The present invention relates to process for preparation of amorphous form of a HIV protease inhibitor compound which is atazanavir bisulfate.
The sulfate salt of Atazanavir is marketed under proprietary name of REYATAZ™ as capsule; oral dosage form equivalent to 100/150/200 mg by Bristol Mayer Squibb in USA. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1).
The chemical structure of atazanavir sulfate is as provided below:
(Figure Removed)
REYATAZ™ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
U.S. Pat. No. 5,849,911 (hereinafter refers to as '911 patent) to Fassler et al. discloses a series of azapeptide HIV protease inhibitors including atazanavir.
The '911 patent and US patent 6,300,519 describe the process for preparation of atazanavir compound by the reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate and p-toluenesulfonic acid in methanol to produce acetal (II), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIM) in hot isopropanol gives the expected addition product (IX), which by treatment with HCI or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed
with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyO-N.N.N'.N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF to obtain atazanavir (Scheme-1).
US patent 5,912,352 (hereinafter refers to '352 patent) describes the preparation of intermediate compound (IX), which is then further converted to atazanavir.
The '352 patent mentions the preparation of intermediate compound (IX) by the cyclization of 4-cyanobenzoic acid methyl ester (XII) with acetylene at 15 atm by means of cobaltocene in toluene at 180°C to produce 4-(2-pyridyl)benzoic acid methyl ester (XIII), which is saponified with NaOH in methanol to the corresponding acid (XIV). The activation of (XIV) with isobutyl chloroformate yields the mixed anhydride (XV), which is condensed with N-(tert-butoxycarbonyl)-L-phenylalaninal (XVI) and KCN in dichloromethane, affording (XVII). The reaction of (XVII) with tert-butyl carbazate (V) by means of acetic acid in methanol gives hydrazone (XVIII), which is reduced to hydrazine (XIX) by means of sodium cyanoborohydride in THF. The isomerization of (XIX) by means of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTDE) in hot diglyme yields hydrazide (XX), which is finally reduced to intermediate (IX) with diisobutylaluminum hydride in dichloromethane/THF. The intermediate (IX) then further converted to atazanavir (Scheme-2).
The processes mentioned above are also disclosed by Drugs of the Future 1999, 24(4). 375-380.
(I)
(Scheme Removed)
Scheme 1: Synthesis of Atazanavir
(Scheme Removed)
Scheme 2: Synthesis of Intermediate (IX)
U.S. Pat. No. 6,087,383 to Singh et al. discloses crystalline bisulfate salt of an azapeptide HIV protease inhibitor known as atazanavir.
Example 3 of Singh et al. describes the preparation of atazanavir bisulfate in the form of Type-ll crystals which are hydrated hygroscopic and Type-l crystals which appear to be an anhydrous/desolvated crystalline form.
US patent application 20050256202 (hereinafter designated as '202 application) to Soojin et al. disclosed novel forms of Atazanavir bisulfate, which are designated as Pattern C and Form E3 along with their processes for preparation. The '202 application mentions pattern C as partially crystalline form and Form E3 as highly crystalline form of the triethanolate solvate of atazanavir bisulfate. This patent application indicates the Type-l crystals as Form A.
Amorphous form of atazanavir bisulfate/sulfate is known in prior art. The present inventors come to know about amorphous form of atazanavir bisulfate through European medicine agency web page. (http://www.emea.eu.int/humandocs/Humans/EPAR/revataz/revataz.htm)
It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms. For some therapeutic indications one bioavailability pattern may be favored over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form. During our laboratory experimentation as a part of process development, an amorphous form of atazanavir sulfate resulted while recovering atazanavir sulfate in different solvents.
In comparison to prior art processes, the amorphous form of atazanavir or its salts obtained by the present inventors is of high purity and free flowing. The process for the preparation of the amorphous form of the present invention is simple, efficient, eco-friendly and easily scalable. The process of the present invention for the preparation of atazanavir or its salts in amorphous form is high yielding.
To overcome the problems associated with the prior art processes for obtaining amorphous form of atazanavir or its sulfate salt, the inventors of the present invention provide here an efficient and simple process to obtain atazanavir or its salts in amorphous form.
The various aspects given below describe the nature of present invention in detail.
A first aspect of the present invention provides a process for the preparation of atazanavir or its salt in amorphous form comprising
a) Refluxing/dissolving atazanavir or its salt in organic solvent
b) filtering the solution of step a) and
c) spray drying the filtrate of step b) under inert atmosphere
d) recovering amorphous atazanavir or its salt.
Atazanavir or its salt prepared by any conventional methods is poured into organic solvent to dissolve. If required, the solution is refluxed / stirred to dissolve the solid material at 20-50°C. This solution is then filtered and the filtrate is spray dried at 40-120°C under inert atmosphere to achieve amorphous nature of atazanavir or its salt. The spray dried product so obtained is dried under vacuum to recover highly pure amorphous atazanavir or salt in high yield.
Organic solvent as hereinabove mentioned in the first aspect of the invention is any solvent which is capable of dissolving the atazanavir or its salt. A skilled artisan can easily select the organic solvent on the basis of boiling point, polarity and solubility nature (or dielectric constant) of the solvent. By way to define first aspect of the invention, present inventors like to specify some of the organic solvents, mentioned below, but these are not intended to limit the scope of the invention. These includes alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 2-pentanol, denatured spirit and n-octanol; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone; esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and ethylene chloride; aromatic hydrocarbons such as xylene, toluene, benzene, substituted benzene, substituted toluene, substituted xylenes and substituted benzyl; aliphatic hydrocarbons such as hexane, heptane and petroleum ether; cycloalkyl hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, substituted cyclohexane and substituted cycloheptane; ether such as tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether and methyl tert-butyl ether; nitriles such as acetonitrile, propionitrile; polar aprotic solvents such as dimethylacetamide, dimethylformamide and
dimethylsulphoxide or mixtures thereof. Preferably, the alcoholic solvents are used for the purpose.
Spray drying is performed in any inert environment known to a person skilled in the art. The environment used by present inventors is nitrogen atmosphere.
The spray dried product obtained is further dried under vacuum at 40-120° for 4-5 hours.
Salt is especially the pharmaceutically acceptable salt of atazanavir. This includes acid addition salt, preferably with inorganic acids, for example hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with strong organic sulfonic, sulfo or phosphoric acids or N-substituted sulfamic acids (preferably: pKa<1). Other salts with organic acid include, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, glucuronic acid, galacturonic acid, methanesulfonic or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3-or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
The salt preferentially selected is the sulfate salt i.e. atazanavir sulfate.
The term 'atazanavir sulfate' as employed herein refers to atazanavir sulfate as well as atazanavir bisulfate.
A second aspect of the present invention provides a process for the preparation of atazanavir sulfate in amorphous form comprising
a) Refluxing/dissolving atazanavir sulfate in organic solvent
b) filtering the solution of step a) and
c) spray drying the filtrate of step b) under inert atmosphere
d) recovering amorphous atazanavir sulfate.
The process conditions, organic solvents etc. are similar to as described in first aspect of the invention.
Amorphous nature of atazanavir sulfate is confirmed by means of spectral techniques i.e. XRD and IR.
A third aspect of the present invention provides a process for the preparation of atazanavir or salt thereof in amorphous form, which process comprises
a) dissolving atazanavir or its salt in organic solvent
b) filtering the solution of step a) and
c) drying the filtrate of step b) by agitated thin film dryer
d) recovering the pure product.
Atazanavir or its salt prepared by any conventional methods is poured into organic solvent to dissolve. If required, the solution is refluxed / stirred to dissolve the solid material at 20-50°C. This solution is then filtered and the filtrate is dried by means of buchi rotavapour. Vacuum (< 15 mm) is applied to the rotavapour and it is rotated at 60-200°C before applying the filtrate into it. The filtrate is then charged to the rotavapour at a feed rate of approximately 2-6 ml per minute at 60-200°C under vacuum. The resultant product is then dried under vacuum at 40-60°C for 3-6 hours.
The terms 'organic solvent' and 'salt' used herein has the same meaning as described in first aspect of the present invention. Preferably, the organic solvent used in this aspect is alcoholic solvent and the salt prepared is atazanavir sulfate.
The term 'atazanavir sulfate' as employed herein refers to atazanavir sulfate as well as atazanavir bisulfate.
A fourth aspect of the present invention provides a process for the preparation of atazanavir sulfate in amorphous form, which process comprises
a) dissolving atazanavir sulfate in organic solvent
b) filtering the solution of step a) and
c) drying the filtrate of step b) by agitated thin film dryer
d) recovering the pure product.
The process conditions, organic solvents etc. are similar to as described in third aspect of the invention.
Amorphous nature of atazanavir sulfate is confirmed by means of spectral techniques i.e. XRD and IR.
The term 'atazanavir sulfate' as employed herein refers to atazanavir sulfate as well as atazanavir bisulfate.
A fifth aspect of the present invention is to provide a simple and efficient method for the preparation of amorphous form of atazanavir or salt thereof which comprises recovering amorphous atazanavir or salt thereof from a solution thereof in a suitable organic solvent by spray drying or agitator thin film drying technique.
The terms 'organic solvent' used herein has the same meaning as described in first aspect of the present invention.
Amorphous atazanavir sulfate obtained by following foregoing aspects of the invention is substantially free of impurities.
Other techniques to prepare amorphous form of a compound are lyophilization, solvent evaporation, solvent precipitation, freeze drying, roller drying and mortor pestle etc. These techniques can be used to prepare amorphous atazanavir or salts thereof.
In the following figures, drawings are briefly described.
Fig. 1: FTIR of amorphous atazanavir sulfate obtained by following example 1. Fig. 2: XRD of amorphous atazanavir sulfate obtained by following example 1. Fig. 3: FTIR of amorphous atazanavir sulfate obtained by following example 2. Fig. 4: XRD of amorphous atazanavir sulfate obtained by following example 2. Fig. 5: FTIR of amorphous atazanavir sulfate obtained by following example 3. Fig. 6: XRD of amorphous atazanavir sulfate obtained by following example 3.
The present invention is further illustrated by the following examples, which are not intended to limit the scope of this invention in any way.
EXAMPLE 1
To a three necked round bottom flask, Atazanavir sulphate (5.0 g) was added in Methanol (100 ml) and the solution was stirred to dissolve the solid material at 30-35°C. The suspended particle was filtered off and the filtrate was spray dried at 65-85°C under nitrogen atmosphere.
The spray dried product so obtained is dried under vacuum at 45-50°C for 4-5 hrs. It was analyzed by XRD and confirmed as amorphous atazanavir sulfate.
EXAMPLE 2
To a three necked round bottom flask, Atazanavir sulphate (5.0 g) was added in Methanol (100 ml) and the solution was stirred to dissolve the solid material at 30-35°C. The suspended particles were filtered off. Vacuum (< 15 mm) was applied to Buchi rotavapor and it was rotated at 80-90°C. The methanolic filtrate was charged to the rotavapor at a feed rate of ~2-3 ml per minute at 85-95°C under vacuum. The resultant product was dried under vacuum at 45-50°C for 4-5 hours. The dried material was analysed by XRD and confirmed as amorphous atazanavir sulfate.
EXAMPLE 3
To a three necked round bottom flask, Atazanavir sulphate (5.0 g) was added in ethanol (100 ml) and the solution was stirred to dissolve the solid material at 30-35°C. The suspended particles were filtered off. Vacuum (< 15 mm) was applied to Buchi rotavapor and it was rotated at 85-95°C. The ethanolic filtrate was charged to the rotavapor at a feed rate of ~2-3 ml per minute at 85-95°C under vacuum. The resultant product was dried under vacuum at 45-50°C for 4-5 hours. The dried material was analysed by XRD and confirmed as amorphous atazanavir sulfate.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present aspects and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

WE CLAIM:
1. A process for the preparation of atazanavir or its salt in amorphous form
comprising
a) Refluxing/dissolving atazanavir or its salt in organic solvent
b) filtering the solution of step a) and
c) spray drying the filtrate of step b) under inert atmosphere
d) recovering amorphous atazanavir or its salt.
2. A process for the preparation of atazanavir sulfate in amorphous form
comprising
a) Refluxing/dissolving atazanavir sulfate in organic solvent
b) filtering the solution of step a) and
c) spray drying the filtrate of step b) under inert atmosphere.
d) recovering amorphous atazanavir sulfate

3. The process of claim 1 or 2 wherein the organic solvent is any solvent capable of
dissolving atazanavir or its salt form.
4. The process of claim 3 wherein the organic solvent is polar organic solvent.
5. The process of claim 1 or 2 wherein the filtrate is spray dried at temperature
range between 40-120°C.
6. The process of claim 1 or 2 wherein recovery comprises drying of spray dried
product under vacuum.
7. The process of claim 1 or 2 wherein inert atmosphere is of nitrogen.
8. A process for the preparation of atazanavir or salt thereof in amorphous form, which process comprises
a) dissolving atazanavir or its salt in organic solvent
b) filtering the solution of step a)
c) drying the filtrate of step b) by agitated thin film dryer
d) recovering the pure product.
9. A process for the preparation of atazanavir sulfate in amorphous form, which
process comprises
a) dissolving atazanavir sulfate in organic solvent
b) filtering the solution of step a)
c) drying the filtrate of step b) by agitated thin film dryer
d) recovering the pure product.

10. The process of claim 8 or 9 wherein the organic solvent is any solvent capable
of dissolving atazanavir or its salt form.
11. The process of claim 10 wherein the organic solvent is polar organic solvent.
12. The process of claim 8 or 9 wherein buchi rotavapor is used as agitated thin film
dryer.
13. The process of claim 8 or 9 wherein the filtrate is dried by agitated thin film dryer
at a temperature range between 60°C to 200°C.
14. The process of claim 8 or 9 wherein the product is recovered through drying
under vacuum.
15. A process for the preparation of amorphous atazanavir or salt thereof which
comprises recovering amorphous atazanavir or salt thereof from a solution
thereof in a suitable organic solvent by spray drying or agitator thin film drying
technique.
16. The process of claim 15 wherein the suitable organic solvent is any solvent
capable of dissolving atazanavir or its salt form.
17. Amorphous atazanavir sulfate substantially free from impurities.
18. Atazanavir or salt thereof in amorphous form obtained by a process comprising
lyophilization, solvent precipitation, freeze drying, solvent evaporation, roller
drying, spray drying, agitator thin film drying or mortor pestle technique.
19. The process of claim 1, 8, 15 or 18 wherein the salt is selected from
hydrohalide, sulfate, bisulfate, phosphate, salt of carboxylic acids and salt of
amino acids.
20. Amorphous atazanavir sulfate of high purity.