IES20001035A2 - A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt - Google Patents

Abstract

A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt includes the addition of extra methyl tert-butyl ether to the reaction mixture to supersaturate the crystallisation matrix. A seed slurry is made up in a make-up/delivery vessel and delivered, under pressure, to the reaction mixture. The process produces crystalline atorvastatin calcium within a consistent size range on a factory scale.

Description

Introduction The invention relates to an improved process for producing crystalline atorvastatin calcium which is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-p,6dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1heptanoic acid hemi calcium salt.

Atorvastatin is useful as a selective and competitive inhibitor of the enzyme 3hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols such as cholesterol. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin as well as some of its metabolites are pharmacologically active in humans and are thus useful as a hypolipidemic and hypocholesterolemic agent. The liver is the primary site of action and the principal site of cholesterol synthesis. Clinical and pathological studies show that elevated plasma levels of total cholesterol and associated triglycerides promote human atherosclerosis and are risk factors for developing cardiovascular disease.

United States Patent Number 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-l-yl) alkyl]—4 -hydroxy-pyran-2-ones including trans (±)-5-(4-fluorophenyl)-2-(l-methylethyl)N,4-diphenyl-l-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lHpyrrole-3-carboxamide.

United States Patent Number 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the R form of the ring-opened acid of trans -5-(430 IE Ο 0 J Ο 3 5 WAKNO1/C/IESD -2fiuorophenyl)-2-(l-methylethyl)-N, 4-diphenyl-l-[(2-tetrahydro-4-hydroxy-6oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide, i.e., [R-(R*,R*)J-2-(4fluorophenyl)-p, 6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid.

The above described atorvastatin compounds have been prepared by a superior convergent route disclosed in the following United States Patent Numbers 5,003,080; 5,097,045; 5,103,024; 5,124,482 and 5,149,837 which are herein incorporated by reference and Baumann K.L., Butler D.E., Deering C.F., et al, Tetrahedron Letters 1992;33:2283-2284.

One of the critical intermediates disclosed in United States Patent Number 5,097,045 has also been produced using novel chemistry, as disclosed in United States Patent Number 5,155,251, which is herein incorporated by reference and Brower P.L., Butler D.E., Deering C.F., et al, Tetrahedron Letters 1992;33:2279-2282.

United States Patent Numbers 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,5109,488; W097/03960; WO98/09543 and WO99/32434 which are herein . incorporated by reference, disclose various processes and key intermediates for - / preparing atorvastatin.

Atorvastatin is prepared as its calcium salt, i.e., [R-(R*, R*)]-2-(A-fluorophenyl)-p, 6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-ΙΗ-pyrrole25 1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration.

It was unexpectedly found that on scale up to a commercial factory scale, the average crystal size of atorvastatin calcium was in some instances smaller than expected.

IE ο Ο 1 Ο 3 5 WARNOI/C/ESD -3The object of the present invention is therefore to provide a process for producing crystalline atorvastatin calcium on a factory scale which routinely and consistently produces material in a consistent size range.

Statements of Invention According to the invention there is provided a factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of:reacting a mixture of atorvastatin lactone and methyl tefr-butyl ether with sodium hydroxide to form the ring-opened sodium salt; extracting the aqueous layer thus formed with methyl tert-butyl ether; adding a charge of methyl iert-butyl ether to a vessel containing the product rich aqueous layer to supersaturate the crystallisation matrix; sealing the reaction vessel; heating the contents of the vessel to 47 to 57°C; and adding calcium acetate hemihydrate to form atorvastatin trihydrate hemi calcium salt.

In a preferred embodiment of the invention the process includes the step of adding a seed mixture to the pressurised reaction vessel.

In one embodiment of the invention the seed mixture is a mixed slurry which is prepared in a pressurised slurry make-up/delivery vessel by: •Ε Ο Ο 1 ο 3 5 -4WARN01/C/IESD introducing water into the make-up/delivery vessel; introducing methanol into the make-up/delivery vessel; and subsequently adding seed crystals of atorvastatin trihydrate hemi calcium salt to the make-up/delivery vessel.

Preferably the process includes the step of agitating the methanol and water to produce a solvent mixture before addition of the seed crystals to the seed makeup/delivery vessel.

In one embodiment of the invention the process includes the step of mixing the mixture of water, methanol and atorvastatin to form a seed crystal slurry for delivery from the pressurised slurry make-up/delivery vessel into the reaction vessel.

Preferably the slurry make-up/delivery vessel is pivotally mounted on a support frame to mix the solvent and/or the seed crystal slurry.

In one embodiment delivery of the seed slurry is commenced not more than 5 minutes after addition of calcium acetate. Preferably delivery of the seed slurry is commenced not less than 3 minutes after addition of calcium acetate.

Brief Description of the Drawings The invention will be more clearly understood from the following description given by way of example only with reference to the accompanying drawings in which:Fig. 1 is a perspective view of a make-up/delivery vessel used in the process of the invention; ΙΕ η ο 1035 WARNOl/C/IESD -5Fig. 2 is a front elevational view of the make-up/delivery vessel; and Fig. 3 is a side view of the make-up/delivery vessel illustrating the direction of movement when the vessel is rocked.

Detailed Description The invention will be more clearly understood from the following description given 10 by way of example only.

Crystalline atorvastatin calcium is a white to off white solid that is insoluble in aqueous solutions of pH4 and above. Atorvastatin calcium is very slightly soluble in distilled water, pH7.4 phosphate buffer and acetonitrile, slightly soluble in ethanol and freely soluble in methanol. Crystalline atorvastatin calcium trihydrate has the following chemical structure: Scheme 1 The process for the preparation of atovastatin calcium from atorvastatin lactone involves saponification in a water/methyl alcohol/methyl tert-butyl ether (2-6WARN01/C/IESD methoxy-2-methyl-propane; tert butyl methyl ether) mixture with sodium hydroxide. The aqueous layer containing the sodium salt of atorvastatin is washed with methyl fert-butyl ether to remove small quantities of process impurities. A small aliquot of methyl r^rt-hutyl ether is added to the crystallisation matrix. Sodium-to-calcium salt metathesis with concurrent crystallisation is accomplished by the slow addition of an aqueous calcium acetate solution to the sodium salt solution. To assure crystallisation simultaneous with addition, the reaction mixture is seeded with crystalline atorvastatin shortly after the start of the calcium acetate addition. The product is isolated by filtration and, after washing with water/methyl alcohol and water, is centrifuged, vacuum dried and milled to give crystalline atorvastatin as the trihydrate. This reaction scheme is shown in Scheme 2 below. 2. Ca(OAc)2 1.2NaOH(aq)/ MTBE/MeOH Ca++ .3H2O + 2NaOAc Scheme 2 Primarily the crystallisation matrix consists of water, some methanol, methyl tertbutyl ether and sodium atorvastatin.

Methyl ietf-butyl ether is an organic compound which is liquid at room temperature. It is used in the process for preparing atorvastatin to remove process-generated impurities and/or impurities present in the lactone.

IE 0 0 1 0 3 5 WARN01/C/IESD -7Methyl /zri-butyl ether is very volatile and in the crystallisation matrix could be lost to the headspace of the reaction vessel thereby disturbing the equilibrium of the crystallisation matrix.

It was found that the addition of an extra charge of methyl fefr-butyl ether after extractions with methyl tert-butyl ether ensures a supersaturated crystallisation matrix which compensates for any loss to the headspace and was surprisingly found to result in the formation of crystals of a consistent size.

It is important that a sealed system is maintained throughout the atorvastatin calcium process to prevent the loss of solvents to evaporation.

As the system is sealed and operated under pressure it was also important to be able to add the seed slurry to the reaction vessel under pressure.

Figs. 1 to 3 illustrate a make-up/delivery vessel 1 to charge, under pressure, atorvastatin calcium seed crystals to a reaction vessel. The make-up delivery vessel 1 comprises a funneled base 2, a top lid 3 and a generally cylindrical side wall 4 extending between the base 2 and the lid 3. The base 2 has an outlet pipe 5 fitted with a manually operated valve 6. An outlet hose may he connected via a quick release coupling to the outlet pipe 5.

The lid 3 has an inlet pipe 10 with a flanged end 11 and a side branch 12 fitted with a manual valve 13 for connection via a quick-release coupling to a feed hose. The lid 3 has a connecting line 15 with a pressure gauge 16 and a pressure relief valve 17.

A pair of diametrically opposed pins 19 are mounted to and extend outwardly of the side wall 4 to engage in mountings 20 carried on a support frame 21 having ground IE 0 0 1 0 3 5 WARNOl/C/IESD -8engaging castors 22. A handle 25 in the form of a length of pipe is attached to the vessel sidewall 4 to facilitate rocking motion of the vessel 1 to mix the contents.

In use, solvents are added through the inlet pipe 10 and atorvastatin calcium seed, is added after removal of lid, 3. Thorough mixing is facilitated by rocking the vessel 1. This process is carried out under pressure and, on completion of mixing, the contents of the vessel 1 are rapidly delivered under pressure though the outlet line 5 to a reaction vessel.

The invention will be more clearly understood from the following example.

Example 1 250kg atorvastatin lactone, 1028kg methyl tert-butyl ether and 496kg of methanol are charged to a 6000 litre glass lined reaction vessel. The lactone is prepared as described in US 5,273,995, the entire contents of which are incorporated by reference. The reaction mixture is agitated and heated to about 30°C to dissolve the lactone. When the lactone is dissolved, approximately 3200 litres of caustic solution is added (19kg of sodium hydroxide 97.5% dissolved in 3165 litres of deionised water). The contents of die vessel are heated to 47 to 57°C and agitated for at least 45 minutes.

After cooling to 25 to 35°C under an inert atmosphere the contents are allowed to settle and the organic layer is discarded. 765kg methyl tert-butyl ether is charged to the aqueous layer, the contents mixed and allowed to settle. The organic layer is discarded.

WARN01/C/IESD -963kg of extra methyl tert-butyl ether is charged to the product rich aqueous layer in the reaction vessel which is then sealed. The contents of the sealed reaction vessel are heated to 47 to 57°C maintaining a pressurised system.

A solution of calcium acetate (40kg calcium acetate hemihydrate in 1365 litres deionised water) is transferred to the pressurised vessel. Shortly after commencement of the calcium acetate addition the transfer is stopped and atorvastatin trihydrate hemi calcium salt Form I seed, prepared as described in US5,969,156 which is herein incorporated by reference, is introduced.

A seed slurry is prepared by charging 37 litres deionised water and 13kg methanol to a stainless steel make-up/delivery vessel 1 as described above with reference to Figs. 1 to 3. The solvent mixture is agitated by rocking the vessel 1 back and forth. 3.6kg atorvastatin calcium seed crystals are then charged to the solvent mixture. The contents of the delivery vessel 1 are then mixed by rocking until a seed slurry is formed. Pressure is applied to the make-up/delivery vessel 1 so that the pressure in the vessel 1 is greater than that of the reaction vessel to which its contents are to be delivered. The make-up/delivery vessel 1 is then attached to the reaction vessel via a flexible hose attached to the outlet pipe 5 and the seed slurry is charged rapidly over 2 to 3 minutes, under pressure, into the reaction vessel. We have found that for optimum results the seed slurry delivery should be commenced not more than 5 and not less than 3 minutes after the addition of calcium acetate.

After the addition of the seed slurry the calcium acetate addition is immediately resumed to complete the calcium transfer.

The product cake is washed first with a methanol/water solution followed by a water wash. The product is dried at 60° to 70°C under vacuum for 1 to 4 days to yield atorvastatin calcium Form I. The dried product is then loaded into drums. ΙΕ ο Ο 1 Ο 3 5 WARNO1/C/IESD -10 We have found that the process facilitates routine production of atorvastatin calcium on a factory scale with a consistent size range.

The invention is not limited to die embodiments hereinbefore described which may 5 be varied in detail.

Claims (6)

Claims

1. A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps oftreacting a mixture of atorvastatin lactone and methyl tert-butyl ether with sodium hydroxide to form the ring-opened sodium salt; extracting the aqueous layer thus formed with methyl tert-butyl ether; adding a charge of methyl tert-butyl ether to a vessel containing the product rich aqueous layer to supersaturate the crystallisation matrix; sealing the reaction vessel; heating the contents of the vessel to 47 to 57°C; and adding calcium acetate hemihydrate to form atorvastatin trihydrate hemi calcium salt.

2. A process as claimed in claim 1 including die step of adding a seed mixture to the pressurised reaction vessel, the seed mixture being a mixed slurry which is prepared in a pressurised slurry make-up/delivery vessel by: introducing water into the make-up/delivery vessel; introducing methanol into the make-up/delivery vessel; and subsequendy adding seed crystals of atorvastatin trihydrate hemi calcium salt to the make-up/delivery vessel. IE 0 0 1 0 3 5 -12WARN01/C/IESD

3. A process as claimed in claim 2 including the step of agitating the methanol and water to produce a solvent mixture before addition of the seed crystals to the seed make-up/delivery vessel, followed by the step of mixing the mixture

4. 5 of water, methanol and atorvastatin to form a seed crystal slurry for delivery from the pressurised slurry make-up/delivery vessel into the reaction vessel, preferably the slurry delivery vessel is pivotally mounted on a support frame to mix the solvent and/or the seed crystal slurry.

5. 10 4. A process as claimed in any preceding claim wherein delivery of the seed slurry is commenced not more than 5 minutes after the addition of calcium acetate, preferably not less than 3 minutes after the addition of calcium acetate.

6. 15 5. Crystalline atorvastatin trihydrate hemi calcium salt prepared by a process as claimed in any preceding claim.