SI22166A - New synthesis of rosuvastatin - Google Patents

Abstract

A new synthesis of substituted heterocyclic compounds in which at least one substituent is attached by the Wittig's reaction which a respective phosphonium trifluoroacetate is entering into.

Description

NEW ROSUVASTATIN SYNTHESIS

FIELD OF THE INVENTION

The invention belongs to the field of pharmaceuticals, to the knowledge of pharmaceutical systems, that is to say preparations, preparations, pharmaceutical formulations, more specifically to the field of organic synthesis, and more specifically to the field of statin synthesis.

BACKGROUND OF THE INVENTION

Statins such as simvastatin, pravastatin, lovastatin, atorvastatin, rosuvastatin and fluvastatin are prepared by fermentation or chemical synthesis or a combination of both. Presumably, the pharmaceutical efficacy of statins is related to their structure, wherein the heptanoic or heptenoic acid (or its salt or lactone form) is bound to a nucleus which may be heterocyclic, e.g. substituted pyrimidine. The synthetic approach may be the binding of this side chain to the nucleus, where it is important that the reaction can be well controlled, and because of the complexity of the starting compounds, that the yields are sufficiently large

DESCRIPTION OF THE INVENTION

A general aspect of the invention is a statin synthesis process, characterized in that it involves the reaction of a Vittig reagent formed from a starting compound (in the reaction of a phosphonium salt with a base) of the formula Het ^ P ⁺ R ₃ Αρη wherein R is the same or different and R is a selected alternative C1 - C10 of alkyl, aryl and alkyl aryl, and A represents the anion of strong organic acids, and Het forms the skeleton of a statin, preferably selected from

Preferably, the invention relates to the synthesis of rosuvastine, which involves the reaction of a suitable starting compound with a heterocyclic dish wherein A is a trifluoroacetate anion with a compound of the formula:

OHC '

-TBDMS \ z-COOMe

Also contemplated by the invention are novel compounds of the formula: F

P ⁺ R ₃ Αρη wherein each R is independently selected from C 1 -C 10 alkyl, aryl and alkyl aryl, and A 'is selected from anions of organic sulfonic acids and anions of halogenated aliphatic or aromatic acids.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the synthesis of a statin, preferably rosuvastatin, wherein the aldehyde-containing side chain is attached to phosphonium salts of anions of strong organic acids, preferably organic sulfonic acids and halogenated aliphatic and aromatic acids, preferably phosphonium mesylate, fluoroacetate trifluoroacetate. Strong organic acids preferably have a pKa below 4, more preferably below about 1.

Preferably, the phosphonium salts are selected from (optionally substituted) C1-C10 alkyl, aryl and alkyl aryl phosphonium salts, especially preferably butyl, ethyl, propyl, methyl, or phenyl.

The invention thus relates in particular to the Wittig reaction of coupling a reagent containing an aldehyde group, preferably an alkyl or alkyl aryl ester of 3-tert-butyldimethylsilyl-oxy-4-oxo-butanoic acid, especially preferably a C1-C6 alkyl ester, most preferably preferably methyl ester to triphenylphosphonium or tributylphosphonium optionally substituted acetate, preferably substituted pyrimidinium tributylphosphonium trifluoroacetate, and the resulting intermediate is further converted into a statin tert-butyl ester and further / or statin or. a salt thereof, preferably in rosuvastatin or a calcium salt thereof.

The invention is illustrated by the following schemes in which Pmd is 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-ylmethyl, Si t-butyldimethylsilyl, malate is malic acid methyl ester and TBR t -butyl ester of rosuvastatin:

Shemal

Pmd-TFA (Pmd-Trifluoroacetate)

Pmd-PBu ₃ -TFA (Pmd-tributylphosphonium · trifluoroacetate)

Scheme 2

The pyrimidinium core of rosuvastatin can be replaced by the corresponding different core of other statins of the invention. TBDMS, in addition to tert-butyldimethylsilyl, may also represent another suitable protecting group.

It is known that carboxylic acid esters do not normally react with phosphines, however, we have attempted the formation of Pmd-phosphonium carboxylates from Pmd-carboxyl esters and trialkyl phosphines or triphenylphosphines. However, Pmd-trifluoroacetate (Pmd-TFA) - formed in 98 -100% yield from PmdOH and trifluoroacetic anhydride - has been shown to mature with tributylphosphine at approximately 120 ° C in Pmd-tributylphosphonium acetate in 90% yield.

The Pmd-PBu ₃ -TFA salt was also tested in the next step of the VVittig reaction presented in Scheme 2 and found to have excellent properties: because unlike Pmd-PR3, bromides and Pmd-PBu ₃ mesylate are well soluble in THF , unlike Pmd-PBu ₃ mesylate, it is more stable in drying (not "mediated"), and in the Wittig reaction, 90% of the area for Pmd-Si-malate was achieved in the Wittig reaction compared to Pmd-PBu ₃ mesylate.

Pmd-triphenylphosphonium trifluoroacetate (88% area, HPLC) was also prepared, which slowly crystallized from ibutyl acetate and i-propyl acetate. (benzoyl chloride). Pmd-acetate, however, did not react with tributylphosphine even at 170 ° C for 3 h, whereas Pmd-benzoate formed only 7% of the phosphonium product.

The use of Pmd-PBu ₃ -TFA compared to Pmd-PR ₃ halides (bromides) is superior in the VVittig reaction, as it yields better yields and fewer by-products.

The following experiments illustrate the invention but do not limit it in any way.

1 / Synthesis of Pmd-trifluoroacetate from Pmd-OH and trifluoroacetic anhydride:

21.0 g Pmd-OH

10.2 ml of TFA anhydride

13.2 ml of N-ethyl-diisopropylamine (DIPEA)

120 ml of dichloromethane (DKM)

Pmd-OH, DKM and DIPEA were mixed on an ice bath. TFA anhydride was added within 5 minutes while stirring. Then stirred for 1 hour at s.t. HPLC shows 98% + area for the product and about 0.5% starting material.

Pour the reaction mixture into a separatory funnel and wash with 2 x 120 ml demi water.

The organic phase was evaporated on a rotary evaporator under reduced pressure at 50 ° C.

27.5 g of product (100%) are obtained.

Previously, 3.5 g and 10.5 g of carbon black were performed with 98% and 100% yield and 98% + HPLC area, respectively.

2 / Synthesis of Pmd-tributylphosphonium trifluoroacetate:

24.0 g of Pmd-trifluoroacetate

16.0 ml tributylphosphine (90% content, Aldrich)

110 ml of chlorobenzene

The reactants and solvent were stirred for 1 hour at 120 - 125 ° C. Cool to 40 ° C and add 160 ml of ether while stirring. The mixture was stirred for 1 hour on ice, the precipitate was filtered off and washed with 3 x 30 ml of ether.

Dry in an oil pump vacuum at 90 ° C overnight.

30.51 g of product (88%) were obtained.

At 12.0 g, the yield was 90% (98% area HPLC). After ether precipitation, the suspension was cooled overnight in the refrigerator. The efficiency is increased by cooling at lower temperatures.

3 / Synthesis of Pmd-triphenylphosphonium trifluoroacetate

2.0 g Pmd-trifluoroacetate 1.24 g triphenylphosphine 8.0 ml chlorobenzene

The reactants and solvent were stirred for 4 hours at 120 - 125 ° C in an oil bath. HPLC shows 89% of the product area and below 1% of the starting material.

The solvent was evaporated on a rotary evaporator at 60 ° C. 3.3 g of the crude product are obtained as a clear pale brown resin.

With the addition of i-propyl acetate or i-butyl acetate, the product slowly crystallizes out as a crystalline substance

4 / Synthesis of Pmd-mesylate:

3.5 g Pmd-OH

2.0 g of methanesulfonyl anhydride

2.2 ml DIPEA 20 ml DKM7

Pmd-OH, DKM, and DIPEA were stirred on an ice bath and methanesulfonyl anhydride was added in three portions during mixing over 2 minutes. Then stirred for another 2 hours at s.t.

The reaction mixture was washed with 20 ml of 1% H3PO4 and 20 ml of demi water.

The solvent was evaporated on a rotary evaporator in vacuo at 50 ° C.

4.30 g of product (100%) are obtained. The product crystallizes from i-PrOAc / n-hexane.

5 / Synthesis of Pmd-tributylphosphonium mesylate:

0.86 g Pmd-mesylate 0.60 ml tributylphosphine 5.0 ml i-PrOAc

The reagent and solvent were stirred for 30 minutes at 80 ° C. Cool to 60 ° C and add 5.0 ml of n-hexane while stirring. Cool to s.t. , stirred for 1 hour, the precipitate was filtered off and washed with 2 x 5 ml of ether.

1.12 g of product (89%) are obtained, which begins to be dried under vacuum in a vacuum oven at 100 ° C. The product is poorly soluble in THF, which is important in the VVittig reaction.

Claims (11)

REQUIREMENTS A process for the synthesis of a statin, characterized in that it involves the reaction of a Vittig reagent formed from a starting compound of the formula Het ^/ ^ P ⁺ R ₃ Αρη wherein R is the same or different and R is selected from C 1 -C 10 alkyl, aryl and alkyyl aryl radicals, and A represents the anion of strong organic acids, and Het forms the statin skeleton. A method according to the preceding claim wherein Het is selected from 3. The process for the synthesis of rosuvastatin, characterized in that it involves the reaction of a Vitig reagent formed from a starting compound of the formula wherein R is the same or different and R is selected from C1-C10 alkyl, aryl and alkyl aryl radicals, and A represents a strong organic anion acid. A process according to any one of the preceding claims, characterized in that A is selected from anions of organic sulfonic acids and anions of halogenated aliphatic or aromatic acids. Ί 5. The method of synthesizing rosuvastatin according to any one of the preceding claims, characterized in that A is a trifluroacetate anion. A process according to any one of the preceding claims, wherein said Vittig reagent is reacted with a compound of the formula: O-TBDMS OHC ^ ''' ^{/ CO} ° ^Me wherein each R is independently selected from C 1 -C 10 alkyl, aryl and alkyl aryl, and A' is selected from anions of organic sulfonic acids and anions of halogenated aliphatic or aromatic acids. A compound according to the preceding claim wherein all three R are independently selected from butyl, ethyl, propyl, methyl, or phenyl, and A- represents CF ₃ COO '. The compound of the preceding claim wherein all three R are butyl. Use of a compound according to any one of claims 7 to 9 for the synthesis of rosuvastatin. A pharmaceutical formulation containing a statin prepared according to any one of claims 1 to 6. A pharmaceutical formulation containing rosuvastatin prepared according to any one of claims 3 to 6.