US2002161244A1PendingUtilityA1
Preparation of cis-6,6-dimethyl-3-oxa-bicyclo(3.1.0)hexan-2-one
Priority: Apr 22, 1998Filed: Apr 29, 2002Published: Oct 31, 2002
Est. expiryApr 22, 2018(expired)· nominal 20-yr term from priority
C07D 307/32C07D 307/77C07C 61/35C07D 307/93C07D 307/33
35
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Claims
Abstract
The invention provides a process for preparing an enantiomerically enriched cis-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexan-2-one by reacting a sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y .
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for preparing an enantiomerically enriched cis-6,6-dimethyl-3-oxa-bicyclo(3.1.0)hexan-2-one comprising:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; and c) reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in an ether or polar solvent; wherein M is an alkali metal and y is 1; M is a quaternary ammonium cation and y is 1; or M is an alkaline earth metal cation and y is 2.
2 . The process of claim 1 , comprising forming the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone by performing a Sharpless asymmetric dihydroxylation of a C 1-4 alkyl ester of 3,3-dimethyl-4-pentenoate.
3 . The process of claim 1 , wherein the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone is formed by reacting a sulphonic acid chloride with the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone.
4 . The process of claim 1 , wherein the C 1-6 alkoxide is tert-butoxide.
5 . The process of claim 1 , wherein the alkali metal is sodium or potassium; wherein the quaternary ammonium cation is NH 4 or N(CH 3 ) 4 ; and wherein the alkaline earth metal cation is calcium or magnesium.
6 . The process of claim 1 , wherein M(C 1-6 alkoxide) y is potassium tert-butoxide.
7 . The process of claim 1 , wherein the sulphonic ester is an alkylsulphonyl ester or a phenylsulphonyl ester.
8 . The process of claim 1 , wherein the sulphonic ester is a mesyl ester or a tosyl ester.
9 . The process of claim 1 , wherein the ether solvent is tetrahydrofuran; and wherein the polar solvent is N,N-dimethylformamide.
10 . The process of claim 1 , wherein the enantiomerically enriched cis-6,6-dimethyl-3-oxa-bicyclo(3.1.0)hexan-2-one has an enantiomeric excess greater than 90%.
11 . The process of claim 10 , wherein the enantiomerically enriched cis-6,6-dimethyl -3-oxa-bicyclo(3.1.0)hexan-2-one has an enantiomeric excess greater than 98%.
12 . A process for preparing an enantiomerically enriched compound of formula (VI):
wherein X and Y are independently halogen, C 1-3 alkyl or C 1-3 haloalkyl;
comprising the steps of:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; and
c) forming an enantiomerically enriched 6,6-dimethyl-3-oxabicyclo(3.1.0)hexan-2-one by reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in an ether or polar solvent; wherein M is an alkali metal and y is 1; M is a quaternary ammonium cation and y is 1; or M is an alkaline earth metal cation and y is 2;
d) forming an enantiomerically enriched compound of formula (VII):
by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan-2-one; and
e) ring opening the enantiomerically enriched compound of formula (VII) to produce the enantiomerically enriched compound of formula (VI).
13 . The process of claim 12 , wherein the compound of formula (VII) is produced by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan-2-one in a DIBAL solution in the presence of a solvent at a low temperature.
14 . The process of claim 13 , wherein the solvent is tetrahydrofuran.
15 . The process of claim 12 , wherein X and Y are independently fluorine, chlorine, bromine, methyl or trifluoromethyl.
16 . The process of claim 12 , comprising forming the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone by performing a Sharpless asymmetric dihydroxylation of a C 1-4 alkyl ester of 3,3-dimethyl-4-pentenoate.
17 . The process of claim 12 , wherein the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone is formed by reacting a sulphonic acid chloride with the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone.
18 . The process of claim 12 , wherein the C 1-6 alkoxide is tert-butoxide.
19 . The process of claim 12 , wherein the alkali metal is sodium or potassium; wherein the quaternary ammonium cation is NH 4 or N(CH 3 ) 4 ; and wherein the alkaline earth metal cation is calcium or magnesium.
20 . The process of claim 12 , wherein M(C 1-6 alkoxide) y is potassium tert-butoxide.
21 . The process of claim 12 , wherein the sulphonic ester is an alkylsulphonyl ester or a phenylsulphonyl ester.
22 . The process of claim 12 , wherein the sulphonic ester is a mesyl ester or a tosyl ester.
23 . The process of claim 12 , wherein the ether solvent is tetrahydrofuran; and wherein the polar solvent is N,N-dimethylformamide.
24 . The process of claim 12 , wherein the enantiomerically enriched compound of formula (VI) has an enantiomeric excess greater than 90%.
25 . The process of claim 24 , wherein the enantiomerically enriched compound of formula (VI) has an enantiomeric excess greater than 98%.
26 . A process for producing an enantiomerically enriched compound of formula (V):
wherein X and Y are each independently halogen, C 1-3 alkyl or C 1-3 haloalkyl;
comprising the steps of:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
c) forming an enantiomerically enriched 6,6-dimethyl-3-oxabicyclo(3.1.0)hexan-2-one by reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in an ether or polar solvent; wherein M is an alkali metal and y is 1; M is a quaternary ammonium cation and y is 1; or M is an alkaline earth metal cation and y is 2;
d) forming an enantiomerically enriched compound of formula (VII):
by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan-2-one;
e) ring opening the enantiomerically enriched compound of formula (VII) to produce an enantiomerically enriched compound of formula (VI):
wherein X and Y are as defined herein; and
f) oxidizing the enantiomerically enriched compound of formula (VI) to form the enantiomerically enriched compound of formula (V).
27 . The process of claim 26 , wherein the compound of formula (VII) is produced by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan-2-one in a DIBAL solution in the presence of a solvent at a low temperature.
28 . The process of claim 27 , wherein the solvent is tetrahydrofuran.
29 . The process of claim 26 , wherein X and Y are independently fluorine, chlorine, bromine, methyl or trifluoromethyl.
30 . The process of claim 26 , comprising forming the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone by performing a Sharpless asymmetric dihydroxylation of a C 1-4 alkyl ester of 3,3-dimethyl-4-pentenoate.
31 . The process of claim 26 , wherein the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone is formed by reacting a sulphonic acid chloride with the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone.
32 . The process of claim 26 , wherein the C 1-6 alkoxide is tert-butoxide.
33 . The process of claim 26 , wherein the alkali metal is sodium or potassium; wherein the quaternary ammonium cation is NH 4 or N(CH 3 ) 4 ; and wherein the alkaline earth metal cation is calcium or magnesium.
34 . The process of claim 26 , wherein M(C 1-6 alkoxide) 6 is potassium tert-butoxide.
35 . The process of claim 26 , wherein the sulphonic ester is an alkylsulphonyl ester or a phenylsulphonyl ester.
36 . The process of claim 26 , wherein the sulphonic ester is a mesyl ester or a tosyl ester.
37 . The process of claim 26 , wherein the ether solvent is tetrahydrofuran; and wherein the polar solvent is N,N-dimethylformamide.
38 . The process of claim 26 , wherein the enantiomerically enriched compound of formula (V) has an enantiomeric excess greater than 90%.
39 . The process of claim 38 , wherein the enantiomerically enriched compound of formula (V) has an enantiomeric excess greater than 98%.
40 . A sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone.
41 . The sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone recited in claim 40 , wherein the sulphonic ester is an alkylsulphonyl ester or a phenylsulphonyl ester.
42 . The sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone recited in claim 40 , wherein the sulphonic ester is a mesyl ester or a tosyl ester.
43 . The sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone recited in claim 40 , wherein the sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone is enantiomerically enriched.
44 . The sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone recited in claim 43 , wherein the sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone has an enantiomeric excess greater than 90%.
45 . The sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone recited in claim 44 , wherein the sulphonic ester of β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone has an enantiomeric excess greater than 98%.
46 . A process for preparing cis-6,6-dimethyl-3-oxa-bicyclo(3.1.0)hexan-2-one comprising:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; and c) reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in a suitable solvent, wherein M is a suitable cation and y fulfills valency requirements.
47 . A process for preparing an enantiomerically enriched compound of formula (VI):
wherein X and Y are independently halogen, C 1-3 alkyl or C 1-3 haloalkyl;
comprising the steps of:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone; and
c) forming an enantiomerically enriched 6,6-dimethyl-3-oxabicyclo(3.1.0)hexan-2-one by reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in a suitable solvent, wherein M is a suitable cation and y fulfills valency requirements;
d) forming an enantiomerically enriched compound of formula (VII):
by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan-2-one; and
e) ring opening the enantiomerically enriched compound of formula (VII) to produce the enantiomerically enriched compound of formula (VI).
48 . A process for producing an enantiomerically enriched compound of formula (V):
wherein X and Y are each independently halogen, C 1-3 alkyl or C 1-3 haloalkyl;
comprising the steps of:
a) forming an enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
b) forming a sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone;
c) forming an enantiomerically enriched 6,6-dimethyl-3-oxabicyclo(3.1.0)hexan-2-one by reacting the sulphonic ester of the enantiomerically enriched β,β-dimethyl-γ-(hydroxymethyl)-γ-butyrolactone with a compound of formula M(C 1-6 alkoxide) y in a suitable solvent; wherein M is suitable cation and y fulfills the valency requirements;
d) forming an enantiomerically enriched compound of formula (VII):
by reducing the enantiomerically enriched 6,6-dimethyl-3oxabicyclo(3.1.0)hexan- 2-one;
e) ring opening the enantiomerically enriched compound of formula (VII) to produce an enantiomerically enriched compound of formula (VI):
wherein X and Y are as defined herein; and
f) oxidizing the enantiomerically enriched compound of formula (VI) to form the enantiomerically enriched compound of formula (V).Join the waitlist — get patent alerts
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