Method for the preparation of hexahydro-furo-[2,3-b]furan-3-ol

• US 20040249175A1
• Filed: 03/09/2004
• Published: 12/09/2004
• Est. Priority Date: 09/10/2001
• Status: Active Grant

• Current Assignee: Janssen Sciences Ireland Unlimited Company (Johnson & Johnson)
• Original Assignee: Tibotec Pharmaceuticals (Johnson & Johnson)
• Inventors: Kesteleyn, Bart Rudolf Romanie, Surleraux, Dominique Louis Nestor
• Granted Patent: US 7,126,015 B2
• Time in Patent Office: Days
• US Class Current: 549/464
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 307/20 Oxygen atoms
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a method for the preparation of hexahydro-furo[2,3-b]furan-3-ol as well as novel intermediates for use in said method. More in particular the invention relates to a stereoselective method for the preparation of hexahydro-furo[2,3-b]furan-3-ol, and to a method amenable to industrial scaling up.

Claims

1. A method for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7) starting from an intermediate of formula (1) wherein P¹ and P² represent each independently a hydrogen, a hydroxy-protecting group or may together form a vicinal-diol protecting group,

2. A method according to claim 1 wherein the intermediate of formula (3) is transformed into an intermediate of formula (6) by making use of a Nef reaction.

3. A method according to claims 1 for the synthesis of hexahydro-furo[2,3-b]-furan-3-ol of formula (7), which comprises the steps of:

a) condensing an intermediate of formula (1)

resulting in an (α

,β

-unsaturated ester of formula (2),

b) reacting said ester of formula (2) with nitromethane resulting in an intermediate of formula (3),

c) submitting said intermediate of formula (3) to a Nef reaction leading to intermediates of formula (4) and (4′

)

d) transforming said intermediates of formula (4) and (4′

) into an intermediate of formula (6) and,

e) converting intermediate of formula (6) to the compound of formula (7) by an intramolecular cyclisation reaction.

4. A method according to claim 1 for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7), which comprises the steps of:

a) condensing an intermediate of formula (1) with CHR²R⁵—

C(═

O)—

OR¹ wherein R⁵ represents a hydrogen, a carboxylic ester, a phosphonium salt or a phosphonate ester,

resulting in an α

,β

-unsaturated ester of formula (2)

b) reacting said ester of formula (2) with nitromethane resulting in an intermediate of formula (3),

c) submitting said intermediate of formula (3) to a Nef reaction by treating it with a base and subsequently with a strong acid resulting in a mixture of intermediates of formula (4) and (4′

),

d) only in case R² is different from hydrogen, decarboxylating the intermediates of formula (4) and (4′

) thus forming intermediates of formula (5) and (5′

) respectively,

e) reducing intermediates of formula (4) and (4′

), or intermediates of formula (5) and (5′

) with a suitable reducing agent resulting in intermediate of formula (6) and,

f) converting intermediate of formula (6) to the compound of formula (7) by an intramolecular cyclisation reaction.

5. A method according to claim 1 for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7.1) starting from an intermediate of formula (1), wherein P¹ and P² taken together form an isopropylidene,

6. A method according to claim 3 wherein intermediate of formula (3) is submitted to a Nef reaction using acidic quenching while keeping the temperature below −

10°

C. during said quenching.

7. A method according to claim 4 wherein the decarboxylation of intermediates of formula (4) and (4′

) is performed in a buffered aqueous solution.

8. A method according to claim 3 wherein intermediate (6) is prepared via reduction of intermediates of formula (4) and (4′

) or intermediates of formula (5) and (5′

) using lithium borohydride in tetrahydrofuran or NaBH₄ in the presence of LiCl.

9. A method according to claim 3 wherein the cyclisation of intermediate of formula (6) to the compound of formula (7) is performed by adding a strong acid to the reaction mixture containing intermediate of formula (6).

10. A method according to claim 9 wherein the cyclisation reaction is performed at a temperature lower then 5°

C.

11. A method according to claim 10 wherein the temperature of the reaction mixture while adding the strong acid to the reaction mixture remains lower than −

5°

C.

12. A method according to claim 1 wherein an intermediate of formula (3) is prepared by a process comprising the steps of first condensing an intermediate of formula (1) with nitromethane, resulting in an intermediate of formula (8) and secondly, reacting said intermediate of formula (8) with CHR²R⁸—

C(═

O)—

OR¹ wherein R⁸ is hydrogen or a carboxylic ester.

13. A method according to claim 12 wherein the carboxylic ester is defined as C(═

O)—

OR¹.

14. A method according to claim 1 wherein an intermediate of formula (6) is prepared by a process comprising the steps of first reducing intermediate of formula (3) wherein R² is hydrogen with a suitable reducing agent, resulting in an intermediate of formula (9) and secondly submitting the obtained intermediate of formula (9) to a Nef reaction by treatment with a base and then with a strong acid.

15. A method according to claim 1 wherein hexahydro-furo[2,3-b]furan-3-ol of formula (7) is isolated by adding a small excess of a tertiary amine, followed by the removal of water and removal of formed salts.

16. A method according to claim 1 wherein R¹ and R³ each independently are C_1-6alkyl, aryl or arylC_1-6alkyl or together with the atoms to which R¹ and R³ are attached form a 6 to 8-membered cyclic group optionally substituted with C_1-6alkyl, aryl or arylC_1-6alkyl, and wherein R⁴ is C_1-6alkyl.

17. A method according to claim 1 wherein R¹, R³ and R⁴ each independently are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl.

18. A method according to claim 1 wherein P¹ and P² together form an acid labile vicinal-diol protecting group.

19. A method according to claim 1 wherein P¹ and P² is a dialkyl methylene radical.

20. A method according to claims 4 wherein R⁵ is hydrogen, R¹O—

C(═

O)—

, (R⁶)₃P═

wherein R⁶ is alkyl, aryl or aralkyl, or (R⁷O)₂P(═

O)—

wherein R⁷ is alkyl, aryl, aralkyl.

21. An intermediate having the formula (3),

22. An intermediate having the formula (4) or (4′

),

23. An intermediate having the formula (5) or (5′

),

24. An intermediate according to claim 23 wherein the intermediate has the formula (5a)

25. An intermediate according to claim 24 in crystalline form.