EP2094661A2 - Process for the preparation of atazanavir - Google Patents

Process for the preparation of atazanavir

Info

Publication number
EP2094661A2
EP2094661A2 EP07848883A EP07848883A EP2094661A2 EP 2094661 A2 EP2094661 A2 EP 2094661A2 EP 07848883 A EP07848883 A EP 07848883A EP 07848883 A EP07848883 A EP 07848883A EP 2094661 A2 EP2094661 A2 EP 2094661A2
Authority
EP
European Patent Office
Prior art keywords
compound
atazanavir
preparation
methoxycarbonyl
added
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07848883A
Other languages
German (de)
French (fr)
Inventor
Roberta Pizzocaro
Stefania Galimi
Alessia Rossi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fidia Farmaceutici SpA
Original Assignee
Fidia Farmaceutici SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fidia Farmaceutici SpA filed Critical Fidia Farmaceutici SpA
Priority to EP07848883A priority Critical patent/EP2094661A2/en
Publication of EP2094661A2 publication Critical patent/EP2094661A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom

Definitions

  • the present invention relates to a process for the preparation of Atazanavir.
  • Atazanavir ([3S-(3R*,8R*,9R*,12R*)]-3,12-bis(l,l-dimethylethyl)- 8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6, 10,13-pentaazatetradecanedioic acid dimethyl ester)
  • (I) is a known antiviral agent and anti-HIV protease inhibitor, disclosed in EP 0 900 210 and in its equivalent US 5,849,911. These patents disclose preparation methods based on different synthetic approaches and intermediates; some of them are schematically represented and discussed below:
  • N-methoxycarbonyl-L-ferMeucine (1) is reacted with amino derivatives (2) and (3) respectively, while in scheme 3 epoxide (4) is reacted with hydrazine (5).
  • These processes suffer from some drawbacks and are difficult to carry out on an industrial scale.
  • N-methoxycarbonyl-L-terMeucine is very expensive; the synthesis of compounds (2) and (5) (schemes 1 and 3) is troublesome, with selectivity issues between the amino groups and compound (4) of scheme 3 is poorly stable.
  • the process of scheme 2 requires the use of a large excess of N- methoxycarbonyl-L-terMeucine (at least three equivalents); moreover, compound (3) is difficult to isolate and handle, and highly hygroscopic.
  • the present invention relates to a process for the preparation of Atazanavir (I)
  • Step a) is usually carried out in a mixture of a chlorinated solvent and an aprotic polar solvent, preferably selected from methylene chloride, chloroform and dimethylformamide, dimetylacetamide, DMPU, more preferably methylene chloride and dimethylformamide, in the presence of a condensing agent such as DCC, at a temperature of about 0 0 C, preferably between 0 and 5°C.
  • Step b) is usually carried out in methanol and ammonium formate and
  • step c) is carried out in a chlorinated solvent, preferably methylene chloride.
  • the compound of formula (6) can be prepared by reacting the hydrazine of formula (9)
  • the process of the invention is advantageous over the above-discussed prior art in that it avoids the use of amino-derivative (3) and it requires lower amounts of N-methoxycarbonyl-L-ferMeucine.
  • the filtrate was transferred into a one-liter round bottom flask and added with a solution of 33.6 g of K 2 HPO 4 -3H 2 O in 45 ml water at 0°-5°C, then 4-(pyridin-2- yl)benzylhydrazine was added keeping the temperature below 10 0 C and the resulting mixture was allowed to stand overnight.
  • the suspension was filtered and the organic layer was washed with water, with a solution of 27.5 g of NaH 2 PO 4 H 2 O in 45 ml water, and again with water, then separated and stirred with a solution of 12.1 g of 30% sodium hydroxide in 45 ml water.
  • the sodium hydroxide solution was discharged and the organic layer was washed in sequence with water, a sodium hydrogen phosphate solution (the same as above), water and brine, then separated and dried over sodium sulphate. After evaporation of the solvent under vacuum the title compound (18.5 g) was obtained as a yellowish solid.
  • Example 2 Preparation of t-Boc-protected compound (6)
  • epoxide (10) and 18.5 g of compound (9), prepared as described in example 1, were heated at 80 0 C for 48 hours in toluene (110 ml).
  • the reaction mixture was then cooled and filtered.
  • the solid was washed with toluene and dried to give 13.8 g of an off-white product.
  • Example 6 Preparation of Atazanavir Compound (8) (9.47 g), obtained according to example 5, was suspended in 200 mL of CH 2 Cl 2 , added with 1.99 g of diisopropyl ethylamine, and the resulting mixture was cooled to about O 0 C. 1.45 g of methyl chloroformate in 25 mL of CH 2 Cl 2 were added dropwise over about 2 hours. The suspension was then stirred for about half an hour at 0 0 C and added with an aqueous solution of 10% NaHCO 3 (100 mL) at O 0 C with vigorous stirring.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a process for the preparation of Atazanavir, which comprises reacting the hydrochloride salt of compound (6) with N-methoxycarbonyl-L-tert-leucine, the removal of the benzyloxycarbonyl group and the reaction with methoxycarbonyl chloride. The process is particularly advantageous in that it allows to use reduced amounts of N-methoxycarbonyl-L-tert-leucine and avoids the use of unstable intermediates.

Description

PROCESS FOR THE PREPARATION OF AT AZANA VIR
Field of the invention
The present invention relates to a process for the preparation of Atazanavir.
Background of the invention
Atazanavir (I) ([3S-(3R*,8R*,9R*,12R*)]-3,12-bis(l,l-dimethylethyl)- 8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6, 10,13-pentaazatetradecanedioic acid dimethyl ester)
(I) is a known antiviral agent and anti-HIV protease inhibitor, disclosed in EP 0 900 210 and in its equivalent US 5,849,911. These patents disclose preparation methods based on different synthetic approaches and intermediates; some of them are schematically represented and discussed below:
*" ATAZANAVIR
Scheme 1 ATAZANAVIR
Scheme 2
ATAZANAVIR 4 5
Scheme 3
In the processes of schemes 1 and 2 N-methoxycarbonyl-L-ferMeucine (1) is reacted with amino derivatives (2) and (3) respectively, while in scheme 3 epoxide (4) is reacted with hydrazine (5). These processes suffer from some drawbacks and are difficult to carry out on an industrial scale. In particular, N-methoxycarbonyl-L-terMeucine is very expensive; the synthesis of compounds (2) and (5) (schemes 1 and 3) is troublesome, with selectivity issues between the amino groups and compound (4) of scheme 3 is poorly stable. The process of scheme 2 requires the use of a large excess of N- methoxycarbonyl-L-terMeucine (at least three equivalents); moreover, compound (3) is difficult to isolate and handle, and highly hygroscopic.
There is still therefore the need for an improved process for the synthesis of Atazanavir.
Disclosure of the invention
The present invention relates to a process for the preparation of Atazanavir (I)
(I) comprising the following steps: a) reaction of the hydrochloride salt of compound (6)
(6) with N-methoxycarbonyl-L-ferMeucine (1)
to give compound (7)
7 b) removal of the benzyloxycarbonyl group to give compound (8)
8 and c) treatment of compound 8 with methoxycarbonyl chloride to give Atazanavir (I).
Step a) is usually carried out in a mixture of a chlorinated solvent and an aprotic polar solvent, preferably selected from methylene chloride, chloroform and dimethylformamide, dimetylacetamide, DMPU, more preferably methylene chloride and dimethylformamide, in the presence of a condensing agent such as DCC, at a temperature of about 00C, preferably between 0 and 5°C. Step b) is usually carried out in methanol and ammonium formate and
Pd/C as catalyst, while step c) is carried out in a chlorinated solvent, preferably methylene chloride.
The compound of formula (6) can be prepared by reacting the hydrazine of formula (9)
(9) either with epoxide (10)
(10) or with epichloridrine (11)
(H) followed by acid treatment to remove the tBoc group. Compound (6) is further treated with hydrochloric acid to give the hydrochloride salt. Usually, the removal of the tBoc group is carried out with an amount of hydrochloric acid also sufficient to form the hydrochloride salt of compound (6).
The process of the invention is advantageous over the above-discussed prior art in that it avoids the use of amino-derivative (3) and it requires lower amounts of N-methoxycarbonyl-L-ferMeucine.
Moreover, the removal of the benzyloxycarbonyl (Cbz) group is a clean reaction and compound (6), its precursors and compounds (7) and (8) can be isolated in the crystalline form, which makes their work-up easier. Compound (6) is novel and is a further object of the invention.
The invention will be now illustrated in greater detail by means of some examples.
EXAMPLES Example 1 - Preparation of compound (9)
In a 250 mL round bottom flask a solution of Cbz-tert-leucine (12.3 g) in CH2Cl2 (45 mL) was added with 7.9 g of HOBt (1-hydroxy lH-benzotriazole) in 27 ml of DMF. The mixture was cooled to 0°-5°C, then added with 10.1 g of DCC dissolved in 10 ml Of CH2Cl2, keeping the temperature below 100C; after about one hour at this temperature, the suspension was filtered and the solid was washed on the filter with small amounts of CH2Cl2. The filtrate was transferred into a one-liter round bottom flask and added with a solution of 33.6 g of K2HPO4-3H2O in 45 ml water at 0°-5°C, then 4-(pyridin-2- yl)benzylhydrazine was added keeping the temperature below 100C and the resulting mixture was allowed to stand overnight. The suspension was filtered and the organic layer was washed with water, with a solution of 27.5 g of NaH2PO4 H2O in 45 ml water, and again with water, then separated and stirred with a solution of 12.1 g of 30% sodium hydroxide in 45 ml water. Thereafter, the sodium hydroxide solution was discharged and the organic layer was washed in sequence with water, a sodium hydrogen phosphate solution (the same as above), water and brine, then separated and dried over sodium sulphate. After evaporation of the solvent under vacuum the title compound (18.5 g) was obtained as a yellowish solid.
Example 2 - Preparation of t-Boc-protected compound (6) In a 250 ml round bottom flask 11.3 g of epoxide (10), and 18.5 g of compound (9), prepared as described in example 1, were heated at 800C for 48 hours in toluene (110 ml). The reaction mixture was then cooled and filtered. The solid was washed with toluene and dried to give 13.8 g of an off-white product.
Example 3 - Preparation of compound (6) hydrochloride salt
In a round bottom flask 13.8 g of the compound of example 2, were dissolved in THF (45 mL) and 15 mL of water. The solution was cooled to 0°-5°C, added with 37% HCl maintaining the temperature below 100C, then heated at 300C for 16 hours; after this time the mixture was cooled to room temperature and the organic solvent was evaporated in vacuo. The resulting solution was stirred and added first with ethyl acetate (200 mL), then with 200 mL of NaHCO3 saturated solution. The aqueous phase was discharged and the organic phase was dried over anhydrous sodium sulphate, filtered, and evaporated in vacuo. 12.2 g of the hydrochloride salt was obtained as a yellowish solid, which was used without further purifications for the following step. Example 4 - Preparation of compound (7) In a round bottom flask methoxycarbonyl-terMeucine (1) (4.16) g was dissolved in CH2Cl2 (40 mL) and DMF (10 mL). This solution was added with 3.42 g of HOBt, cooled to 0-50C and added again with 4.54 g of DCC in 20 mL of CH2Cl2. The resulting suspension was stirred at 0-50C for about one hour, then added with a suspension of (6) hydrochloride salt (12.2 g) in CH2Cl2 (20 mL) and stirred at O0C overnight. The solid was filtered off and the filtrate was evaporated in vacuo to an oily residue which was taken-up with 100 mL of EtOAc; the precipitated solid was filtered off. The filtrate was washed twice with a 5% aqueous solution of NaHCO3, and the organic phase was separated, dried over anhydrous sodium sulphate and evaporated in vacuo, to obtain a solid residue which was taken up with acetone. The resulting suspension was heated to 6O0C for about 10 minutes, then cooled to room temperature to precipitate a white solid which was filtered and washed with acetone on the filter. The filtrate was evaporated in vacuo, and this procedure (taking up with acetone/heating, cooling and filtering) was repeated twice, thereby obtaining 12.2 g of the title compound as a white solid. Example 5 - Preparation of compound (8)
Compound 7 (12.2 g), obtained as described in example 4, was suspended in methanol (90 mL), then added with 1.33 g of Pd-C 5% and the suspension was heated to reflux. The mixture was then cooled to 400C, and a solution of 4.93 g of ammonium formate in methanol/water was added over about one hour. The reaction was heated at 400C for about one hour, then cooled to about 25-3O0C. The suspension was filtered and the filtrate was evaporated in vacuo to a solid residue, which was added with 100 mL of EtOAc and washed with a 5% aqueous solution of NaHCO3. The organic phase was dried over anhydrous sodium sulphate, filtered, and evaporated in vacuo to yield 9.47 of compound 8 as a white solid, which was used for the next step without further purification.
Example 6 - Preparation of Atazanavir Compound (8) (9.47 g), obtained according to example 5, was suspended in 200 mL of CH2Cl2, added with 1.99 g of diisopropyl ethylamine, and the resulting mixture was cooled to about O0C. 1.45 g of methyl chloroformate in 25 mL of CH2Cl2 were added dropwise over about 2 hours. The suspension was then stirred for about half an hour at 00C and added with an aqueous solution of 10% NaHCO3 (100 mL) at O0C with vigorous stirring. The organic phase was the separated, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo to afford 8.46 g of a white solid, which was hot-crystallised from ethanol (65 mL) and water (33 mL). The resulting solid was filtered, washed on the filter with an ethanol/water mixture and dried, to obtain 5.1g of Atazanavir as a white solid.

Claims

1. Process for the preparation of Atazanavir (I)
(D comprising the following steps: a) reaction of the hydrochloride salt of compound (6)
(6) with N-methoxycarbonyl-L-terMeucine (1)
(1) to give compound (7)
(7) b) removal of the benzyloxycarbonyl group to give compound (8)
(8) and c) treatment of compound (8) with methoxycarbonyl chloride to give
Atazanavir.
2. The process of claim 1 wherein the hydrochloride salt of the compound of formula (6) is prepared by reacting hydrazine of formula (9)
(9) either with epoxide (10)
(10) or with epichloridrine (11)
(H) followed by acid treatment with hydrochloric acid.
3. The compound of formula (6)
(6) as an intermediate for the preparation of Atazanavir.
EP07848883A 2006-11-28 2007-11-13 Process for the preparation of atazanavir Withdrawn EP2094661A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07848883A EP2094661A2 (en) 2006-11-28 2007-11-13 Process for the preparation of atazanavir

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06024597A EP1930324A1 (en) 2006-11-28 2006-11-28 Process for the preparation of atazanavir
PCT/IB2007/003470 WO2008065490A2 (en) 2006-11-28 2007-11-13 Process for the preparation of atazanavir
EP07848883A EP2094661A2 (en) 2006-11-28 2007-11-13 Process for the preparation of atazanavir

Publications (1)

Publication Number Publication Date
EP2094661A2 true EP2094661A2 (en) 2009-09-02

Family

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Family Applications (2)

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EP06024597A Withdrawn EP1930324A1 (en) 2006-11-28 2006-11-28 Process for the preparation of atazanavir
EP07848883A Withdrawn EP2094661A2 (en) 2006-11-28 2007-11-13 Process for the preparation of atazanavir

Family Applications Before (1)

Application Number Title Priority Date Filing Date
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Country Status (2)

Country Link
EP (2) EP1930324A1 (en)
WO (1) WO2008065490A2 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2272830A1 (en) 2009-06-18 2011-01-12 Esteve Química, S.A. Preparation process of an antivirally heterocyclic azahexane derivative
WO2011107843A2 (en) 2010-03-01 2011-09-09 Lupin Limited Process for the preparation of atazanavir sulfate substantially free of diastereomers
WO2013014633A1 (en) 2011-07-27 2013-01-31 Ranbaxy Laboratories Limited Process for preparation of atazanavir or its bisulfate salt

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5849911A (en) * 1996-04-22 1998-12-15 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008065490A3 *

Also Published As

Publication number Publication date
EP1930324A1 (en) 2008-06-11
WO2008065490A3 (en) 2008-08-14
WO2008065490A2 (en) 2008-06-05

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