Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof
View Patent ↗The present invention provides for a process for preparing racemic methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate, its corresponding salt: (2S, 3R, 4S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-D-tartaric acid (“D-DTTA”) salt or a (2R, 3S, 4R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-L-tartaric acid salt (“L-DTTA”) in a high enantiomeric excess. This invention also provides for a process for preparing a (2S, 3R, 4S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate dibenzoyl-D-tartaric acid (“D-DBTA”) salt or a (2R, 3S, 4R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate L-tartaric acid (“L-DBTA”) salt in a high enantiomeric excess. Further, this invention provides a process for preparing intermediates II, IIB, III, IV, IV salt, V, VI, and VII.
1. A process for preparing a (1R, 2S, 5S) salt of Formula IA or a (1S, 2R, 5R) salt of Formula IaA:
wherein
R represents an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl substituted aralkyl, cycloalkyl, or substituted cycloalkyl group; “Xd” is selected from D-DTTA (di-p-toluoyl-D-tartaric acid) and D-DBTA (dibenzoyl-D-tartaric acid), and “XI” is selected from L-DTTA (di-p-toluoyl-L-tartaric acid) and L-DBTA (dibenzoyl-L-tartaric acid), said process comprising:
(i) converting a compound of formula II
to a compound of formula III:
(ii) reducing the compound of formula III to yield a compound of formula IV:
(iii) oxidizing the compound of formula IV to yield the racemic mixture comprising the imines of formulae Va and Vb:
(iv) cyanating the racemic mixture of the imines of formulae Va and Vb to form a racemic mixture of trans-compounds of formula VI:
(v) optionally without isolation, performing a solvolysis on the formula VI racemic mixture of compounds with ROH, where R is defined above, to form the formula VII racemic mixture of compounds:
and
(vi) reacting the formula VII racemic mixture of compounds with an acid selected from: (i) di-p-toluoyl-D-tartaric acid and dibenzoyl-D-tartaric acid to form the salt compound of Formula IA,
and (ii) di-p-toluoyl-L-tartaric acid and dibenzoyl-L-tartaric acid salt to form the salt compound of formula IaA,
wherein R, XI, and Xd are as defined above.
2. The process according to claim 1 , wherein R is alkyl.
3. The process according to claim 1 , wherein R is (C 1 -C 8 )alkyl.
4. The process according to claim 1 , wherein R is benzyl or phenyl.
5. The process according to claim 1 , wherein the compound of formula II is converted to a compound of formula III in one step.
6. The process according to claim 1 , wherein the compound of Formula II is converted to a compound of Formula III in a process comprising a first step of converting the compound of Formula II to a compound of formula IIB wherein R 1 is aralkyl, substituted aralkyl, or alkenyl; and
a second step of converting a compound of Formula IIB to a compound of Formula III.
7. The process according to claim 6 , wherein R 1 is benzyl or allyl.
8. The process according to claim 1 wherein the formula VII racemic mixture of compounds is reacted with di-p-toluoyl-D-tartaric acid to precipitate a (1R, 2S, 5S)-I di-p-toluoyl-D-tartaric acid salt of a compound of formula IA.
9. The process according to claim 8 , wherein the enantiomer excess in the precipitate is 90-98% ee.
10. The process according to claim 8 , wherein the enantiomer excess in the precipitate is 94-96% ee.
11. The process according to claim 1 , wherein the racemate of formula VII is reacted with di-p-toluoyl-L-tartaric acid to precipitate a (1S, 2R, 5R)-I di-p-toluoyl-L-tartaric acid salt of a compound of formula IaA.
12. The process according to claim 11 , wherein the enantiomer excess in the precipitate is 90-98% ee.
13. The process according to claim 11 , wherein the enantiomer excess in the precipitate is 95-97% ee.
14. The process of claim 11 wherein “R” is methyl.
15. The process of claim 11 further comprising a step wherein the precipitate is separated from the supernatant and the supernatant is reacted with di-p-toluoyl-D-tartaric acid to precipitate a (1R, 2S, 5S)-I di-p-toluoyl-D-tartaric acid salt of a compound of formula IA.
16. The process of claim 1 wherein conversion Step 1 is carried out using DMAP and formamide.
17. The process of claim 1 wherein conversion Step 1 is carried out using ammonium hydroxide and butyl acetate.
18. The process according to claim 1 , wherein the reducing agent in reducing Step 2 is selected from the group consisting of lithium aluminum hydride, lithium borohydride, sodium bis(2-methoxyethoxy)aluminum dihydride, and borane.
19. The process according to claim 1 , wherein the oxidizing agent in oxidizing Step 3 is selected from the group consisting of K 2 S 2 O 8 /AgNO 3 ; iodosobenzene; manganese (IV) dioxide; and H 2 O 2 /[(R,R)- or (S,S)-Salen]Mn III Cl.
20. The process according to claim 1 , wherein the oxidizing Step 3 further comprises isolating the product compound of Formula (V) by extracting the reaction mixture with MTBE, adding methanol the MTBE extract and distilling off the MTBE to provide a methanol solution of the compound of Formula (V).
21. The process according to claim 1 , wherein the cyanating agent in cyanating Step 4 is selected from: (i) HCN; and (ii) an KCN, NaCN, and trimethylsilyl cyanide (TMSCN) in the presence of an acid.
22. The process according to claim 1 , wherein the solvent for the solvolysis Step 5 is methanol.
23. The process according to claim 1 , wherein solvolysis Step 5 further comprises an acid selected from the group consisting of HCl, HBr, Hl, and H 2 SO 4 .
24. The process according to claim 1 wherein the formula VII racemic mixture of compounds is reacted with dibenzoyl-D-tartaric acid to precipitate a (1R, 2S, 5S)-I dibenzoyl-D-tartaric acid salt of the compound of formula IA.
25. The process according to claim 24 , wherein the enantiomer excess is 85% ee-95% ee.
26. The process according to claim 25 , wherein the enantiomer excess is 85% ee-90% ee.
27. The process according to claim 1 , wherein the racemate of formula VII is reacted with dibenzoyl-L-tartaric acid to precipitate a (1S, 2R, 5R)-I dibenzoyl-L-tartaric acid salt of a compound of formula IaA.
28. The process according to claim 27 , wherein the enantiomer excess in the precipitate is 85% ee-95% ee.
29. The process according to claim 28 , wherein the enantiomer excess in the precipitate is 85% ee-90% ee.
30. The process of claim 27 wherein “R” is methyl.
31. The process of claim 30 further comprising a step wherein the precipitate is separated from the supernatant and the supernatant is reacted with di-p-toluoyl-D-tartaric acid to precipitate a (1R, 2S, 5S)-I di-p-toluoyl-D-tartaric acid salt of a compound of formula IA.
32. The process of claim 24 wherein “R” is methyl.