SK287854B6 - Method for preparation of 4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonyl-amino)-5-pyrimidincarbaldehyde and its use - Google Patents

Abstract

A process for preparation of 4-(4-fluorophenyl)-6-isopropyl- 2-(N-methyl-N-methylsulfonyl-amino)-5-pyrimidinecarbaldehyde of the general formula (I), wherein the preparation process is characterized by oxidizing [4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)-5-pyrimidin-5-yl]methanol of the general formula (III) in the presence of a catalytic amount of a reagent containing nitroxyl radical, preferably 2,2,6,6-tetramethylpiperidine-1-oxyl or 4-acetamido-2,2,6,6- tetramethylpiperidine-1-oxyl.

Description

Technical field

The invention relates to an improved process for preparing 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl- N -methylsulfonylamino) -5-pyrimidinecarbaldehyde of formula (I).

This substance is a key intermediate for the synthesis of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3A, 55) -3 hemi-calcium salt, 5-dihydroxy-6-heptenoic acid known under the non-proprietary name rosuvastatin of formula (II). This substance is a significant hypolipidemic of the statin family.

OH

C a

2>

(H) / ²

BACKGROUND OF THE INVENTION

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde can be prepared from commercially available [4- (4-fluorophenyl) -6-isopropyl-2 - (N-methyl-N-methylsulfonylamino) -5-pyrimidin-5-yl] methanol of formula (III). which is oxidized according to Shionogi's patent (EP 0 521 471) with a catalytic amount of tetrapropylammonium perutenate with 4-methylmorpholine Woxide as a cooxidant in the presence of activated molecular sieves (Scheme 1).

Scheme 1

(D) (d)

The oxidation yield according to the patent is 71%. A considerable disadvantage of the above process is the use of an expensive catalyst which is practically impossible to recycle and the use of column chromatography to isolate the product. Such a process is then inefficient from an industrial point of view.

Another procedure was used by Ranbaxy (WO 03/097614), which used oxidized activated manganese dioxide in an 80% yield. The process is apparently cheaper than the Shionogi solution, but a considerable disadvantage is the manganese oxide waste, since 6 g of activated manganese dioxide need to be used per 1 g of starting material. Such a process is difficult to apply from an ecological point of view and the disposal of the resulting manganese-containing waste is very expensive. From a process point of view, the filtration of manganese oxides after the reaction must not be lengthy when working on an industrial scale.

As a result, it is necessary to look for technologies that will bring about a more efficient approach, also with regard to environmental aspects.

SUMMARY OF THE INVENTION

The present invention is an improved process for the preparation of 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-A ^/ -metylsulfonylamino) -5-pyrimidinecarbaldehyde I. The process comprises the surprising discovery that the oxidation takes place more easily in the presence of a catalytic amount of a nitroxyl radical-containing reagent. A suitable example of such an agent is 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or derivatives thereof. In carrying out the oxidation according to the invention, any substances capable of converting the nitroxyl radical to the corresponding oxoammonium salt can be used as oxidizing agents. The reaction may be carried out in a variety of solvents, for example dichloromethane or acetonitrile are preferred.

Particularly suitable oxidizing agents are alkali metal hypochlorites or calcium hypochlorite, sodium hypochlorite being particularly suitable. A preferred oxidant is sodium hypochlorite, which is a very cheap, industrially produced oxidant. Similarly, appropriate bromates can be used, for example sodium bromate, which can be used directly or can be generated in situ by reacting suitable oxidizing agents with suitable bromides. Alkali metal hypochlorite or calcium hypochlorite, preferably sodium hypochlorite, but also hydrogen peroxide in combination with transition metal catalysts, can be used as the oxidants used for the formation of bromates. As the bromide ion source, inorganic metal bromides can be used, preferably sodium or potassium bromide.

Due to the low cost of the catalysts and oxidants used, the process is more efficient than the previously described processes. From the ecological point of view, a small amount of waste is produced which is much more acceptable than in the previously described processes. In the case of using the most preferred combination, i. j. 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), sodium hypochlorite and potassium bromide are sodium chloride and minute amounts of potassium bromide and catalyst. Such technology is then easier to use on an industrial scale. Further improvement can be achieved using polymer-supported 2,2,6,6-tetramethylpiperidine-1-oxyl, for example, macroporous polystyrene-2,2,6,6-tetramethylpiperidine-1-oxoammonium-p-toluene sulfonate (MP) (TsOTEMPO) or polyamine-bound 2,2,6,6-tetramethylpiperidine-1-oxyl (PIPO). Work with such catalysts is possible in both homogeneous and heterogeneous phases, depending on the nature of the solvent. In a heterogeneous system, the catalyst can then be recycled after filtration. Another case is the immobilization of 2,2,6,6-tetramethylpiperidine-1-oxyl on silica gel when the catalyst thus prepared can be operated in a heterogeneous phase.

DETAILED DESCRIPTION OF THE INVENTION:

Oxidation of [4- (4-fluorophenyl) -6-isopropyl-2- (N -methyl-N-methylsulfonylamino) -5-pyrimidin-5-yl] methanol (III) is preferably carried out in inert solvents, preferably dichloromethane, or acetonitrile, catalysed by 2,2,6,6-tetramethylpiperidine-1-oxyl or one of its derivatives, for example 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl, in an amount of 0.5 to 5 mole% to the starting material. This is a significant difference compared to tetrapropylammonium perutenate, which has to be used in an amount of 10 mole% based on the starting material. Either a commercial sodium hypochlorite may be used or a freshly prepared solution of sodium hypochlorite, potassium (Organic Synthesis, Coli. Vol. 2, p. 428), or sodium hypobromite (Organic Synthesis, Coli. Vol. 6, p. 803). It is also possible to use a mixture of said alkali hypochlorites with alkali bromides. These oxidizing agents can be used in concentrations of 0.3 M to 2 M, usually it is necessary to adjust the pH so that the pH of the mixture is between 8.6 to 9.7, preferably 9.5. This pH adjustment can be carried out in principle by any base, the use of sodium bicarbonate has proven to be best. Due to the slight instability of the oxidizing agents mentioned, it is usually necessary to check the end of the reaction by TLC or HPLC. 2,2,6,6-Tetramethylpiperidine-1-oxyl can be used as a pure substance or bound on polymeric supports or on silica gel. After completion of the reaction, the reaction mixture is shaken with water, optionally dilute hydrochloric acid and saturated sodium thiosulfate solution, and after drying the organic phase, the solvent is evaporated to give a white crystalline solid. The substance may then be recrystallized from a suitable solvent or solvent mixture.

The use of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as an oxidant of commercial sodium hypochlorite together with a catalytic amount of potassium bromide has proven to be a preferred embodiment of the reaction, most preferably it is used in an amount of 5 to 20 mol% relative to to the starting material. Most preferably, the reaction is carried out at temperatures in the range of 10-15 ° C and dichloromethane is used as the solvent.

The compound of formula (I) produced by the above process is further used to produce rosuvastatin of formula (II). Any or a known or well-developed process can be used to produce the final product II.

An example of a suitable process for processing an intermediate produced according to the invention into the final product is the process according to EP 0 521 471 outlined in Scheme 2.

Scheme 2

F.

I ' i CHO, F -Are you-- | 1 i. í í  Are you- - / ^ \ O 0 Those f '► ABOUT T about L // ..11 .. X. COOMe N <- N Ph ₃ P; _:> . --SOjCHs 1 J !. A ...... ^COOMe · IV 715i, \ '- i ^(E> / N V - <V N N SO ₂ CH ₃ ·· '(R) IN

(E) \ ... Y —N

SO ₂ CH ₃ —Si - oo

.. X, .COOMe IE ´ IL lllrío

DMB

NaBH ₄ / - 78 “c 85%

N \

OH OH 11 ('sj' - 'TŔT-' vi

COOMe

N 'SO ₂ CH ₃

F / I.

/ c xi, »fiU - I I

CaCI, N .. L '..

• NN '\ SO ₂ CH ₃

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives to the preparation of 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidinecarbaldehyde (I) according to the invention, are merely illustrative of the invention and scope of the invention. they do not restrict in any way.

Example 1

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde I [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl- N-methylsulfonylamino) -5-pyrimidin-5-yl] methanol (III) (0.5 g) was dissolved in dichloromethane (20 mL), and 2,2,6,6-tetramethylpiperidine-1-oxyl ( 2 mg) and a solution of potassium bromide (20 mg) in water (1 mL). Sodium hypochlorite solution (ca. 1 M) at pH 9.2 and 5-10 ° C was then added to the reaction mixture over one hour until the starting material disappeared, which was controlled by TLC. The reaction mixture was then washed with water (5 mL) and 8% sodium thiosulfate in water (5 mL). After drying the organic phase and evaporating the solvent, the product was obtained as a white crystalline solid (0.45 g, 91%). H NMR (250 MHz, CDC1 ₃₎ <r: l, 33 (d, 611, J = 6.4); 3.55 (s, 3H); 3.64 (s, 3H); 4.02 (m, 1H); 7.23 (m, 2 H); 7.63 (m, 2 H); 9.98 (s, 1H).

MS for C ₁₆ H ₁₈ FN ₃ O ₃ S [M] ⁺ calcd 351.1; found 351.8.

Example 2

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde I [4- (4-Fluorophenyl) -6-isopropyl-2 - (- methyl-) N-methylsulfonylamino) -5-pyrimidin-5-yl] methanol III (0.5 g) was dissolved in dichloromethane (20 mL), and 2,2,6,6-tetramethylpiperidine-1-oxyl (1 mg) was added to the solution. ) and a solution of potassium bromide (20 mg) in water (1 mL). Freshly prepared potassium hypochlorite solution (Organic Synthesis, Coll. Vol. 2, p. 428) (ca. 1 M) was then added to the reaction mixture at 5-10 ° C for one hour until the starting material disappeared, which was controlled by TLC. . The pH of the solution was kept between 9.2 and 9.4 during the addition. The reaction mixture was then washed with 2.5% HCl (5 mL) containing 20 mg potassium iodide, water (5 mL), 8% sodium thiosulfate solution in water (5 mL) and again with water (4 x 5 mL). After drying the organic phase and evaporating the solvent, the product was obtained as a white crystalline solid (0.40 g, 80%).

Example 3

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde I [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl- N-methylsulfonylamino) -5-pyrimidin-5-yl] methanol III (0.5 g) was dissolved in dichloromethane (20 mL), and 2,2,6,6-tetramethylpiperidine-1-oxyl (1 mg) was added to the solution. ) and a solution of potassium bromide (20 mg) in water (1 mL). Sodium hypochlorite solution (ca. 1 M) was added to the reaction mixture over 1 hour at pH 9.47 and 5-10 ° C until disappearance of the starting material, which was controlled by TLC. The reaction mixture was then washed with 2.5% HCl (5 mL) containing 20 mg of potassium iodide, water (5 mL), 8% sodium thiosulfate solution in water (5 mL) and again with water (4x5 mL). After drying the organic phase and evaporating the solvent, the product was obtained as a white crystalline solid (0.43 g, 86%).

Example 4

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde I

Following the procedure of Example 3 using 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl, 89% of the product was obtained.

Example 5

4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) -5-pyrimidine-carbaldehyde 1- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl) -A-methylsulfonylamino) -5-pyrimidin-5-yl] methanol III (0.5 g) was dissolved in dichloromethane (20 mL) and 2,2,6,6-tetramethylpiperidine-1-oxyl bound to the solution was added to the solution. polymer (30 mg, Aldrich cat no. 56-609-8) and a solution of potassium bromide (20 mg) in water (1 mL). Sodium hypochlorite solution (ca. 1 M) was then added to the reaction mixture over 1 hour at pH 9.47 and 5-10 ° C until disappearance of the starting material, which was controlled by TLC. The reaction mixture was then filtered, washed with water (5 mL) and 10% sodium thiosulfate in water (5 mL). After drying the organic phase and evaporating the solvent, the product was obtained as a white crystalline solid (0.45 g, 91%).

Claims (15)

PATENT CLAIMS 1. Preparation of 4- (4-fluorophenyl) -6-isopropyl] -2- (N-methyl-W _{J-methylsulfonylamino)} -5-pyrimidinecarbaldehyde of formula (I) characterized in that the [4- (4-fluorophenyl) 6-Isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -5-pyrimidin-5-yl] methanol of formula (III) is oxidized in the presence of a catalytic amount of a nitroxyl radical reagent of 2.2 , 6,6-tetramethylpiperidine-1-oxyl or 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl. Process according to claim 1, characterized in that 2,2,6,6-tetramethylpiperidine-1-oxyl or 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl is used in an amount of 0 5 to 5 mol% based on the amount of starting material. The method of claim 1 or 2, wherein the nitroxyl radical-containing reagent is bound to a polymeric carrier. The process according to claims 1 to 3, characterized in that the nitroxyl radical-containing reagent is bound to the silica gel surface. Process according to any one of the preceding claims, characterized in that the reaction is carried out at a temperature of -20 ° C to 30 ° C. Process according to any one of the preceding claims, characterized in that the reaction is carried out at a pH of 8.6 to 9.6. Process according to any one of the preceding claims, characterized in that the reaction is carried out in dichloromethane. Process according to any one of claims 1 to 6, characterized in that the reaction is carried out in acetonitrile. Process according to any one of the preceding claims, characterized in that a substance capable of converting the nitroxyl radical to the corresponding oxoammonium salt is used as the oxidizing agent. The method of claim 9, wherein the oxidizing agent is used in an amount of 1 equivalent to 1.2 equivalents based on the amount of starting material. Process according to claims 9 and 10, characterized in that sodium hypochlorite is used as the oxidizing agent. Process according to claims 9 and 10, characterized in that potassium hypochlorite is used as the oxidizing agent. The process according to claims 9 and 10, characterized in that sodium hypochlorite with the addition of potassium bromide is used as the oxidizing agent. The process according to claim 13, characterized in that the potassium bromide is used in an amount of 5-20 molar% with respect to the starting material. Process according to Claim 9, characterized in that potassium bromate is used as the oxidizing agent.