Methods for the preparation of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol

• US 7,595,408 B2
• Filed: 03/31/2005
• Issued: 09/29/2009
• Est. Priority Date: 03/31/2004
• Status: Active Grant

• Current Assignee: Janssen Sciences Ireland Unlimited Company (Johnson & Johnson)
• Original Assignee: Tibotec Pharmaceuticals (Johnson & Johnson)
• Inventors: Quaedflieg, Peter Jan Leonard Mario, Liebregts, Constantinus Simon Maria, Vijn, Robert Jan, Lommen, Franciscus Alphons Marie, Kooistra, Jacob Hermanus Matheus Hero, Kesteleyn, Bart Rudolf Romanie
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US10/599,497
• Publication Number:
  US 20070208184A1
• Time in Patent Office: 1,643 Days
• Field of Search: 549/311, 549/302, 549/464
• US Class Current: 549/311
• CPC Class Codes: C07D 307/20 Oxygen atoms
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one.

Claims

1. A method for the synthesis of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol having the structure of formula (6),

2. A method according to claim 1 which method further comprises crystallizing intermediate of formula α

-(4) with a solvent prior to the reduction thereof.

3. A method according to claim 1 which method further comprises

a) epimerizing with acid intermediate of formula β

-(4) into the intermediate of formula α

-(4); and

4. A method according to claim 3 which method further comprises after crystallizing intermediate of formula α

-(4),

a) epimerizing with acid intermediate of formula β

-(4) in the mother liquor of said crystallization into the intermediate of formula α

-(4); and

5. A method according to claim 3 wherein the epimerization of compound of formula β

-(4) to compound of formula α

-(4) and crystallization of compound of formula α

-(4) occur simultaneously.

6. A method according to claim 5, wherein the simultaneous epimerization of compound of formula β

-(4) to compound of formula α

-(4) and the crystallization of compound of formula α

-(4) is performed in methanol in the presence of an acid by evaporation or partial evaporation of the methanol.

7. A method according to claim 1 which method comprises the steps of:

a) treating compound of formula (3) with a base and subsequently with an acid in the presence of a non-methanolic solvent; and

subsequently reacting with methanol under acidic conditions;

8. A method according to claim 7 wherein compounds of formula (3) are obtained by reacting compounds of formula (2) with nitromethane and a base

9. A method according to claim 8 wherein compounds of formula (2) are obtained by condensing an intermediate of formula (1) or its hydrate, hemihydrate or a mixture thereof with phosphonates of the formula (R⁶O)₂P(═

O)—

CH₂—

C(═

O)OR¹, wherein

P¹ and P² are as defined in claim 1,

R¹ is as defined in claim 1,

R⁶ is alkyl, aryl or aralkyl,

10. A method according to claim 7 wherein P¹ and P² together form a dialkyl methylene radical.

11. A method according to claim 8 wherein the base employed for the conversion of compounds of formula (2) into compounds of formula (3) is DBU or TMG or derivatives thereof.

12. A method according to claim 9 wherein the phosphonate of the formula (R⁶O)₂P(═

O)—

CH₂—

C(═

O)OR¹ is triethyl phosphonoacetate (TEPA).

13. A method according to claim 7 wherein the conversion of compounds of formula (3) into compounds of formula (4) is performed with a base selected from the group of sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof.

14. A method according to claim 8, wherein the conversion of compounds of formula (2) into compounds of formula (4) is performed by using DBU or TMG as the base in the conversion of compounds of formula (2) to compounds of formula (3), not isolating compounds of formula (3) and using sodium or lithium methoxide as additional base in the conversion of compounds of formula (3) to compounds of formula (4).

15. A method according to claim 7 wherein the acid employed in the conversion of compounds of formula (3) into compounds of formula (4) is concentrated sulphuric acid in an amount of 2.5 to 5 equivalents based on compound of formula (2) as a 20 to 80 wt % solution in methanol.

16. A method according to claim 2 wherein crystallization of compound of formula α

-(4) is performed in an alcohol.

17. A method according to claim 16 wherein the alcohol is isopropanol, t-amyl alcohol or t-butanol.

19. A method according to claim 3 wherein epimerization of compound of formula β

-(4) into compound of formula α

-(4) is performed with 0.05 to 1.5 equivalents of MeSO₃H in methanol.

20. A method according to claim 3 wherein the epimerization is performed at a temperature between 40°

C. and reflux temperature.

18. A method for the conversion of compound of formula β

-(4) into the compound of formula α

-(4) which comprises an epimerization with acid