Process for the synthesis of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
The present invention is concerned with novel processes for the preparation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. These compounds have pharmaceutical utility and are known to be useful for treating e.g., depression, anxiety disorders, eating disorders and urinary incontinence.
1. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof, comprising:
contacting 3,4-dichlorophenylacetonitrile and (S)-epichlorohydrin of the formula:
in the presence of a base, to give cyclopropyl compounds of the formula II:
followed by reducing the compounds of formula II with a reducing agent to give amino alcohol compounds of the formula III:
followed by chlorinating the compounds of formula III with a chlorinating agent to give chloro compounds of the formula IV:
followed by cyclodehydration of the compounds of the formula IV with a base to give the compound of formula I, or a pharmaceutically acceptable salt thereof.
2. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof, comprising:
cyclodehydration of the compound of the formula IV-I:
with a base to give the compound of formula I, or a pharmaceutically acceptable salt thereof.
3. The process of claim 1 wherein the step of contacting 3,4-dichlorophenyl-acetonitrile and (S)-epichlorohydrin in the presence of a base to give cyclopropyl compounds of the formula II, the base is selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide, potassium t-pentoxide, potassium amylate, lithium diisopropylamide (LDA), lithium tetramethylpiperidide (LiTMP), sec-butyllithium, and tert-butyllithium.
4. The process of claim 3 wherein the base is selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and lithium hexamethyldisilazide (LiHMDS).
5. The process of claim 4 wherein the base is sodium hexamethyldisilazide (NaHMDS).
6. The process of claim 1 wherein the step of reducing of the compounds of the formula II with a reducing agent to give amino alcohol compounds of the formula III, the reducing agent is selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride-borontrifluoride etherate, a dialkylborane, 9-borabicyclo[3.3.1]-nonane (9-BBN), and lithium aluminum hydride (LAH).
7. The process of claim 6 wherein the reducing agent is borane dimethyl sulfide complex.
8. The process of claim 1 wherein the step of chlorinating the compounds of the formula III with a chlorinating agent to give chloro compounds of the formula IV, the chlorinating agent is selected from thionyl chloride, SO 2 Cl 2 , and Ph 3 P/CCl 4 .
9. The process of claim 8 wherein the chlorinating agent is thionyl chloride.
10. The process of claim 1 wherein the step of cyclodehydration of the compounds of the formula IV with a base to give the compound of formula I, the base is selected from sodium hydroxide, potassium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, Et 3 N, i-Pr 2 NEt, DABCO and DBU.
11. The process of claim 10 wherein the base is sodium hydroxide.
12. The process of claim 1 wherein the steps are conducted sequentially without isolation of the compounds of formula II, formula III, or formula IV.
13. The process of claim 1 , further comprising isolating the compound of formula I or a pharmaceutically acceptable salt thereof.
14. The process of claim 1 , further comprising isolating a pharmaceutically acceptable salt of formula I.
15. The process of claim 2 , further comprising isolating the compound of formula I or a pharmaceutically acceptable salt thereof.
16. The process of claim 2 , further comprising isolating a pharmaceutically acceptable salt of formula I.
17. The process of claim 2 , wherein the compound of the formula IV-I is prepared by chlorinating compounds of formula III:
with a chlorinating agent.
18. A compound which is selected from the group consisting of:
or a salt thereof.
19. A compound which is selected from the group consisting of:
or a salt thereof.