Tertiary butyl-(e)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4r,6s)-2,2-dimethyl[1,3]dioxane-4-yl]acetate and method for its preparing, diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-ylmethyl]phosphine oxide, methods for preparing (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoic acid and its derivatives

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

 

This invention relates to new chemical method and, more specifically, to a new chemical process for the preparation of tert-butyl(E)-(6-{2-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl)acetate of the formula I:

(hereinafter called BEM), which is useful, for example, as a chemical intermediate in the production of pharmaceuticals useful for the treatment of, among others, hypercholesterolemia, hyperlipoproteinemias and atherosclerosis. The invention further includes a new original material used in the specified process and the use of the process in the production of inhibitors of HMG COA reductase.

In European patent application, publication isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S) - for 3,5-dihydroxide-6-ANOVA acid and its sodium salt and calcium salt (pictured below):No.(EPA) 0521471 describes (E)-7-[4-(4-forfinal)-6-

(hereinafter called the General title "Agent") as inhibitors of HMG COA reductase. The agent receives the restoration of methyl ester of 7-[4-(4-forfinal)-6-isopropyl-2-[N-methyl-N-methylsulphonyl)amino]pyrimidine-5-yl-(3R)-3-hydroxy-5-oxo-(E)-heptenophos acid with subsequent processing. However, the Agent can be obtained from the BEM using processing acids is th (for removal of the acetonide protective group), followed by treatment with a base (for cleavage of the ester group) and (as described in EPA 0521471) transformation of the initially formed salt into the free acid or calcium salt.

At present inventors opened helpful and possessing the advantages of the method of obtaining VEM.

According to the invention proposes a method of obtaining VEM (formula I), including the interaction of diphenyl[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-ylmethyl]-phosphine oxide of the formula III:

(hereinafter called the DPPO) with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate of formula II:

(hereinafter called BFA) in the presence of a strong base.

The process is carried out in a suitable solvent or mixture of solvents, such as ether or aromatic solvents or their mixtures. Particularly suitable solvents are, for example, tetrahydrofuran (THF), dimethoxyethane and toluene or mixtures thereof. One of them is particularly preferred THF and THF to toluene.

Suitable bases for use in the method include, for example, amide base, altimetry and metal hydrides. Specific examples of bases are bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide lithium utility and sodium hydride. Particularly preferred is, for example, bis(trimethylsilyl)amide, sodium (NaHMDS).

The reaction may be carried out at a temperature within the Ah, for example, from -20 to -90°such as -40 to -90°With, for example, from -40 to -80°C. a Comfortable temperature for the reaction is, for example, the temperature of the mixture of acetone and solid carbon dioxide (about -75°).

The process is mainly carried out with 1.0 to 1.2 equivalents of base (equivalent DPPO), for example, 1.05 to 1.2 equivalents and preferably of 1.05 to 1.12 equivalents. Although BFA may be present in large excess, it is more convenient to use from 1.0 to 1.35 equivalent (equivalent DPPO) and preferably of 1.05 to 1.3 equivalents, especially of 1.05-1.15 equivalents.

The method of the invention allows to obtain significantly improved yields and product quality in comparison with the method, when as a starting material instead of DPPO use appropriate dialkylphosphate (RHO(Alkyl)2).

Source material DPPO, representing another aspect of the present invention can be obtained, as described in the examples below, based on their Olkiluoto ether 2-amino-4-(4-forfinal)-6-isopropylpyrimidine-5-carboxylic acid, for example methyl ester, which can be obtained according to the method described in Japanese patent application No. 06-256318 or ethyl ester, which can be obtained as described in EPA 0521471. BFA can be obtained, as described in EPA 0319847 (example 6).

Another aspect of the present invention is the way I obtain the compounds of formula IV:

in which R1denotes hydrogen or a pharmaceutically acceptable cation, which includes:

(1) the interaction DPPO with a BFA in the presence of a strong base (described above) with the formation of BEM;

(2) cleavage dihydroxy-protective group (acetonide) (for example, using acid hydrolysis, such as with the use of HCl in THF or acetonitrile); and

(3) cleavage of tert-butilkoi ester groups in terms of the primary environment with the formation of the compounds of formula IV in which R1is a pharmaceutically acceptable cation (e.g., using a solution of a metal hydroxide in a polar solvent, for example, using aqueous sodium hydroxide in ethanol or acetonitrile with the formation of the sodium salt);

optionally followed by neutralization with the formation of the compounds of formula IV in which R1denotes hydrogen;

and/or with subsequent transformation into another compound of formula IV in which R1denotes a pharmaceutically acceptable cation (e.g., the transformation of the sodium salt of calcium salt processing water-soluble calcium salt such as calcium chloride) in aqueous conditions).

Suitable conditions for the stages (2), (3) and further optional stages are similar or the same as the conditions that resulted is installed in EPA 0521471 and/or EPA 0319847, included in the present invention as a reference material. To obtain the calcium salt of the compounds of formula IV, as illustrated on page 1, preferably in stage (2), (3) and transformation into calcium salt through metilenovuju salt mainly carried out as described in example 7, with named stages constitute another aspect of the invention.

Obviously, it is clear that in the above-described processes BFA can be replaced with a compound of General formula V:

in which R1and R2represent a protective group of an alcohol, such as described in EPA 0319847 and GB 2244705, which are included in this work as reference material, and R3denotes a protective group of carboxylic acid, such as C1-C8-alkyl (C1-C4-alkyl), with the formation of the compounds of formula VI:

The compound of formula VI can be converted to the Agent by removal of the protective groups of the alcohol or diol and transformation group COOP3in a group COOH or its pharmaceutically acceptable salt. These processes are the additional features of the present invention.

The invention is further illustrated by, but not limited to, the following examples.

Getting 1

Getting DPPO

Stir a mixture of methyl is about ester 4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-carboxylic acid (12.0 g) in toluene (55 ml) cooled to -10° With and within 2 hours add diisobutylaluminium (50 ml, 1.5 M solution in toluene), keeping the temperature below 0°C. After the addition the mixture is stirred for 30 min at 0°C. To the mixture is added methanol (0,64 ml) while maintaining the temperature at 0°C. the Mixture was then added over 2 h to a stirred mixture of concentrated hydrochloric acid (23,3 ml), water (40,5 ml) and acetonitrile (24 ml) at 40°maintaining the temperature of the mixture at 40°C. After the addition the mixture is stirred for 30 min at 40°and then blown off with nitrogen (to remove possibly present isobutane). Cool the mixture to 20°and leave to stand for 20 minutes the Organic phase is separated and washed with a mixture of concentrated hydrochloric acid (0.7 ml) and water (30 ml). To the organic phase, add acetonitrile (24 ml) and the mixture is washed with sodium bicarbonate solution (0,038 g) in water (120 ml).

The organic phase is heated to 40°and then from 40 to 80°using a nitrogen purge. The mixture is concentrated by distillation at atmospheric pressure, collecting 54 ml of distillate. To the concentrated solution was added acetonitrile (24 ml) and then with stirring trichromacy phosphorus (1.2 ml) while maintaining the temperature of the mixture at 20°C. After the addition the mixture is stirred for 30 min at 20°C. the Mixture is added dropwise within 30 min the water (36 ml), maintaining the temperature at 20°C. the Mixture is stirred for 5 min and the organic phase is separated. The organic phase is washed with sodium bicarbonate solution (0,027 g) in water (36 ml) and then water (36 ml). The organic phase is distilled under reduced pressure until, until it is collected 29 ml of distillate. The mixture is cooled to 60°and add ethyldiphenylphosphine (7,47 ml). The mixture is stirred for 3 hours at 60°C, then heated to boiling under reflux. Add toluene (40 ml) and the mixture cooled to 0°C for 2 hours. The product is collected by filtration, washed with cold toluene (10 ml) and dried in vacuum at 50°receiving DPPO (14,66 g);1H NMR (Dl3, 270 MHz): 7,42 [m, 10P(C6)2], 7,12 [m, 2H, Ar-H], 6,92 [m, 2H, Ar-H], 3,92 [d, 2H,P], 3,51, 3.46 in [2×s, 6N, NSO2], 3,43 [hept., 1H, WITH(CH3)2], 1,25 [d, 6N, SN(With)2].

Methyl ester of 4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-carboxylic acid was obtained as follows.

A mixture of methyl ester 2-amino-4-(4-forfinal)-6-isopropylpyrimidine-5-carboxylic acid (19,0 g), tert-pentoxide, sodium (22, 95mm g) and dimethoxyethane (190) - Rev. l), stirred for 30 min at 25° C. Stir the mixture cooled to -10°and added dropwise to methanesulfonanilide (8,4 ml), maintaining the temperature of the mixture at -5°C. After 20 min add dimethylsulfate (8.1 ml), and give the mixture heated to 25°C. the Mixture is stirred for 1 hour at 25°and add a solution of tert-pentoxide, sodium (1,91 g) dimethoxyethane (10 ml). The mixture is stirred for 1 hour at 25°C. Add a solution of sodium chloride (13.3 g) in water (133 ml)and the mixture stirred for 10 min at 25°C. the Mixture is left to stand for 15 min, and the lower aqueous phase is separated and discarded. To remaining mixture add water (38 ml) and stirred the mixture for 30 min at 25°C. the Mixture is then heated to complete dissolution. The mixture is slowly cooled to 25°C for 1 hour. The mixture is cooled to 0°C, stirred for 1 hour and suspended solid material collected by filtration. The solid is washed with cold (0° (C) a solution of a mixture (50/50) water/dimethoxyethane (20 ml). The solid is dried in vacuum at 60°receiving methyl ester 4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-carboxylic acid (19,35 g);1H NMR (270 MHz, Dl3): of 7.69 (m, 2H), 7,14 (m, 2H), 3,71, 3,60, 3,51 (3×, N), 3,20 (m, 1H), 1,32 (d, 6N).

Example 1

The mixture DPPO (19,17 g) and THF (227 ml) is heated in a short time up to 40°until on the, until it forms a clear solution, then the environment will make inert alternating vacuum and nitrogen (5 cycles). The mixture is immersed in acetone/CO2bath, cooling the contents to -75°C. To the reaction mixture for 10 min added from a dropping funnel with the smoothing pressure bis(trimethylsilyl)amide, sodium (or 37.4 ml of 1.0 M solution in THF), keeping the temperature below -74°and forming a red solution of the anion. In the mixture through an addition funnel miss tetrahydrofuran (10 ml) for rinsing and the mixture is stirred for 1 hour at -76°receiving a red suspension. To the suspension for 20 min portions add BFA (80 ml ~13,5% volume/volume solution in toluene) from a dropping funnel with the smoothing pressure, keeping the temperature below -73°C. Rinse the addition funnel over a mixture of toluene (20 ml) and stirred the mixture for another 15 minutes at -76°C. the Cooling bath is removed and give the slurry be heated for 1.5 hours to 10°C. Add one portion of glacial acetic acid (3,21 g) in water (15 g), raising the temperature to 18°and dissolving all solids, and the mixture is stirred for another 5 minutes

The mixture is concentrated by distillation at atmospheric pressure (110°in the shirt) to a temperature of 94°collecting all 274 ml of distillate. The concentrated mixture is cooled to 40°add water (40 is l), and the mixture is stirred for 5 min, and then leave to stand for 15 minutes Lower aqueous phase is discarded. Add sodium bicarbonate (2,99 g) in water (40 ml)and the mixture stirred for 5 min and then left to settle for 15 minutes Lower aqueous phase is discarded. Add water (30 ml), and stirred the mixture for 5 min and allow it to settle for 15 minutes Lower aqueous phase is removed.

The organic phase is transferred into a distillation apparatus with toluene (20 ml) and concentrated by distillation at atmospheric pressure (125-130°in the shirt) to a temperature of 116°collecting 85 ml of distillate. Create a vacuum (400-500 mbar) and bring more of 16.5 ml of distillate to a temperature of 111°C. Relieve the vacuum and leave the concentrated mixture was cooled to 80°C. Added with rapid stirring warm Meon (140 ml, 50° (C) and leave the mixture to self-cool to 20°C for 30 min, during which time the precipitate solid. The advanced suspension is cooled to 2°C for 30 min, then the solid is collected by filtration on a porous filter, applying suction to the absolutely dry state. The solid is washed with cold Meon (60 ml, 2°) and again sucked off to the absolutely dry state, and then transferred into a vacuum drying oven and dried overnight (50°C, 200 mbar), receiving VE is (14,01 g, 67,7%).1H NMR (Dl3, 270 MHz) 7,65 [m, 2H, Ar-H], 7,09 [m, 2H, Ar - H], 6,52 [DD, 1H, Ar-CH=C], vs. 5.47 (DD, 1H, Ah-=SN], 3,57, 3,50 [2×s, 6N, N, SO2], 3,38 [hept., 1H, Ah-IU2], 2,45, 2,30 [2×DD, 2H, CCO2-t-Bu], 1,55, 1,13 [dt, DD, 2H,acetonide], 1,50, 1,40 [2C, 6N, (WITH)2acetonide], a 1.45 [s, N, CO2(With)2], 1,27 [DD, 6N, Agsn(With)2].

Examples 2-6

Described in example 1 procedure is made using table 1 ratio of reactants and temperature. See also outputs the resulting BEM.

1,06
Table 1
Weight DPPOThe pace.(°)EQ. NaHMDSEQ. BFAOutput VEM
10,00 g-751,121,2069,2%
18,12 g-751,121,2069,6%
12,08 g-751,061,2672,8%
19,17 g-401,0556,7%
to 9.57 g-901,051,1072,0%
to 9.57 g-601,051,1070,1%

Example 7

A mixture of I (5.0 g) and acetonitrile (35 ml) is stirred in an inert atmosphere at 40°C. For 30 min to the resulting solution was added 0.02 M hydrochloric acid (9.5 ml), maintaining the temperature at 35-42°C. the Mixture is stirred for 3 hours at 40°and then cooled to 25°C. Add under stirring at 25°With 1.0 M sodium hydroxide solution (9.5 ml)and the mixture stirred at 25° another hour. Add sodium chloride (4.7 g)and the mixture cooled to -5°C for one hour. Add at -5°With a sufficient amount of 1 M hydrochloric acid (9.5 ml) and sodium chloride (2.4 g) to achieve a pH of 3.4 to 4.0, and the mixture is stirred at this temperature for 5 minutes, the Mixture is left to stand for 10 min at -5°C, resulting in formation of two layers. The bottom layer is separated and removed. To the remaining solution was added at -5°With acetonitrile (65 ml)and the mixture filtered through the filter material. Add at -5°With a 40%solution of methylamine in water (1.1 ml)and the mixture is heated to 30°C for 40 min and maintained at this temperature for 90 minutes the mixture is Then cooled to 0� With over 40 min and maintain at this temperature for 90 minutes the Formed solid is collected by filtration and washed with acetonitrile (2×12 ml). Solid, representing metilenovuju salt of the compounds of formula IV (R1=N

+
3
), dried in vacuum at 35° (a 3.87 g). To stir the mixture methylamino salt (6.0 g) in degassed water (30 ml) add 8%weight/weight of aqueous sodium hydroxide (5,44 ml) and the mixture is stirred for another hour. The mixture is filtered and concentrated under reduced pressure at 40°until then, until it is collected 24 ml of distillate. Add water (24 ml) and again concentrate the mixture under reduced pressure at 40°until then, until it is collected 24 ml of distillate. Add water (30 ml) and added dropwise at 20°With a solution of dihydrate of calcium chloride (1,03 g) in water (6 ml). The mixture is stirred for 45 min and the resulting solid is filtered off. The solid is washed with water (36 ml) and dried in vacuum at 40°receiving calcium salt of (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S) - for 3,5-dihydroxide-6-ene acid.

1. The way to obtain tert-butyl-(6-{2-[4-(4-shall terphenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate, comprising the reaction of diphenyl[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)-amino]pyrimidine-5-ylmethyl]phosphine oxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base, the process is carried out in ether or aromatic solvents or their mixtures at a temperature ranging from -20 to -900C.

2. The method according to claim 1, in which the strong base is bis(trimethylsilyl)amide and sodium.

3. The method according to claim 1 or 2, in which the reaction is carried out in a solvent selected from tetrahydrofuran, dimethoxyethane and toluene and mixtures thereof.

4. The method according to any one of claims 1 to 3, in which the equivalent of the phosphine oxide used is 1.0-1.2 equivalents of the base.

5. The method according to any one of claims 1 to 4, in which the equivalent of the phosphine oxide used is 1.0-1.35 equivalent tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate.

6. Diphenyl[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide.

7. Tert-butyl-(6-{2-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate.

8. The method of obtaining the compounds of formula IV

in which R1denotes hydrogen or a pharmaceutically acceptable cation, which includes:

(1) is eakly diphenyl [4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base, when this process is carried out in ether or aromatic solvents or their mixtures at a temperature ranging from -20 to -900With obtaining tert-butyl-(6-{2-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate of formula I;

(2) the removal from the product of stage (1) dihydrexidine groups by acid hydrolysis;

(3) the removal from the product of stage (2) tert-butilkoi ester groups in terms of the primary environment with the formation of the compounds of formula IV in which R1is a pharmaceutically acceptable cation; with the further optional neutralization with the formation of the compounds of formula IV in which R1denotes hydrogen;

and/or subsequent optional conversion of the compounds of formula IV in another of its salt, when R1denotes a pharmaceutically acceptable cation.

9. The method of obtaining the compounds of formula VI

comprising the reaction of diphenyl[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with the compound of the formula V

in the presence of a strong base, where R1and R2each independently represents a group of the Sabbath.

,

where R3represents a (1-8C)alkyl.



 

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< / BR>
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< / BR>
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< / BR>
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