# US 5,708,186 A · Stereoselective process

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- Number: US 5,708,186 A
- Document ID: US5708186A
- Status: Granted
- Kind: A
- Application number: 08/761,175
- Filed: 1996-12-06
- Granted: 1998-01-13
- Earliest claimed: 1996-12-06
- Inventors: Paul N. Devine; David M. Tschaen; Richard M. Heid, Jr.
- Web page: https://patentgrep.com/patent/US5708186A

## CPC

- C07D 295/185: from aliphatic carboxylic acids
- C07D 317/54: Radicals substituted by oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention relates to a method for the stereoselective synthesis of a 2-aryloxycarboxylic acid using a chiral auxiliary to enhance the stereoselectivity of the alkylation of the .alpha.-halo acid with an aryloxy group.

## Claims

### Claim 1

A process for the preparation of a compound of formula: ##STR42## wherein: * designates a stereogenic center;
R.sup.c is: a chiral auxiliary except R.sup.c cannot be ##STR43## R is (a) (C.sub.1 -C.sub.6)-alkyl,
(b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R.sup.4, R.sup.5 and R.sup.6 ;
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) --NH.sub.2,
(e) --NH(C.sub.1 -C.sub.4)-alkyl,
(f) --N›(C.sub.1 -C.sub.4)-alkyl!.sub.2,
(g) --SO.sub.2 NHR.sup.7,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.6)-alkyl,
(j) --OR.sup.7,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2).sub.m --OR.sup.7,
(p) --CONR.sup.7 R.sup.12,
(q) --COOR.sup.7, or
(r) -phenyl;
R.sup.4 and R.sup.5 on adjacent carbon atoms can be joined together to form a ring structure: ##STR44## A represents: (a) --Y--C(R.sup.8).dbd.C(R.sup.9)--,
(b) --Y--C(R.sup.8).dbd.N--,
(c) --Y--N.dbd.C(R.sup.8)--,
(d) --Y--›C(R.sup.10)(R.sup.10)!.sub.s --Y--,
(e) --Y--C(R.sup.8)(R.sup.8)--C(R.sup.8)(R.sup.8)--,
(f) --C(R.sup.8).dbd.C(R.sup.9)--Y--,
(g) --N.dbd.C(R.sup.8)--Y--,
(h) --C(R.sup.10)(R.sup.10)--C(R.sup.10)(R.sup.10)--Y--, or
(i) --C(R.sup.8 ).dbd.C(R.sup.9)--C(R.sup.8).dbd.C(R.sup.9)--;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is --O--, --S(O).sub.n -- and --N(R.sup.12)--;
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl,
(d) (C.sub.1 -C.sub.6)-alkylphenyl, or
(e) (C.sub.3 -C.sub.7)-cycloalkyl;
R.sup.8 and R.sup.9 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.7,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.12, or
ix) --CONR.sup.7 R.sup.12,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.7,
(g) --CONR.sup.7 R.sup.12,
(h) --NR.sup.7 R.sup.12,
(i) --NR.sup.7 CONR.sup.7 R.sup.12,
(j) --NR.sup.7 COOR.sup.12,
(k) --SO.sub.2 NR.sup.7 R.sup.12,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.12 ;
R.sup.10 is:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl unsubstituted or substituted with one of the following substituents:
i) --OH,
ii) --NR.sup.7 R.sup.12,
iii) --COOR.sup.7,
iv) --CONHR.sup.7, or
v) --CONR.sup.7 R.sup.12, or
(c) Cl, or F;
R.sup.12 is
(a) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) --OR.sup.7,
ii) --N›R.sup.7 !.sub.2,
iii) --NH.sub.2,
iv) --COOR.sup.7,
v) --N›CH.sub.2 CH.sub.2 !.sub.2 Q,
vi) --CF.sub.3, or
vii) --CON(R.sup.7).sub.2 ;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CO›NR.sup.7 !.sub.2,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) --NH.sub.2,
vii) --NH›(C.sub.1 -C.sub.4)-alkyl!,
viii) --N›(C.sub.1 -C.sub.4)-alkyl!.sub.2, or
ix) --CON›CH.sub.2 CH.sub.2 !.sub.2 Q;
(c) --(C.sub.1 -C.sub.4)-alkylaryl, wherein aryl is as defined above,
(d) (C.sub.3 -C.sub.7)-cycloalkyl,
(e) ##STR45## or (f) CF.sub.3 ;
R.sup.7 and R.sup.12 on the same nitrogen atom they may join together to form a ring selected from the group consisting of: morpholinyl, piperazinyl, or pyrrolyl, or
Q is O, S or --NR.sup.7 ;
which comprises alkylating a derivative ##STR46## wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate; with an aryloxy derivative: ##STR47## wherein M.sup.+ is Na.sup.+, K.sup.+, Li.sup.+, or N(R.sup.16).sub.4.sup.+ ; and R.sup.16 is H or (C.sub.1 -C.sub.6)-alkyl;
in an organic solvent at a temperature range of about -60.degree. C. to about 30.degree. C. for about 30 minutes to 30 hours to give an alkylated derivative bearing the chiral auxiliary: ##STR48##

### Claim 2 (depends on 1)

The method as recited claim 1, wherein: R.sup.c is selected from the group consisting of: ##STR49## R.sup.a is (C.sub.1 -C.sub.6)-alkyl, phenyl or cyclohexyl; R.sup.13 is (C.sub.1 -C.sub.6)-alkyl, phenyl or cyclohexyl; and
R.sup.14 and R.sup.15 are independently: (C.sub.1 -C.sub.10)-alkyl, or R.sup.14 and R.sup.15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.

### Claim 3 (depends on 2)

The method as recited claim 2, wherein R.sup.c is: ##STR50##

### Claim 4 (depends on 3)

The method as recited claim 3, wherein the organic solvent in the alkylation step is tetrahydrofuran and t-butanol.

### Claim 5 (depends on 4)

The method as recited claim 4, wherein M.sup.+ in the alkylation step is Li.sup.+.

### Claim 6 (depends on 5)

The method as recited claim 5, wherein the reaction time in the alkylation step is about one hour.

### Claim 7 (depends on 6)

The method as recited claim 6, wherein the reaction temperature in the alkylation step is about room temperature.