SK284027B6 - Process for the preparation of N-[5-(diphenylphosphinoylmethyl)- 4-(4-fluorphenyl)-6-isopropylpyrimidin-2-yl]-N- methylmethansulfonamide - Google Patents

Abstract

N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorphenyl)-6- isopropylpyrimidin-2-yl]-N-methylmethansulfonamide of formula (I) is made by the reaction of [4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulphonylaminopyrimidin-5-yl]methanol with chlorodiphenylphosphine. The compound of formula (I) is intermediate in the synthesis of pharmaceutically active substance, particularly HMG-Co A reductase inhibitors.

Description

Technical field

The present invention relates to a process for the preparation of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide.

BACKGROUND OF THE INVENTION

N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide is an intermediate for the manufacture of pharmaceutical active substances, for example HMG-Co A reductase inhibitors (Bioorg. Med. Chem. Chem. 1997, 5, 437).

It is an object of the present invention to find improved availability of said intermediate.

The object could be solved in a novel way according to claim 1.

An important advantage of the synthesis according to the invention is its applicability in mass production.

SUMMARY OF THE INVENTION

According to the invention, the preparation of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of formula (I)

by reacting [4- (4-fluorophenyl) -6-isopropyl-2- (N -methyl-N-methylsulfonylaminopyrimidin-5-yl) methanol of formula (II)

with chlorodiphenylphosphine.

[4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino-pyrimidin-5-yl) methanol of formula (II) can be readily obtained by reduction of the corresponding ester with e.g. di-isobutylalium hydride (EP) -A- 0521471).

The reaction of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylaminopyrimidin-5-yl) methanol of formula (II) with chlorodiphenylphosphine can be carried out either directly or by prior deprotonation. with chlorodiphenylphosphine and subsequent treatment with a base.

According to the "deprotonation" variant, [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylaminopyrrolidin-5-yl) methanol of formula (II) is conveniently mixed with a deprotonating agent customary in the art. Preferably, sodium hydride is used, usually deprotonation is carried out at room temperature, followed by reaction with chlorodiphenylphosphine The reaction with chlorodiphenylphosphine is conveniently carried out at a temperature between 80 and 200 ° C.

Chlorodiphenylphosphine can directly serve as a solvent. However, it is possible to use, as far as possible, a high boiling inert solvent such as e.g. toluene or xylene or decalin, as well as the corresponding isomeric mixtures.

The reaction may be carried out in the presence of a catalyst. Suitable catalysts are iodine, an alkali metal iodide, such as e.g. sodium or potassium iodide, an alkyl halide such as e.g. methyl or ethyl iodide, or dihaloalkane such as e.g. dibromomethane. Preferably, an alkali metal iodide is used. The amount of catalyst is usually chosen in the range from 1 mol% to 20 mol%, based on the alcohol of formula (II) used.

The reaction according to the direct variant is conveniently carried out at a temperature of from -20 to 130 ° C, preferably at +20 to 120 ° C.

Chlorodiphenylphosphine can directly serve as a solvent in the "deprotonation" variant. However, it is possible to use, as far as possible, a high boiling inert solvent such as e.g. toluene or xylene or decalin, as well as the corresponding isomeric mixtures.

Following the reaction with chlorodiphenylphosphine, the reaction mixture is mixed with a base. Suitable bases are alkali metal hydroxides such as e.g. aqueous sodium or potassium hydroxide solution or alkali metal carbonates such as e.g. sodium or potassium carbonate.

Optionally, a conventional phase-transfer catalyst such as e.g. tetraalkylammonium. Good results can also be achieved by using crown ethers.

N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of formula (I) may be isolated in a manner known in the art, e.g. extraction with a suitable solvent from the reaction mixture as well as crystallization from the mixture.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

1.00 g (2.83 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 5 mL of cis % trans-decalin and mixed with 204 mg (4.68 mmol) of sodium hydride (55% dispersion in mineral oil). After 30 min. at room temperature was added with vigorous stirring over 6 min. 680 mg (2.93 mmol) of chlorodiphenylphosphine. 52.2 mg (0.35 mmol) of sodium iodide was added and heated at 184-186 ° C for 2 hours 15 minutes. After cooling to room temperature, 50 ml of a 38-40% sodium hydrogensulfite solution and 50 ml of ethyl acetate were mixed. The organic phase was separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. 1.74 g of crude product were obtained, which was purified by chromatography on silica gel (eluent: n-hexane / ethyl acetate 1: 2). 382.4 mg (25.1%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was obtained as a colorless solid. (Mp 184-185 ° C).

1 H NMR (DMSO-d ⁶ , 400 MHz): δ = 1.11 (d, J = 6.6 Hz, 6H; 3.28 (sept, J = 6.6 Hz, 1H); 3.40 ( s, 3H);

3.51 (s, 3H); 4.05 (d, J = 12.6Hz, 2H); 7.07 (t, J = 8.9Hz, 2H); 7.35 (m. 2H);

7.42 (m, 4H); 7.5-7.9 (m, 6H).

¹³ C NMR (DMSO-d ⁶ , 100 MHz): δ = 21.52 (q);

29.12 (td);

31.94 (d); 33.07 (q);

41.53 (q);

114.50 (sd); 115.03 (dd);

128.54 (dd); 130.21 (dd); 130.84 (dd); 131.64 (dd); 133.41 (sd);

134.51 (sd);

156.54 (sd); 162.10 (sd); 165.86 (sd); 176.49 (sd).

Example 2 N- [5- (Diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

282.8 mg (0.80 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 4.5 mL of xylene (isomeric mixture) and mixed with 55 mg (1.30 mmol) of sodium hydride (55% dispersion in mineral oil). After 35 min. at room temperature was added over 5 min with vigorous stirring. 185 mg (0.84 mmol) of chlorodiphenylphosphine in 1.5 ml of xylene and then 20 h. heated to 135 ° C. After cooling to room temperature, 15 ml of water were added and extracted with 10 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with 2 x 10 ml ethyl acetate. The combined organics were dried _(MgSO4) and concentrated in vacuo. 510 mg of crude product was obtained, which was purified by chromatography on silica gel (eluent: n-hexane / ethyl acetate 1: 2, then ethyl acetate). 230 mg (53.5%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was isolated as a colorless solid.

Example 3 N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

512 mg (1.45 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 8 mL of toluene and mixed with 96 mL mg (2.20 mmol) of sodium hydride (55% dispersion in mineral oil). After 1 hour at room temperature was added over 5 min with vigorous stirring. 333.5 mg (1.44 mmol) of chlorodiphenylphosphine in 2.5 ml of toluene. Sodium iodide (28.7 mg, 0.19 mmol) was admixed and heated to 108 ° C for 22 h. After 6 hours was mixed with an additional 28.7 mg (0.19 mmol) of sodium iodide. After cooling to room temperature, 30 ml of 38-40% sodium hydrogen sulphite solution were admixed and extracted with 50 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were vacuum vacuumed. 740 mg of a crude product was obtained, which was purified by chromatography on silica gel (eluent: ethyl acetate), and 212.7 mg (27.3%) of N- [5- (diphenylphosphinoyl-methyl) -4- (4-methyl-4-methoxyphenyl) was isolated. (fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide as a colorless solid.

Example 4 N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

502.6 mg (1.42 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 8 mL of xylene (isomeric) mixture) and mixed with

96.6 mg (2.21 mmol) of sodium hydride (55% dispersion in mineral oil). After 1 hour at room temperature was added over 5 min with vigorous stirring. 340.8 mg (1.47 mmol) of chlorodiphenylphosphine in 2.5 ml of xylene. Sodium iodide (34.6 mg, 0.23 mmol) was admixed and heated for 19 h. at 136 ° C. After 3 hours was mixed with another 25.1 mg of sodium iodide. After cooling to room temperature, 30 ml of dilute sodium hydrogen sulphite solution were added and extracted with 50 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were concentrated in vacuo. 906 mg of crude product was obtained, which was purified by chromatography on silica gel (eluent: ethyl acetate). 315.9 mg (41.3%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was isolated as a colorless solid.

Example 5 (direct reaction) N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

1.05 mg (2.95 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 7 g of toluene with cooling in an ice bath and stirred with 820 mg (3.69 mmol) of chlorodiphenylphosphine. Heat for 3 hours. to 108 ° C. After cooling to room temperature, 553 mg (4.43 mmol) of aqueous potassium hydroxide solution (45%) and 97.5 mg (0.29 mmol) of tetrabutylammonium bromide were admixed and stirred at 60 ° C for 1 hour. stirred vigorously. The heat source was removed and the still warm reaction mixture was mixed with 20 ml of water. The mixture was allowed to cool slowly to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water and toluene and dried under vacuum at 40 ° C. 1.04 g (64.1%) was isolated;

97.6%) N- [5- (diphenylphosphinoyl-methyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide as a colorless solid.

Example 6 (direct reaction) N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.03 mg (5.69 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 13 g of toluene and Cooling in an ice bath was mixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 2 g of toluene. It was heated at 111 ° C for 2.5 hours. After cooling to room temperature, 1.08 g (8.66 mmol) of 45% potassium hydroxide and 175 mg (0.574 mmol) of tetrabutylammonium bromide were admixed and stirred at 60 ° C for 2 hours. stirred vigorously. To the warm reaction mixture was added 30 mL of water. The mixture was stirred briefly at 60 ° C, allowed to slowly cool to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (10 mL) and cold toluene (10 mL) and dried under vacuum at 40 ° C. 2.66 g (84.1%; content: 96.6%) of N- [5- (diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N were isolated. methyl methanesulfonamide as a colorless solid.

Example 7 (direct reaction) N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.02 mg (5.69 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 13.1 g of toluene and with cooling in an ice bath was mixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in

1.9 g toluene. Heat for 3 hours. to 109 ° C. After cooling to room temperature, 590 mg (8.94 mmol) of solid potassium hydroxide and 159 mg (0.582 mmol) of 18-Crown-6 were admixed and stirred at 60 ° C for 3.5 hours. stirred vigorously. To the warm reaction mixture was added 30 mL of water. The mixture was stirred briefly at 60 ° C, allowed to slowly cool to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (10 mL) and cold toluene (10 mL) and dried under vacuum at 40 ° C. 1.82 g (59.5%) was isolated;

95.9%) N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide as a colorless solid.

Example 8 (direct reaction) N- [5- (Diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

2.02 mg (5.69 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 13.1 g of toluene and mixed with 1.71 g (7.69 mmol) of chlorodiphenylphosphine in ice bath

1.9 g toluene. It was heated at 111 ° C for 2.5 hours. After cooling to room temperature, 1.17 g (8.78 mmol) of 30% potassium hydroxide and 182 mg (0.597 mmol) of tetrabutylammonium chloride were added thereto at 60 ° C for 3.5 hours. stirred vigorously. To the warm reaction mixture was added 30 mL of water. The mixture was stirred briefly at 60 ° C, allowed to slowly cool to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (10 mL) and cold toluene (10 mL) and vacuum dried at 40 ° C. 2.18 g (71.3%; content: 97.3%) of N- [5- (diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was isolated as colorless solid (m.p. 184-185 ° C).

Example 9 (direct reaction) N- [5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

A suspension of 9.29 g (26.3 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] methanol in 26 g of toluene was cooled in It was mixed with 7.64 g (34.4 mmol) of chlorodiphenylphosphine in an ice bath. It was washed with a little toluene and heated at 111 ° C for 2 hours. After cooling to room temperature, 4.94 g of 45% potassium hydroxide and 873 mg (2.71 mmol) of tetrabutylammonium bromide were admixed and stirred at 60 ° C for 1 hour. stirred vigorously. To the warm reaction mixture was added 100 mL of water. The mixture was stirred briefly at 60 ° C, allowed to slowly cool to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (30 mL) and cold toluene and vacuum dried at 40 ° C. 11.74 g (78.4%; content: 94.4%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide were isolated. in the form of a colorless solid.

Example 10 (direct reaction without phase-transfer catalyst)

N- [5- (Difenylfosfinoylmetyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methyl-methanesulfonamide

2.03 g (5.69 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -pyrimidin-5-yl] methanol was added to 13 g of toluene and Cooling in an ice bath was mixed with 1.69 g (7.60 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. It was heated at 109 ° C for 2.5 hours. After cooling to room temperature, 1.09 g (8.74 mmol) of 45% potassium hydroxide was admixed and stirred at 60 ° C for 2 hours. 45 min. stirred vigorously. To the warm reaction mixture was added 30 mL of water. The mixture was stirred briefly at 60 ° C, allowed to slowly cool to 4 ° C and the precipitated solid was filtered off. The product was washed with cold water (10 mL) and cold toluene (10 mL) and vacuum dried at 40 ° C. 2.44 g (76.8%; content: 99.1%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was isolated as colorless solid.

Example 11 (direct reaction) N- [5- (Diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide

A solution of 60.08 g (0.170 mmol) of [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidin-5-yl] -methanol in ca. 485 ml of toluene was mixed at 60 ° C with 42.55 g (0.192 mol; 99.7% content) of chlorodiphenylphosphine. It was left for 2.5 hours. This solution was added to a 60 ° C mixture of 70.66 g of potassium hydroxide (20%) and 5.04 g (0.017 mol) of tetrabutylammonium chloride and washed with 13 ml of toluene. It was stirred for 2 hours. at 60 ° C and 215 ml of water and 108 ml of toluene were added. At about 80 ° C, the aqueous phase was separated and the organic phase was extracted twice more with 215 ml of hot water each time. It was then azeotropically dewatered on a dewatering device and left for 2 hours. cool to 0 ° C. The resulting crystals were filtered off and washed twice with 160 ml of toluene. After vacuum drying at 40 ° C, 81.94 g (89.7%) of N- [5- (diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide was obtained in the form of colorless solid [HPLC content: 100%].

Claims (10)

A process for the preparation of N- [5- (diphenylphosphmoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl] -N-methylmethanesulfonamide of formula (1), characterized in that it is reacted [4- (4) -fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino-pyrimidin-5-yl) -methanol of formula (II) with chlorodiphenylphosphine. A process according to claim 1, characterized in that [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylaminopyrimidin-5-yl) methanol of formula (II) is reacted ( II) directly with chlorodiphenylphosphine and then with a base. A process according to claim 1, characterized in that [4- (4-fluorophenyl) -O-isopropyl-2- (N-methyl-N-methylsulfonylaminopyrimidin-5-yl) methanol of formula (II) is first deprotonates. 4. The process according to claim 3, wherein the deprotonation is carried out with an alkali metal hydride or an alkalihexaalkyldisilazane. Process according to claim 3 or 4, characterized in that the reaction is carried out by means of a catalyst. The process according to claims 3 to 5, characterized in that iodine, an alkali metal iodide, an alkyl halide or a dihaloalkane are used as the catalyst. The process according to claims 3 to 6, wherein the reaction with chlorodiphenylphosphine is carried out at a temperature between 80 and 200 ° C. The process according to claim 2, wherein the direct reaction with chlorodiphenylphosphine is carried out at a temperature between -20 and 130 ° C. Process according to Claim 2 or 8, characterized in that an alkali metal hydroxide is used as the base. Process according to claim 2, 8 or 9, characterized in that the reaction is carried out by means of a phase-transfer catalyst.