ZA200303734B

ZA200303734B - A lactonization process.

Info

Publication number: ZA200303734B
Application number: ZA200303734A
Authority: ZA
Inventors: Frantisek Picha; Theodorus Hendricus Ant Peters; Jacobus Maria Lemmens
Original assignee: Synthon Bv
Priority date: 2003-05-14
Filing date: 2003-05-14
Publication date: 2004-05-14

Description

. A LACTONIZATION PROCESS

Antihypercholesterolemic compounds lovastatin and simvastatin are widely used in medicine for the lowering of levels of blood cholesterol.

Those compounds are derivatives of mevinic acid and have the following structural formula (1):

HO, 0

Tr

LA g

R jo}

CH IT H CHs

Hae 0) 15wherein when R = H, the compound is lovastatin and, wherein when R = CH; , the compound is simvastatin.

The chemical structure of both compounds is characterised by the presence of a cyclic lactone moiety (4-hydroxy-3, 4,5, 6-tetrahydro-2H-pyran-2-one group) in 20the molecule. Accordingly, the chemical structure as expressed by the formula (1) may be simplified by the common formula (A),

~~ | WO 02072566 PCT/NL02/00161

HO o

LG SE a 5 wherein Q represents the corresponding remaining part of the molecule of lovastatin and simvastatin.

Both compounds may be produced by the fermentation of various microorganisms or they may be 10prepared synthetically or semi-synthetically by methods known in the art.

Fermentation or synthetic methods for preparing lovastatin or simvastatin usually lead to the formation of a dihydroxyacid form (B) or a salt thereof

HO, OX 1G:

X OH a B) wherein X = H, metal cation, ammonia cation, instead to the desired lactone form (A).

Ammonium salts of the dihydroxyacid form (B) are often used as intermediates in production methods as 25these salts are nicely crystalline. Acid and lactone . forms may also be formed in the mixture.

Whenever this occurs, it is necessary to . convert the intermediate dihydroxyacid form (B) (or, accordingly, a salt thereof) into the desired lactone 30form (A).

Hereafter the dihydroxyacid form (B) of compounds of formula (1) may be denoted as the “statin hd } WO 02/072566 PCT/NL02/00161 - acid” or, if appropriate, “lovastatin acid” or “simvastatin acid” of formula (2):

HO, 6).4 1 ~—OH 0 EY

Ss

CHsy = H CH, (2)

CY

5 . wherein R and X are as hereinabove defined.

Lactonization is a process wherein a hydroxy 10acid loses one molecule of water to form an intramolecular ester - a lactone. This reaction is generally catalysed by an acid; the necessary acidity arises either through the ambient acidity of the substrate itself or by addition of a stronger acid, i.e. 15a lactonization agent to enhance lactonization.

Lactonization is an equilibrium process characterized, in the case of statins, by the following equation:

Dihydroxy acid————p lactone + HO (B) — (A) . 25

In order to obtain a high yield of the lactone, means must be employed to shift the equilibrium to the 30lactone side of the equation.The common means of shifting the equilibrium to the lactone side from (B) to (A) is

SN vo. | WO 02072566 PCT/NL02/00161 : the removal of a reaction product from the reaction mixture. ’ One known way of removal of the reaction product during lactonization of a statin acid is the

S5physical removal of water produced from the reaction mixture, e.g. by means of azeotropic distillation. In this arrangement, the statin acid and/or ammonium salt thereof is heated in a suitable solvent, for example toluene, butyl acetate, ethyl acetate, cyclohexane to a 10boiling point thereof, whereby the azeotropic mixture of the solvent and water having a lower boiling point distills off first and the reaction equilibrium is thus shifted to the formation of the lactone. The speed of water and, optionally, ammonia removal may be increased 15by passing a stream of inert gas through the hot reaction mixture. The ambient acidity of the statin acid is believed to be responsible for the lactonization reaction at these high temperatures.

This process has been disclosed e.g. in US 204444784, US 4582915, US 4820850, US 5159104, WO 98-12188 and many others.

An alternate known possibility (US 5393893) is to perform the lactonization in a two-phase system of an organic solvent, in which the lactone is soluble, and an 25aqueous acid, whereby the water formed is displaced from the organic layer, containing the lactone, to the aqueous layer.

Both alternatives have the disadvantage that elevated temperatures and long reaction times are 30necessary to be applied for completing the reaction, whereby statins are sensitive to heating so that impurities may be formed. , One of the most common impurities arises from dimerization of the starting material. For instance, 35simvastatin of pharmaceutically acceptable quality (e.g. the quality of Ph.Eur. monograph) should contain only less than 0.2 % of such dimer.

Another known method is based on the removal of the lactone itself from the reaction medium. In this of vo. WO 02/072566 PCT/NL02/00161 ; arrangement, the statin acid or its salt is dissolved in a water-miscible solvent in the presence of an acidic ’ catalyst and water is added to the reaction mixture, after a certain reaction period, as an antisolvent. The 5lactone is not soluble in water and separates out from the solution, thus shifting the equilibrium in the solution to allow formation of the next lactone. This method has been disclosed in EP 351918 / US 4916239

This reaction does not require elevated temperatures so 10that the potential for forming impurities, particularly dimers, is lower.

However the selection of the water-miscible solvent and the proper amounts and timings of added water is crucial since fast or premature addition of water can 15lead to serious problems in isolation of the product as impurities of similar structure present in the starting statin acid may accordingly separate from the solution and decrease the purity of the obtained lactone.

In addition, all of the above known lactonization methods 20require reaction times longer than one hour for obtaining an acceptable degree of conversion. This together with the necessary subsequent work-up, makes these methods complicated to carry out and economically undesirable.

According to a first aspect, the present 25invention provides a process for synthesizing a compound of formula (1)

HQ, Oo 104

LA

, CH TT H CHs

Hac S comprising the steps of intramolecular esterification, lactonization, of a compound of formula (2):

y

HO, OX 1& +— OH 0 H

SA

CH3 = H CHs 2)

Hye with a lactonization agent in a suitable solvent thus yielding a reaction medium 10wherein R is a hydrogen atom or a lower alkyl group, preferably a methyl group and X is a hydrogen atom or a cation, wherein the lactonization agent forms a hydrated complex with water, released on the lactonization of compound (2) 15into compound (1), which hydrated complex is substantially insoluble in the solvent.

Optionally, the process also comprises the steps of removal of the hydrated complex after the reaction from the reaction mixture and isolation of the 20compound (1) from the reaction medium, preferably without an aid of an antisolvent.

This lactonization of the statin proceeds at ambient temperature, is simple and short and is easily operable on an industrial scale. . 25Furthermore, the process does not require any special techniques or operations for shifting the equilibrium during the reaction.

Preferred aspects of the present invention are also further defined in the claims.

The starting acid form of simvastatin or lovastatin may be employed in a crude or purified state.

Claims

: 1.A process for synthesizing a compound of formula (1) HO 0 Tr

ON . _R Q S (1) HaCY comprising the steps of intramolecular esterification, lactonization, of a compound of formula (2): HO OX T= — OH o E rR Q CH, =H CH 2) HyCY with a lactonization agent in a suitable solvent thus yielding a reaction medium wherein R 1s a hydrogen atom or a lower alkyl group, and X is a hydrogen atom or a cation, wherein the lactonization agent forms a hydrated complex with water, released on the lactonization of compound (2) into compound (1), which hydrated complex is substantially insoluble in the solvent.
2. Process according to claim 1 wherein R is a methyl group. Amended page 27 July 2004
3. Process according to claims 1 or 2 wherein compound (2) 1s subsequently isolated from the reaction medium, and wherein compound (1) is substantially soluble in the solvent.
4. Process according to any one of claims 1 to 3 wherein X is a hydrogen atom, a metal cation or an ammonium cation.
5. Process according to any of the preceding claims wherein the solvent is substantially inert.
6. Process according to any of the preceding claims wherein the solvent is substantially immiscible in water.
7. Process according to any of the preceding claims wherein the solvent is a hydrocarbon solvent or a halogenated hydrocarbon or mixtures thereof.
8. Process according to any of the preceding claims wherein the solvent is a halogenated hydrocarbon solvent.
9. Process according to claim 8 wherein the solvent is a chlorinated hydrocarbon solvent.
10. Process according to claim 9 wherein the sclvent is dichloromethane.
11. Process according to any of the preceding claims wherein the lactonization agent is an acidic compound.
12. Process according to any of the preceding claims wherein the lactonization agent is substantially anhydrous.
13. Process according to any of the preceding claims wherein the lactonization agent is selected from one or more of the following: methane sulphonic acid, phosphorus pentoxide, a strongly acidic ion-exchange resin. Amended page 27 July 2004
14. Process according to any of the preceding claims wherein the lactonization agent is methane sulphonic acid and/or a strongly acidic ion-exchange resin,
15. Process according to any of the preceding claims wherein the lactonization agent binds ammonia upon forming the hydrated complex.
le. Process according to any of the preceding claims wherein the hydrated complex is removed from the reaction medium.
17. Process according to claim 16 wherein the hydrated complex is removed from the reaction medium in a substantially solid form by means of filtration.
18. Process according to claims 16 or 17 wherein before the filtration step a base is added to the reaction medium.
19. Process according to claim 18 wherein the base is an organic amine.
20. Process according to claim 19 wherein the organic amine is a triethylamine and/or pyridine.
21. Process according to claim 20 wherein the organic amine is triethylamine.
22. Process according to any one of claims 1-17 wherein the hydrated complex is removed from the reaction medium by means of extraction with alkalinized water.
23. Process according to any of the preceding claims wherein isolation of compound (1) is carried out without an aid of an antisolvent.
24. Process according to any of the preceding claims 3-23 wherein compound (1) is isclated from the reaction medium by crystallization or by evaporation of the reaction medium to dryness. Amended page 27 July 2004
25. Process according to any of the preceding claims wherein the compound of formula (2) is the ammonium salt of simvastatin acid.
26. Process according to any of the preceding claims wherein the molar ratio between compound (2) and the lactonization agent is roughly 1:1.01 to 1:1.5.
27. Process according to any of the preceding claims wherein lactonization of compound (2) proceeds without heating the reaction medium.
28. Process according to any of the preceding claims wherein lactonization of compound (2) has a reaction time of between 15 and 60 minutes. ’
29. A compound of formula (1): HO 0 0 EH LA CHs H oCH3 ol wherein R 1s a hydrogen atom or a methyl group, obtainable according to any of the preceding claims.
30. A pharmaceutical composition comprising a compound of formula (1) according to claim 29.

"31. A process according to claim 1 substantially as herein described with reference to any one of the illustrative Examples 1 to 4. Amended page 27 July 2004