Quaternary heteroatom containing compounds

Patent metadata

Field	Value
Publication number	US-10906875-B2
Application number	US-201916427629-A
Country	US
Kind code	B2
Filing date	May 31, 2019
Priority date	Jun 24, 2011
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II):

comprising treating a compound of Formula (I):

with a transition metal catalyst and under alkylation conditions as valence and stability permit.

First claim

What is claimed is:

1. A method of synthesizing a pharmaceutical compound comprising treating a compound of Formula (III):

with a transition metal catalyst under alkylation conditions, thereby forming a compound of Formula (IV):

wherein the compound of Formula (IV) comprises one of a (+) enantiomer or a (−) enantiomer in an enantiomeric excess of greater than 50%,
wherein the transition metal catalyst is selected from Mo(CO) 6 , Mo(MeCN) 3 (CO) 3 , W(CO) 6 , W(MeCN) 3 (CO) 3 , [Ir(1,5-cyclooctadiene)Cl] 2 , [Ir(1,5-cyclooctadiene)Cl] 2 , [Ir(1,5-cyclooctadiene)Cl] 2 , Rh(PPh 3 ) 3 Cl, [Rh(1,5-cyclooctadiene)Cl] 2 , Ru(pentamethylcyclopentadienyl)(MeCN)3PF 6 , Ni(1,5-cyclooctadiene) 2 , Ni[P(OEt) 3 ] 4 , tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(4-methoxybenzylidene)acetone)dipalladium(0), Pd(OC(═O)CH 3 ) 2 , Pd(3,5-dimethyoxy-dibenzylideneacetone) 2 , PdCl 2 (R 23 CN) 2 ; PdCl 2 (PR 24 R 25 R 26 ) 2 ; [Pd(η 3 -allyl)Cl] 2 ; and Pd(PR 24 R 25 R 26 ) 4 , wherein R 23 , R 24 , R 25 , and R 26 are independently selected from H, alkyl, alkenyl, alkynyl, carbocycle, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II-), ([2S,3S]-bis[diphenylphosphino]butane)(η 3 -allyl)palladium(II) perchlorate, [S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η- 3 -allyl)palladium(II) hexafluorophosphate, [Pd(S-tBu-PHOX)(allyl)]PF 6 , and cyclopentadienyl(η 3 -allyl) palladium(II);
wherein, as valence and stability permit,
X is selected from —NR 6 — and —O—;
Z is selected from —C(O)— and —CR 7 R 7 —;
A is independently selected at each occurrence from —CR 8 R 8 — and —NR 9 —;
W is absent or selected from —O—, —NR 10 —, and —CR 11 R 11 —;
R 1 is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;
R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15 are independently selected at each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
R 7 , R 8 , and R 11 are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
wherein R 7 and R 8 may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, R 8 and R 11 may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, and when n is 2 or 3, R 8 attached to one carbon may combine with R 8 attached to another carbon to combine with the carbons to which they are bound to form a 3-8-membered ring;

R 6 , R 9 and R 10 are independently selected at each occurrence from hydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide; and
n is 0-3.

2. The method of claim 1 , wherein:
X is —NR 6 —;
A at each occurrence is —CR 8 R 8 —;
W is selected from —NR 10 — and —CR 11 R 11 —; and
n is 0-2.

3. The method of claim 1 , wherein:
X is —O—;
A at each occurrence is —CR 8 R 8 —;
W is selected from —NR 10 —, and —CR 11 R 11 —; and
n is 0-2.

4. The method of claim 1 , wherein the method further comprises a chiral ligand.

5. A method comprising
treating a compound of Formula (III):

with a transition metal catalyst under alkylation conditions, wherein the transition metal catalyst is selected from Mo(CO) 6 , Mo(MeCN) 3 (CO) 3 , W(CO) 6 , W(MeCN) 3 (CO) 3 , [Ir(1,5-cyclooctadiene)Cl] 2 , [Ir(1,5-cyclooctadiene)Cl] 2 , [Ir(1,5-cyclooctadiene)Cl] 2 , Rh(PPh 3 ) 3 Cl, [Rh(1,5-cyclooctadiene)Cl] 2 , Ru(pentamethylcyclopentadienyl)(MeCN)3PF 6 , Ni(1,5-cyclooctadiene)2, Ni[P(OEt) 3 ] 4 , tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(4-methoxybenzylidene)acetone)dipalladium(0), Pd(OC(═O)CH 3 ) 2 , Pd(3,5-dimethyoxy-dibenzylideneacetone) 2 , PdCl 2 (R 23 CN) 2 ; PdCl 2 (PR 24 R 25 R 26 ) 2 ; [Pd(η 3 -allyl)Cl] 2 ; and Pd(PR 24 R 25 R 26 ) 4 , wherein R 23 , R 24 , R 25 , and R 26 are independently selected from H, alkyl, alkenyl, alkynyl, carbocycle, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, allylchloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II-), ([2S,3S]-bis[diphenylphosphino]butane)(η 3 -allyl)palladium(II) perchlorate, [S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η- 3 -allyl)palladium(II) hexafluorophosphate, [Pd(S-tBu-PHOX)(allyl)]PF 6 , and cyclopentadienyl(η 3 -allyl) palladium(II);
wherein, as valence and stability permit,
X is selected from —NR 6 — and —O—;
Z is selected from —C(O)— and —CR 7 R 7 —;
A is independently selected at each occurrence from —CR 8 R 8 — and —NR 9 —;
W is absent or selected from —O—, —NR 10 —, and —CR 11 R 11 —;
R 1 is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen;
R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15 are independently selected at each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
R 7 , R 8 , and R 11 are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
wherein R 7 and R 8 may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, R 8 and R 11 may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, and when n is 2 or 3, R 8 attached to one carbon may combine with R 8 attached to another ca

Assignees

• California Inst Of Techn

Inventors

• Stoltz Brian M
• Virgil Scott C
• White David E
• Yurino Taiga
• Liu Yiyang
• Behenna Douglas C
• Duquette Douglas
• Eidamshaus Christian

Classifications

• C07D211/78 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D211/18

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C07D207/277

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

• C07D207/267

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom · CPC title