NO324982B1 - Process for Preparation of N- (5- (Diphenylphosphinoylmethyl) -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl) -N-methylmethanesulfonamide - Google Patents

Abstract

N-(5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (I) is prepared by reaction of (4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin- 2-yl)methanol (II) with chlorodiphenylphosphine (III). Preparation of N-(5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide of formula (I) comprises the reaction of (4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin- 2-yl)methanol of formula (II) with (III). Ph = phenyl; and Ph' = 4-fluorophenyl.

Description

Description

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

The N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethane-sulfonamide (I) which can be produced according to the invention is an intermediate for the production of pharmaceutical active substances, for example from HMG-Co A reductase inhibitors ( Bioorg. Med. Chem. 1997, 5, 437 ).

The task for the invention consisted in finding an improved access to the above-mentioned intermediate product.

The task could be solved with the new method according to patent claim 1.

According to the invention, the preparation of the N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide with the formula (I) takes place by reacting [4-(4-fluorophenyl) -6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl) methanol of the formula (II)

with chlorodiphenylphosphine.

A significant advantage of the synthesis according to the invention is its applicability on a large scale.

[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl]

the methanol with the formula (II) is available in a simple way by reduction of the corresponding ester with e.g. diisobutylaluminum hydride (EP-A 0521471).

The reaction of the [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino-pyrimidin-5-yl]methanol of the formula (II) with chlorodiphenylphosphine can either take place directly or through a prior deprotonation.

Direct reaction with chlorodiphenylphosphine and subsequent treatment with a base is preferred.

According to the "deprotonation" variant, the [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl]methanol of the formula (II) is appropriately mixed with a deprotonation agent common in the art , advantageously with an alkali hydride or an alkali hexaalkyldisilazane.

Sodium hydride is preferably used. Usually the deprotonation is carried out at room temperature.

The reaction with chlorodiphenylphosphine then takes place.

The reaction with chlorodiphenylphosphine is suitably carried out at a temperature between 80°C and 200°C.

The chlorodiphenylphosphine can act directly as a solvent. However, it is also possible to use the highest possible boiling inert solvent, such as e.g. toluene or xylene or decalin, as well as the individual isomer mixtures.

The conversion can take place in the presence of a catalyst.

Iodine, an alkali iodide, such as, for example, is suitable as a catalyst. sodium or potassium iodide, an alkyl halide, such as methyl or ethyl iodide, or a dihaloalkane such as e.g. dibromoethane. Preferably, an alkali iodide is used.

The amount of catalyst is usually chosen in the range from 1 mol% to 20 mol% in relation to the alcohol of formula II used.

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

Corresponding to the "deprotonation" variant, the chlorodiphenylphosphine can function directly as a solvent. However, it is also possible to use the highest possible boiling inert solvent, such as e.g. toluene or xylene or decalin, as well as the individual isomer mixtures.

In connection with the reaction with chlorodiphenylphosphine, the reaction mixture is mixed with a base.

Suitable bases are the alkali hydroxides, such as an aqueous solution of sodium or potassium hydroxide or of alkali carbonates, such as sodium or potassium carbonate.

Optionally, a normal phase transfer catalyst can be used to accelerate the reaction with the base, such as e.g. a tetraalkylammonium halide. Good results can also be achieved with the use of crown ethers.

The N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethane-sulfonamide of the formula I can be isolated after completion of the reaction in a professional manner, e.g. by extraction with a suitable solvent from the reaction mixture and by crystallization from the mixture.

Examples

Example 1

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

1.00 g (2.83 mmol) [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-pyrimidin-5-yl] methanol was placed in 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, 680 mg (2.93 mmol) of chlorodiphenylphosphine were added with vigorous stirring for 6 min. It was mixed with 52.2 mg (0.35 mmol) of sodium iodide and heated for 2 hours and 15 minutes to 184-186 °C. After cooling to room temperature, it was mixed with 50 ml of 38-40% sodium hydrogen sulphite solution and 50 ml of acetic acid ethyl ester. The organic phase was separated and the aqueous phase extracted with 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. 1.74 g of crude product was obtained, which was purified by chromatography over 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 were obtained in the form of a colorless solid. (Melting point 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 = 12.6 Hz, 2H);

7.07 (t, J = 8.9 Hz, 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-(diphenylphosphinoylmethyl)-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-methylsulfonyl-amino)pyrimidin-5-yl] methanol was placed in 4.5 ml xylene (isomer mixture) and mixed with 55 mg (1.30 mmol) sodium hydride (55% dispersion in mineral oil). After 35 minutes, 185 mg (0.84 mmol) of chlorodiphenylphosphine in 1.5 ml of xylene were added at room temperature under vigorous stirring for 5 minutes and then heated for 20 hours at 135 °C. After cooling to room temperature, it was mixed with 15 ml of water and extracted with 10 ml of ethyl acetate. The organic phase was separated and the aqueous phase extracted with 2 x 10 ml ethyl acetate. Afterwards, the combined organic phases were dried (MgSO 4 ) and evaporated in vacuo. 510 mg of crude product was obtained, which was purified by chromatography over silica gel (eluent: n-hexane/ethyl acetate 1 : 2, then ethyl acetate), and isolated 230 mg (53.5%) of N-[5-(diphenylphosphinoylmethyl)-4- (4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 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-methylsulfonyl-amino)pyrimidin-5-yl] methanol was placed in 8 ml of toluene and mixed with 96 mg (2.20 mmol) sodium hydride (55% dispersion in mineral oil). After 1 hour, 333.5 mg (1.44 mmol) of chlorodiphenylphosphine in 2.5 ml of toluene were added at room temperature under vigorous stirring for 5 minutes. It was mixed with 28.7 mg (0.19 mmol) of sodium iodide and heated for 22 hours at 108 °C. After 6 hours, it was further mixed with 28.7 mg (0.19 mmol) of sodium iodide. After cooling to room temperature, it was mixed with 30 ml of 38-40% sodium hydrogen sulphite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated and the aqueous phase extracted with 50 ml of ethyl acetate. The combined organic phases were then evaporated in vacuo. 740 mg of crude product was obtained, which was purified by chromatography over silica gel (eluent: ethyl acetate), and 212.7 mg (27.3%) of N-[5-(diphenylphosphinoyl-methyl)-4-(4-fluorophenyl)- 6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide in the form of 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-methylsulfonyl-amino)pyrimidin-5-yl] methanol was placed in 8 ml of xylene ( isomer mixture) and mixed with 96.6 mg (2.21 mmol) sodium hydride (55% dispersion in mineral oil). After 1 hour, 340.8 mg (1.47 mmol) of chlorodiphenylphosphine in 2.5 ml of xylene were added at room temperature under vigorous stirring for 5 minutes. It was mixed with 34.6 mg (0.23 mmol) of sodium iodide and heated for 19 hours at 136 °C. After 3 hours, it was further mixed with 25.1 mg of sodium iodide. After cooling to room temperature, it was mixed with 30 ml of dilute sodium hydrogen sulphite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated and the aqueous phase extracted with 50 ml of ethyl acetate. The combined organic phases were then evaporated in vacuo. 906 mg of crude product was obtained, which was purified by chromatography over silica gel (eluent: ethyl acetate), and 315.9 mg (41.3%) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide as a colorless solid.

Example 5 (direct turnover)

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

1.05 g (2.95 mmol) [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-pyrimidin-5-yl] methanol was placed in 7 g of toluene under ice bath cooling and mixed with stirring with 820 mg (3.69 mmol) of chlorodiphenylphosphine. It was heated for 3 hours at 108 °C. After cooling to room temperature, it was mixed with 553 mg (4.43 mmol) aqueous potassium hydroxide (45%) and 97.5 mg (0.29 mmol) tetrabutylammonium bromide and stirred vigorously at 60 °C for 1 h. The heat source was removed and the still warm reaction mixture mixed with 20 ml of water. It 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 in vacuum at 40 °C. 1.04 g (64.1%; Content: 97.6%) of N-[(5-diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.

Example 6 (direct turnover)

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

2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] methanol was placed in 13 g of toluene and under ice bath cooling mixed with 1.67 g (7.51 mmol) chlorodiphenylphosphine in 2 g toluene. It was heated for 2.5 hours at 111 °C. After cooling to room temperature, it was mixed with 1.08 g (8.66 mmol) of a 45% potassium hydroxide solution and 175 mg (0.574 mmol) tetrabutylammonium chloride and stirred vigorously at 60 °C for 2 h. To the hot reaction mixture was added 30 ml of water added. The mixture was briefly stirred at 60 °C, cooled slowly 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 in vacuo at 40 °C. 2.66 g (84.1%; Content: 96.6%) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide were isolated in the form of a colorless solid.

Example 7 (direct turnover)

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

2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-pyrimidin-5-yl] methanol was placed in 13.1 g of toluene and mixed under ice bath cooling with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. It was heated for 3 hours at 109 °C. After cooling to room temperature, it was mixed with 590 mg (8.94 mmol) of solid potassium hydroxide and 159 mg (0.582 mmol) of 18-Crown-6 and stirred vigorously at 60 °C for 3.5 h. To the hot reaction mixture was added 30 ml of water added. The mixture was briefly stirred at 60 °C, cooled slowly 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 in vacuo at 40 °C. 1.82 g (59.5%; Content: 95.9%) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.

Example 8 (direct turnover)

N-[5-(Diphenylphosphinylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine-2-yl]-N-methylmethanesulfonamide

2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-pyrimidin-5-yl] methanol was placed in 13.1 g of toluene and mixed under ice bath cooling with 1.71 g (7.69 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. It was heated for 2.5 hours at 111 °C. After cooling to room temperature, it was mixed with 1.17 g (8.78 mmol) of 30% caustic soda and 182 mg (0.597 mmol) of tetrabutylammonium chloride and stirred vigorously at 60 °C for 3.5 h. To the hot reaction mixture was added 30 ml of water added. It was stirred briefly at 60 °C, cooled slowly 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 in vacuo at 40 °C. 2.18 g (71.3%; Content: 97.3%) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide were isolated in the form of a colorless solid (melting point 184-185 °C).

Example 9 (direct turnover)

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

A suspension of 9.29 g (26.3 mmol) of [4-(4-fluophrenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl] methanol in 26 g of toluene was mixed under ice bath cooling with 7.64 g (34.4 mmol) of chlorodiphenylphosphine. It was flushed with a little toluene and heated for 2 hours at 111 °C. After cooling to room temperature, it was mixed with 4.94 g of a 45% potassium hydroxide solution and 873 mg (2.71 mmol) of tetrabutylammonium bromide and stirred vigorously at 60 °C for 1 h. 100 ml of water was added to the hot reaction mixture. It was briefly stirred at 60 °C, allowed to cool slowly to 4 °C and the precipitated solid was filtered off. The product was washed with cold water (30 ml) and cold toluene (30 ml) and dried in vacuo at 40 °C. 11.74 g (78.4%; Content 94.4%)) N-[5-(diphenyl-phosphinoylmethyl)-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-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide

2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)-pyrimidin-5-yl] methanol was placed in 13 g of toluene and mixed under ice bath cooling with 1.69 g (7.60 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. It was heated for 2.5 hours at 109 °C. After cooling to room temperature, it was mixed with 1.09 g (8.74 mmol) of a 45% potash and stirred vigorously at 60 °C for 2 hours 45 minutes. To the hot reaction mixture was added 30 ml of water. It was briefly stirred at 60 °C, slowly cooled 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 in vacuo at 40°C. 2.44 g (76.8%; Content: 99.1%) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide were isolated in the form of a colorless solid.

Example 11 (direct turnover)

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

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

Claims (10)

1. Process for the preparation of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide of the formula characterized in that the [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl]methanol with the formula is reacted with chlorodiphenylphosphine. 2. Method according to patent claim 1, characterized in that the [4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl]methanol of the formula II is reacted directly with chlorodiphenylphosphine and afterwards with a base. 3. Method according to patent claim "1. characterized in that the [4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-aminopyrimidin-5-yl]methanol with the formula II is first deprotonated . 4. Method according to patent claim 3, characterized in that the deprotonation is carried out with an alkali hydride or an alkali hexaalkyldisilazane. 5. Method according to patent claim 3 or 4, characterized in that the reaction is carried out with the aid of a catalyst. 6. Method according to one of claims 3 to 5, characterized in that iodine, an alkali iodide, an alkyl halide or a dihaloalkane is used as catalyst. 7. Method according to one of claims 3 to 6, characterized in that the reaction with chlorodiphenylphosphine takes place at a temperature between 80 °C and 200 °C. 8. Method according to patent claim 2, characterized in that the direct reaction with chlorodiphenylphosphine takes place at a temperature between -20°C and 130°C. 9. Method according to patent claim 2 or 8, characterized in that an alkali hydroxide is used as a base. 10. Method according to patent claim 2, 8 or 9, characterized in that the reaction takes place with the help of a phase transfer catalyst.