35 (silica gel, 1: 1 pentane: ether).

Example 3 dl-5-Hydroxy-2,2-dimethyl-7- (2-heptyloxy) -4-chromanoin

To a solution of 5,7-dihydroxy-2,2-dimethyl-4-chromanone (18.5 g, 87.1 mmol) and potassium hydroxide (2.44 g, 43.5 mmol) in N, N-dimethylformamide (58). ml) 2-bromo-heptiptan (15.77 g, 88.0 mmol) was added with stirring. The mixture was heated at 100 ° C for 4 days, cooled to room temperature and then added to a mixture of aqueous sodium hydroxide (110 mL, 1N), pyridine (45 mL) and chloroform (150 mL). The mixture was stirred and the chloroform phase was separated. The aqueous phase was extracted with an additional amount of chloroform (150 mL). The combined chloirophof phases were washed with 1N sodium hydroxide solution (2 x 100 ml), dried over sodium sulfate and concentrated to an oily residue. The unreacted 2-bromoheptane was removed by distillation and the residue was purified by silica gel chromatography to give 6.90 g (22.1%) of the title compound as an oil.

NMR: (CDCl ₃ )? 12.4 (one-pot singlet, hydroxyl],

5.7 and 6.0 (two single proton doublets)

J = 3 Hz, arolmatic protons j,

4.1—4.7 (single proton multiplet, ethereal methinj,

2.7 (2-proton singlet, C-3 methylene),

0.7-2.0 (22 protons, multiplet of remaining procoins, gem.dimethyl appearing as; singlet at 1.5).

In the same manner, dl-5-hydroxy-2,2-dimethyl-7- [2- (5-phenylpentyloxy) -4-chromanone was prepared by substituting 2-bromo-5-phenylypentant for 2-bromoheptane, mp 83-84 Deň: 32 ° C.

IR: (KBrj C = O 1639 cm -1 ⁾ .

NMR: .delta

TMS

CDC15

1.3 (D, 3, N-methyl, J = 7 Hz),

1.3-2.0 (M, 4, ethylene),

1.5 (S, 6, gem.dimethyl),

2.7 (S, 2, N-methylene),

2,5-2,9 {Μ, 2, benzyl methylene],

4.1- 4.7 (Μ, 1, methine),

5.9-6.1 (Μ, 2, ArH),

6.1-7.5 (Μ, 5, ArH)

12.2 (S, 1, phenolic proton).

MS: (molecular ion) 354.

Analysis for C 22 H 26 O 4: calculated:

74.55% C, 7.39% H; found:

74.68% C, 7.46% H. dl-5-Hydroxy-2,2-dimethyl-7- (1-methyl-3-phenylpropoxy) -4-chromanone was prepared from 2-bromo-4-phenylbutane as oil:

NMR: á ™ ^s

U _ODCb

1.25, 1.35 (d, 3, methyl),

1.4 (S, 6, gem.dimethyl),

1.6-2.4 (M, 2, methylene),

2.6 (S, 2, benzyl methylene),

2.85 (S, 2, 3 α-methylene),

4.05-4.7 (M, 1, methinyl),

5.9 (5d, 2, ArH),

7.25 (s, 5, ArH).

dl-5-Hydroxy-2,2-dimethyl-7-cyclohexyloxy-4-chromanone was prepared from bromocyclohexane, mp 72-75 ° C.

IR (KBr) C = 0 1626 cm ^-1 , OH 3390 cm ^-1 . MS: (molecular ion) 290.

NMR: á ™ ^with ΐΊΐνιιχ. u _{c [] cl3}

1-2.1 (M, 10, C ₅ H ₁₀ -cyclohexyl),

1,4 (S, 6, g. Dimethyl),

2.65 (S, 2, .alpha.-methylene),

4.0-4.45 (M, 1, cyclohexylmethinyl), 5.85-6.05 (M, 2, ArH),

II, 9 (S, hydroxyl, D ₂ O overlap).

Example 4 dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4-chromanone

To the sodium hydride obtained by washing 9.23 g (192 mmol) of 50% sodium hydride in a mineral oil dispersion in pentane was added dropwise a solution of dl-5-hydroxy-2,2-dimethyl-7- (2-heptyloxy) -4 over 30 minutes. -chromanoin (5.90, 19.2 mmol) in ethyl formate, 34.9 mL (432 mmol). After addition was complete, ether (475 mL) was added and the resulting mixture was heated to reflux. After 18 hours, the reaction was cooled to room temperature and acidified with 1N hydrochloric acid. The organic phase was separated and the aqueous phase was further extracted with ether (3 x 125 mL). The combined ethereal extracts were dried with sodium sulfate and concentrated in vacuo to give 6.41 g (> 100%) of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4 -bromanone in the form of an oil.

NMR: 5 ™ _{C i3}

13.4 (one proton wide singlet, hydroxyl),

11.8 (one proton, singlet, phenolic hydroxyl),

7.4 (single proton wide singlet, vinyl)

6.1, 6.0 (two single proton doublets,

J = 3 Hz, aromatic protons),

4.8-4.2 (single proton multiplet, methine),

2.1-0.7 (20 protons, multiplet remaining protons).

In the same manner, the appropriate reaction of the component of Example 3 was converted to dl-5-hydroxy-3-methylene-2,2-dimethyl-7- [2- (5-phenyl) pentyloxy] -4-chromanone, an oil.

NMR: _.delta

1.3 (D, 3, methyl, J = 7Hz),

1.3-2.0 (M, 4, ethylene),

1.4 (S, 6, gem.dimethyl),

2.3- 2.8 (b.d. T, 2-henzyl methylene),

4.1-4.7 (M, 1, methine),

5.8-6.0 (M, 2, Ar H),

7.0-7.4 (M, 6, aromatic and vinyl protons),

10.0 (S, 1, phenolic proton),

13.3 (b.d., S, 1, hydroxyl), dl-5-Hydroxy-3-hydroxyimethylene-2,2-dimethyl-7- [2- (4-phenylthietyloxy) -4-chromanone, ole).

dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7-cyclothyloxyloxy-4-chromamone:

IR: (KBr) C = O 1620 cm ^-1 , OH 3420 cm ^-1 . MS: (Molecular ion) 318.

NMR: δ ™ ₃

1.1-2.3 (M, 10, C ₅ H ₁₀ -cyclohexyl),

I.55 (S, 6, gem.dimethyl),

4.1- 4.5 (M, 1, cyclohexylmethynyl),

3.9-6.1 (M, 2, Ar H),

7.1-7.5 (d, 1, methinyl),

II, 6 (S, 1, hydroxyl, D ₂ O overlap).

dl-5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-3-phenoxypropyl) -4-chromanone, oil (from the compound of Example 1):

R _f = 0.42 (silica gel, benzene-ethyl acetate 18: 1).

MS: (molecular ion) 368.

Claims (1)

P R E D Ε Ε Τ A process for the preparation of 3-hydroxymethylene-chromianone of the formula I wherein R 2 and R ₅ are hydrogen, methyl or ethyl, Z is C 1 -C 9 alkylene or - (alki) _m —X- (alk ₂ ] _n - wherein each of the substituents (alkj and (alk ₂ ) contains from 1'O 19 to 9 carbon atoms, the sum of the carbon atoms v (alk _t ja (alk,) is not more than 9, _m and _n is 0 or 1, X is O, S, SO or -SO ₂ a VYNALEZU W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, C 3 -C 7 cycloalkyl which is optionally monosubstituted and wherein the substituents are phenyl, p-chlorophenyl or p-fluorophenyl, wherein W is methyl, is Z- (alkj) _m - X - (alk ₂ ) _n , characterized in that the compound of formula II wherein: R 1, R ₄ , R ₅ , Z and W are as defined above, reacted with ethyl formate in the presence of sodium hydride.