CS223418B1 - Method of making the dialcylphosphonate - Google Patents

Description

R is C1-C4 alkyl,

R @ ¹ denotes hydrogen, chlorine, bromine, fluorine, trifluoromethyl or alkoxy or alkyl having 1 to 2 carbon atoms,

R ² is hydrogen, chlorine, bromine, fluorine, trifluoromethyl or alkoxy or alkylnvou group having 1-2 carbon atoms, or Rl and ^R2 together are O-CH-O, x is 0-3, y is 0-3, provided that the sum of x + y does not exceed 3.

Synthetic analogues of natural prostaglandins, tissue hormones with high and multifaceted biological activity, which are derivatives of so-called prostanoic acid, are increasingly used in veterinary practice in the management of the reproductive process of livestock. 1 to 87, (1981)].

one of the key intermediates in the synthesis

CH-CO-CH = P O) (0R) _£ (Π thereof phosphonates of the general formula I, whose preparation has been given considerable attention (Nelson Brit. 1438 093, 03 Jan 1976, Bindra, J. S "Johnson The process for the preparation of the various types of phosphonates varies in the initial synthetic steps according to the desired combination of the x and y indices, which have the meaning given above, but the characteristic of most of the syntheses known so far is the way in which the last reaction step is carried out. consisting in the conversion of an intermediate of formula II,

wherein R, R ^2, x, y have the aforementioned meanings and Z is halogen such as chloro, bromo, in the general formula IIa or an alkoxy group OR ³ in formula IIb comprising alkyl, R ³ having from 1 to 4 carbon atoms, which treating the alkali salt of the corresponding ^{* 1} a dialkyl methylphosphonate of the formula III (RO) 2 P (O] CH 3 (III) wherein R is as above defined. the alkali salt is prepared in situ with a suitable metallation agent, typically n-butyl lithium in aprotic solvents, for example tetrahydrofuran, at temperatures of -78 ° C and immediately processed according to the following scheme 1:

Scheme 1 (RO) _Z P (0) CH ₃ ( _R q) ₂ P (o) CH _from Li (III)

CH 2 CO-Z (II) 2 - (CH 2 -O-ICH 2 -CH 2 CO-CH-P (O) (OR 2,

Hft)

Li + (RO)? P (O) CH, + (III) + Li ~ Z (I)

The above scheme shows that due to the high acidity of the hydrogen atoms of the methylene group adjacent to the phosphorus atom and the carbonyl function, a transmetallation reaction occurs at the expense of the starting phosphonate of formula III, which is therefore used in one or more molar excess. a significant disadvantage of the known production processes. In addition, the re-liberated starting phosphonate III, which is largely non-recoverable, makes it difficult to isolate the desired dialkyl phosphonate of formula I. In the acylation reactions carried out using acyl halides of formula IIa wherein Z is chlorine, bromine, the disadvantages are relatively low yields.

These known processes are followed in a positive manner by the process of the invention. SUMMARY OF THE INVENTION The reaction of the alkyl ester of formula (IIb) with the lithium salt of methylphosphonic acid dialkyl ester (III) is carried out in equimolar amounts in the presence of the lithium salt of spherically hindered secondary amines such as diisopropylamine, dicyclohexylamine and 2,6-dimethylpiperidine. To a solution of the starting phosphonate of formula III in an aprotic solvent (e.g. 1,2-dimethoxyethane) is added at low temperature -60 ± -10 ° C equimolar amounts of a sterically hindered secondary amine (e.g. dlisopropylamine, dicyclohexylamine, 2,6-dimethylpiperidine), obtained the mixture is converted by treatment with n-butyllithium into a mixture of lithium salts which is acylated with an equilibrium amount of an ester of formula (IIb), wherein R ¹ , R ² , R ³ , x, y are as defined above.

Upon acidification of the reaction mixture, the corresponding dialkyl phosphonate of formula (I) is liberated, which is extracted into an organic solvent, while the liberated amine passes into the aqueous phase as the corresponding salt. The procedure is shown in Figure 2.

Scheme 2 to o

. +

O

Q £

Η — B represents a secondary amine.

A particular advantage of the process according to the invention is the use of a cheap and readily available transmetal base, a secondary amine, which allows full utilization of the starting component, the phosphonate of formula III. In working up the reaction mixture, the liberated amine can be readily separated and recovered, at the same time avoiding undesired interference in the isolation of the desired dialkyl phosphonate of formula I, which can be obtained in high yield by this process.

The following examples illustrate the effect of the invention.

Example 1 _ .......

To a solution of 1.24 g (0.01 mol) of the methyl methyl phosphonate of formula III (R is methyl) in 1,2-dimethoxyoxyethane (30 mL) was added under stirring at -50 ° C under an inert atmosphere ( argon) 1.4 ml (0.01 mol) of diisopropylamine and then a solution of n-butyllithium (18 ml of a 1.13 molar solution in hexane, 0.02 mol) was added dropwise so that the temperature did not exceed -50 ° C. A solution of 2.005 g (0.01 mol) of methyl (m-chlorophenoxy) acetate of formula IIb (R ¹ = m-Cl, R ² = H, x = 0, y = 0, R ³ is methyl) was added at the same temperature for 15 minutes. ) in 1,2-dimethoxyethane (10 mL) and held at -50 ° C for 2 hours, then warmed to 0 ° C, acidified with 2.5 mL acetic acid, diluted with 10 mL water and evaporated In the solvent, the organic portion was extracted with 1,2-dichloroethane (4 x 100 mL), from which the remaining diisopropylaminoacetate was removed in 223418 (2 x 10 mL) and saturated sodium bicarbonate (10 mL). Solvent yielded practically pure product of formula I (R = methyl, R ¹ = m-Cl, R ² = H, x = 0, y = 0) in 82% yield, mp 74-77 ° C.

Example 2

To a solution of 1.24 g (0.01 mol) of dimethyl methylphosphonate of formula III in tetrahydrofuran (30 ml) was added 2.00 ml (0.01 mol) of dicyclohexylamine under stirring at -50 ° C under an inert atmosphere, and then a solution of n-butyllithium (18 ml of a 1.13 molar solution in hexane, i.e. 0.02 mol) was added at the same temperature. After 15 minutes, the above temperature, a solution of 1.90 g (0.01 mole) of methyl (m-fluorophenoxy) acetate of formula IIb (R ¹ equals SE- mF, R ² = H, R ³ = methyl, x = 0, y = 0). Following treatment of the reaction mixture in an analogous manner to Example 1, the phosphonate of formula I (R = methyl, R ¹ = im-F, R ² = H, x = 0, y = 0) was obtained in a yield of 73 percent of theory.

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of dialkylphosphonates of the general formula (I), (R) -O-R (CH 2 CO-CH 3 P (O) 1 OR) _from: R is C1-C4 alkyl, R @ ¹ denotes hydrogen, chlorine, bromine, fluorine, trifluoromethyl or alkoxy or C1 -C2 -alkyl, R ² denotes hydrogen or chlorine, bromine, fluorine, trifluoromethyl or alkoxy or alkyl containing 1-2 carbon atoms or R ¹ and R ² together form -O-CH 2 O, x is 0-3, y is 0-3, provided that the sum of x + y does not exceed 3, by reaction of an alkyl ester of formula IIb, Λ - (CH ₂ ) _K -O- (CH 2 -Y-CH 2 COOR '(IIb) wherein R ³ denotes alkyl having 1 to 4 carbon atoms and R ¹ , R ² , x, y are as defined above, with lithium methylphosphonic acid dialkyl ester salts of formula III, CH 3 P (O) (OR) 2, (III) wherein R is as defined above, characterized in that the reaction is carried out in the presence of a lithium salt of sterically hindered secondary amines in an aprotic polar solvent at a temperature of -60 ± 10 ° C, the dialkyl phosphonate of formula I is isolated from the reaction mixture after acidification. 2. The process according to claim 1, wherein the sterically hindered secondary amine is diisopropylamine, dicyclohexylamine or 2,6-dimethylpiperidine. 3. The process of claim 1 wherein the aprotic polar solvent is 1,2-dimethoxyethane. 4. The process of claim 1 wherein the reaction mixture is acidified with an organic acid having 1 to 3 carbon atoms. Severography, n. P., Plant 7, Most Price 2,40 Kčs