Stereospecific process for 3-heterocyclylcycloaliphatic-1,2-diols

Patent metadata

Field	Value
Publication number	US-10450282-B2
Application number	US-201615750388-A
Country	US
Kind code	B2
Filing date	Aug 5, 2016
Priority date	Aug 6, 2015
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

A process for the stereoselective synthesis of chiral 3-heterocyclyl-1,2-dihydroxy cyclohexanes is disclosed. The process involves reacting a tricyclic nitrogenous heterocycle with an allyl carbonate in the presence of a chiral palladium catalyst followed by oxidation of the olefinic bond to provide 3-heterocyclyl-1,2-dihydroxy cyclohexanes, cyclopentanes and corresponding alicyclic heterocycles. Also disclosed are methods for converting the heterocyclyl-1,2-dihydroxy cyclohexanes to 2-amino-6-(heteroaryl)cyclohexanols (and related cyclic compounds).

First claim

The invention claimed is:

1. A process for preparing a substantially enantiomerically pure compound of formula (I):

wherein:
A is selected from the group consisting of a direct bond, —SO 2 —, and —C(═O)—;
B is selected from the group consisting of a direct bond, —O—, —SO— and —SO 2 —;
T is a benzene ring or a five or six membered heteroaromatic ring;
U is a benzene ring or a five or six membered heteroaromatic ring; and
R 1 , R 2 , R 3 and R 4 are chosen independently from H, OH, halogen, cyano, nitro, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )haloalkylthio, —CC(═O)O(C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy;
Q is chosen from direct bond, —CH 2 —, —CH 2 CH 2 —, —O—, —CH(OH)—, —CH(COOR 5 )—, —CH(CONR′R″)—, —CH(CH 2 )NR′R″, —CH(CN)—, —S(O) n —, —CH(NHBoc), —CH(NHCBZ), —NR 6 —,

R 5 is H or (C 1 -C 4 )alkyl;
R 6 is chosen from (C 1 -C 4 )alkyl, (C 1 -C 4 )acyl, (C 4 -C 7 )alkoxycarbonyl, and benzyloxycarbonyl;
R′ and R″ are independently chosen from H, lower alkyl, substituted alkyl, aryl, substituted aryl; or R′ and R″ together with the nitrogen to which they are attached, may form an optionally substituted heterocyclic ring;
said process comprising:
(a) reacting a compound of formula II

with a compound of formula III

wherein R 7 is (C 1 -C 4 )alkyl,
in the presence of a chiral palladium catalyst to provide a product of formula IV

and
(b) oxidizing said product of formula IV with osmium tetroxide to provide I.

2. The process of claim 1 wherein said compounds II and III are reacted in the presence of a chiral palladium catalyst formed from a chiral ligand and a palladium compound chosen from tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, and allylpalladium chloride dimer.

3. The process of claim 2 wherein said chiral ligand is chosen from (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP), 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole (SEGPHOS), 1,2-diaminocyclohexane-N,N′-bis(2-diphenylphosphinobenzoyl) (DACH-phenyl), and 1,2-diaminocyclohexane-N,N′-bis(2-diphenylphosphino-1-naphthoyl) (DACH-naphthyl).

4. The process of claim 1 wherein one of rings T and U is benzene and the other is pyridine, pyrimidine or thiene.

5. The process of claim 1 wherein both of rings T and U are benzene.

6. The process of claim 1 , wherein Q is chosen from —CH 2 —, —O—, —N(Boc)-, —N(Cbz)-, —N(CH 3 )—, and —N(Ac)-.

7. The process of claim 1 wherein A is a direct bond.

8. The process of claim 2 wherein said chiral palladium catalyst is derived from tris(dibenzylideneacetone)dipalladium and a chiral ligand containing the trans-1,2-diaminocyclohexane (DACH) moiety.

9. The process of claim 1 wherein said compound IV is oxidized with osmium tetroxide in the presence of 4-methylmorpholine N-oxide.

10. The process of claim 1 wherein R 1 , R 2 , R 3 and R 4 are chosen independently from H, F, Cl, CH 3 , NO 2 , CF 3 , OCF 3 , OCH 3 , and SCF 3 .

11. The process of claim 10 wherein three of R′, R 2 , R 3 and R 4 are H and the fourth is chosen from H, F, Cl, CH 3 , NO 2 , CF 3 , OCF 3 , OCH 3 , and SCF 3 .

12. The process of claim 1 wherein A is SO 2 .

Assignees

• Icahn School Med Mount Sinai

Inventors

• Ohlmeyer Michael
• Zaware Nilesh
• Kastrinsky David

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D419/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D307/30

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D309/28

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title