CA2238960A1 - Stereoselective process - Google Patents
Stereoselective process Download PDFInfo
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- CA2238960A1 CA2238960A1 CA 2238960 CA2238960A CA2238960A1 CA 2238960 A1 CA2238960 A1 CA 2238960A1 CA 2238960 CA2238960 CA 2238960 CA 2238960 A CA2238960 A CA 2238960A CA 2238960 A1 CA2238960 A1 CA 2238960A1
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- Prior art keywords
- alkyl
- phenyl
- coor7
- group
- aryl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
This invention relates to a method for the stereoselective synthesis of a 2aryloxycarboxylic acid using a chiral auxiliary to enhance the stereoselectivity of the alkylation of the .alpha.-halo acid with an aryloxy group.
Description
W097/21693 PCT~US96~19782 TITLE QF THE INVENTION
STEREOSELECTIVE PROCESS
BACKGROUND OF THE ~VENTION
During the development of a commercially viable asymmetric synthesis of a potent endothelin antagonist, a highly stereoselective synthesis of a key interrnediate, a 2-aryloxycarboxylic acid needed to ~oe developed. A variety of methods of general applicability have been worked out by Durst and Koh utilizing (R)-l O pantolactone as a chiral auxiliary. ~See Koh, K.; Durst7 T. J. Org.
Chem. 1994, 59, 4683.] Pantolactone esters of racemic a-halo acids have been coupled to a variety of phenoxides. Diastereoselectivities ranging from 76-90~o have been obtained in this fashion with the "S"
stereochemistry predomin~ting at the newly formed asymmetric center.
I 5 The "R" stereochemistry can be obtained utilizing (S)-ethyl lactate as the chiral auxiliary although diastereoselectivities are significantly lowered in comparison to pantolactone (60-75%). [For other diastereoselective reactions utilizing pantolactone or ethyl lactate see: (a) Lar.sen, R.D.;
Corley, E.G.; Davis, P.; Reider, P.J., Grabowski, E.J.J. J. Am.
Chem. Soc. 1989, 111, 7650. (b) Koh, K.; Ben, R.N.; Durst, T.
Tetrahedron Lett. 1994, 35, 375. (c) Koh, K.; 13en, R.N.; Durst, T.
T~trahed~ on Lett. 1993, 34, 4473.~ The reaction i~ also characterized by sluggish rates and moderate yields.
The instant invention relates to a highly stereoselective 2 5 coupling reaction mediated ~ith a pyrrolidine derived lactamide as a chiral auxiliary.
W O 97/21693 PCT~US96/19782 SUMMARY OF THE INVENTION
This invention relates to a method for the stereoselective synthesis of a 2-aryloxycarboxylic acid using a chiral auxiliary, such as a compound of formula I to enhance the stereoselectivity of the 5 alkylation of the oc-halo acid with an aryloxy group. The invention also relates to a novel compound of formula:
o N~
Ra wherein: Ra is (Cl-C6)-alkyl, phenyl, or cyclohexyl, which is useful as a chiral auxiliary. Another aspect of this invention is a compound of 1 0 formula:
X
R~ RC
o wherein:
X is Cl, Br, I, Omesylate, Otosylate, Otriflate;
Rc is: a chiral auxiliary;
R is: (Cl-C6)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted as defined hereinbelow.
STEREOSELECTIVE PROCESS
BACKGROUND OF THE ~VENTION
During the development of a commercially viable asymmetric synthesis of a potent endothelin antagonist, a highly stereoselective synthesis of a key interrnediate, a 2-aryloxycarboxylic acid needed to ~oe developed. A variety of methods of general applicability have been worked out by Durst and Koh utilizing (R)-l O pantolactone as a chiral auxiliary. ~See Koh, K.; Durst7 T. J. Org.
Chem. 1994, 59, 4683.] Pantolactone esters of racemic a-halo acids have been coupled to a variety of phenoxides. Diastereoselectivities ranging from 76-90~o have been obtained in this fashion with the "S"
stereochemistry predomin~ting at the newly formed asymmetric center.
I 5 The "R" stereochemistry can be obtained utilizing (S)-ethyl lactate as the chiral auxiliary although diastereoselectivities are significantly lowered in comparison to pantolactone (60-75%). [For other diastereoselective reactions utilizing pantolactone or ethyl lactate see: (a) Lar.sen, R.D.;
Corley, E.G.; Davis, P.; Reider, P.J., Grabowski, E.J.J. J. Am.
Chem. Soc. 1989, 111, 7650. (b) Koh, K.; Ben, R.N.; Durst, T.
Tetrahedron Lett. 1994, 35, 375. (c) Koh, K.; 13en, R.N.; Durst, T.
T~trahed~ on Lett. 1993, 34, 4473.~ The reaction i~ also characterized by sluggish rates and moderate yields.
The instant invention relates to a highly stereoselective 2 5 coupling reaction mediated ~ith a pyrrolidine derived lactamide as a chiral auxiliary.
W O 97/21693 PCT~US96/19782 SUMMARY OF THE INVENTION
This invention relates to a method for the stereoselective synthesis of a 2-aryloxycarboxylic acid using a chiral auxiliary, such as a compound of formula I to enhance the stereoselectivity of the 5 alkylation of the oc-halo acid with an aryloxy group. The invention also relates to a novel compound of formula:
o N~
Ra wherein: Ra is (Cl-C6)-alkyl, phenyl, or cyclohexyl, which is useful as a chiral auxiliary. Another aspect of this invention is a compound of 1 0 formula:
X
R~ RC
o wherein:
X is Cl, Br, I, Omesylate, Otosylate, Otriflate;
Rc is: a chiral auxiliary;
R is: (Cl-C6)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted as defined hereinbelow.
3 PCT~US96/19782 DET~ILED DESCRIPTION OF THE ~VENTION
A method for the stereoselective preparation of a compound of formula:
p~3 ~
R~ RC
o 5 wherein:
~ designates a stereogenic center;
Rc is: a chiral auxiliary;
R is (a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
1 5 R 1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -N02, (d) -NH2, 2 0 (e) -NH~C1-C4)-alkyl, (f) -N[(Cl -C4)-alkyl]2, (g) -S02NHR7, (h) -CF3, (i) (Cl-C6)-alkyl, 2 5 (j) -oR7, (k) -S (O)n-(C 1 -C4)-alkyl, (I) -NHCO-(C 1 -C4)-alkyl, (m) -NHCO-O(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 (n) -CH20-(C 1 -C4)-alkyl, (O) -o-(CH2)m-oR7 (P) -CoNR7R 12, (q) -CooR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
' ~;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R 1 O)(R 1 0)] s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, 2 0 (h) -C(R 1 O)(R 1 O)-C(R 1 O)(R 10) y or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
nisO, I or2;
mi~s2,30r4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, WO 97/21693 PC'r,~JS96~19782 (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (C l -C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (Cl-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituent~ selected from the group consisting of:
i) -OH, ii) -O-(C 1 -C4)-alkyl, iii) -S(O)n-(C 1 -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 vii) -CoNHR7 viii) -oCoR12, or ix) -CoNR7R 12, 2 0 (c) (c3-c7)-cycloalk (d) F, Cl, Br, I, (e) CF3, (f) -CooR7, (g) -CoNR7R 12, 2 5 (h) -NR7R 12, (i) -NR7CoNR7R 12, (j) -NR7CooR 12 (k) -S02NR7R 12, (1) -O-(C 1 -C4)-alkyl, 3 0 (m) -S(O)n-(Cl-C4)-alkyl, or (n) -NHSO2R 12;
R10 is:
(a) H, CA 02238960 1998-0~-28 W O 97/21G93 PCTrUS96/19782 (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R 12, iii) -CooR7~
iv) -CoNHR7, or v) -CoNR7R 12, or (c~ Cl, or F;
I () R 1 2 is (a) (C1-C6)-alkyl, un~ubstituted or substituted with a substituent selected from the group consisting of:
i) -oR7, ii) -N[R7]2, iii) -NH2, iv) -CooR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CoN(R7)2;
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) (Cl-C4)-alkyl, 2 5 ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v) -CooR7, vi) -NH2, 3 () vii) -NH[(Cl-C4)-alkyl], viii) -N[(Cl-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(Cl-C4)-alkylaryl, wherein aryl is as defined above, WO 97/21693 PCT/US9~i~19782 (d) (C3-C7)-cycloalkyl, R,7 N--N
(e) N N, or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or-NlR7;
which comprises alkylating a halo derivative X
R~f RC
o wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
R2 R~
R3 ,r~
1 5 O-M+, wherein M+ is Na+, K+, l_i+, or N(R16)4+; and R16 is H or (Cl-C6)-alkyl;
in an organic solvent at a temperature range of about -60 ~C to about 30 ~C for about 30 minutes to about 30 hours to give an alkylated 2 0 derivative bearing the chiral auxiliary:
~0 R~ Rc A method for the preparation of a compound of formula:
R3 ~' R~OH
S wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary;
I O Ris (a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and 1 5 R6;
R 1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, 2 0 (c) -N02, (d) -NH2, (e) -NH(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 (f) -N[(C 1 -C4)-alkYl]2 (g) -S02NHR7, (h) -CF3, (i) (Cl-C6)-alkyl, s (j) -oR7, (k) -S(O)n-(C 1 -C4)-alkyl, (1) -NHCO-(C 1 -C4)-alkyl, (m) -NHCO-O(C 1 -C4)-aLkyl, (n) -CH20-(C 1 -C4)-alkyl, (o) -0-(CH2)m 0R7 (P) -CoNR7R 12, (q) -CooR7, or (r) -phenyl;
1 5 R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
2 O A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R I O)(R 10)~s -Y-2 5 (e) -Y-C(R~)(R8)-C(R~)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, ~ (h) -C(R 1 O)(R I O)-C(R 1 O)(R 10) -y or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
nisO, 1 or2;
W O 97/21693 PCT~US96/19782 m is 2, 3 or 4;
,s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R~S and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, 2 () ii) -O-(C 1 -C4)-alkyl, iii) -S(O)n-(C 1 -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 2 5 vii) -CoNHR7~
viii) -oCoR12, or ix) -CoNR7R 12~
(c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, 3 0 (e) CF3, (f) -CooR7, (g) -CoNR7R 12, (h) -NR7R 12, (i) -NR7CoNR7R 12, WO 97/21693 PCT~US96~197~2 (i ) -NR7CooR 12 (k) -So2NR7R 12, (I) -O-(C 1 -C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R 12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R 12 iii) -cooR7~
iv) -CoNHR7, or 1 5 v) -CoNR7R 12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a 2 0 substituent selected from the group consisting of:
i) -oR7, ii) -N[R7]2, iii) -NH2, iv) -CooR7, 2 5 v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with 3 0 one or two substituents selected from the group consisting of:
i) (C 1 -C4)-alkyl, ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v ) -CooR7, vi) -NH2, vii) -NH[(C 1 -C4)-alkyl], viii) -N[(C I -C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -~C1-C4)-alkylaryl, wherein aryl is as defined above, (d~ (C3-C7)-cycloalkyl, R,7 N~N
(e) N N, or (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or-NR7;
comprising the steps of:
2 0 1 ) alkylating a halo derivative X
R~f RC
o wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
R ~ R
R3 r~
O-M+, wo 97nl693 PC'r~US96~9782 wherein M+ is Na+, K+, Li+, or N(R16)4+; and R ~ 6 is H
or (Cl-C6)-alkyl;
in an organic solvent at a temperature range of about -60 ~C to about 30 ~C for about 30 minutes to about 30 hours to give an alkylated derivative bearing the chiral auxiliary:
R3 ~' ,J RC
R *~
~ ; and 2) hydrolyzing the chiral auxiliary of the alkylated derivative with an inorganic base and peroxide in an aqueou~s solvent I 0 mixture to give a ,salt of the acid:
R3 ~' ,~O-M+
O
and wherein M+ is Na+, K+, or Li+;
3) neutralizing the salt of the acid with an acidic solution to give 1 5 an acid:
R3 ~
O
CA 02238960 l998-0~-28 The alkylation step can be carried out in organic solvents such as tetrahydrofuran, toluene, xylenes, or dimethylforamide. The alkylation step requires the addition of a solution of the salt of the phenoxide generally prepared by the addition of the salt of t-butoxide to S a tetrahydrofuran solution of the phenol. Phenoxide salts having counterions, such as potassium, sodium, lithium or amrnonium [N(R 16)4+, where R 16 is defined as H or (Cl -C6)-alkyl], are useful in thi.s alkylation step. Thus, the organic solvent is often a mixture of, for example, tetrahydrofuran and t-butanol. The preferred temperature 1 0 range for the alkylation step is 60 ~C to about room temperature (25 ~C).
The hydrolysis step can be carried out using an inorganic base, such as LiOH, KOH, NaOH, KOCH3, NaOCH3, LiOCH3, KOC2H5, NaOC2H5, LiOC2H5, etc. The hydrolysis step also requires 1 5 the presence of a peroxide such as hydrogen peroxide. The aqueous solvent mixtures useful in the hydrolysis .step are tetrahydrofuran-water, toluene-water, dimethylformamide-water or alternatively a polar organic solvent such as methanol, ethanol, or t-butanol.
An acidic solution, such as saturated amrnonium chloride 2 0 solution is useful in the neutralization step.
A chiral auxilary is defined as an easily removable chiral group which is attached at a position near the site of alkylation and i,~;
capable of influencing the direction of nucleophilic attack. Some of the chiral auxiliarie.s useful in this method are:
O O O
~OR, ~N , ~O;
Ra Ra R15 CH3~/
wherein:
Ra is (Cl-C6)-alkyl, phenyl, or cyclohexyl;
R13 is (Cl-C6)-alkyl, phenyl or cyclohexyl;
R 1 4 and R l 5 are independently: (C l -C 1 o)-alkyl, or R 1 4 and R 1 5 3 0 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
A preferred chiral auxiliary useful in this invention S wherein RC is ~ O
An aspect of this invention is a compound of formula:
\
Ra R15 1 0 wherein:
Ra is (Cl-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (Cl-Clo)-alkyl or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring 1 5 selected from the group consisting of piperadinyl or pyrrolidinyl .
Another aspect of this invention is a compound of formula:
X
R~f RC
O
2 0 wherein:
X is Cl, Br, I, Omesylate, Otosylate, Otriflate;
Rc is: a chiral auxiliary;
WO 97/21693 PCT~US96/19782 R is:
(a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naph~yl unsubstituted or substituted with one, two or three sub~titutents defined as R4, R5 and R6;
F~4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -N02, (d) -NH2, (e) -NH(C 1 -C4)-alkyl, 1 5 (f) -NL(Cl -C4)-alkYl]2 (g) -S02NHR7, (h) -CF3, (i) (C 1 -C6)-alkyl, (i) -oR7, 2 0 (k) -s(o)n-(cl-c4)-alkyl~
(1) -NHCO-~C 1 -C4)-alkyl, (m) -NHCO-O(C I -C4)-alkyl, (n) -cH2o-(c 1 -C4)-alkyl, (O) -o-(CH2)m-oR7 2 5 (P) -CONR7R12, (q) -CooR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to 3 0 form a ring ~tructure:
W O 97121693 PCT~US96/19782 A represents:
(a) -Y-C(R~)=C(R9)-, (b) -Y-c(R8)=N
(c) -Y-N=C(R8)-, (d) -Y-[C(R 1 0)(R 10)] s -Y-, (e) -Y-C(R8)(R8~-C(R8)(R~)-, (f) -C(R8)=C(R9)-Y -, (g) -N=C(R~s)-Y-, 1 0 (h) -C(R 1 0)(R 1 0)-C(R 1 0)(R 10) y or (i) -C(R~)=C(R9)-C(R~)=C(R9)-;
nis0, 1 or2;
1 5 m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (Cl-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R~ and R9 are independently:
(a) H, 3 0 (b) (Cl-C6)-aLkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consi.sting of:
i) -OH, ii) -O-(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 iii) -S(O)n-(C l -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 vii) -CoNHR7~
viii) ocoR 12~ or ix) -CoNR7R 12~
(c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -CooR7, (g) -CoNR7R 12, (h) -NR7R 12?
(i) -NR7CoNR7R 12, I S (i ) -NR7~ooR 12 (k) -S02NR7R 12, (l) -O-(C 1 -C4)-alkyl, (m) -S(O)n-(Cl-C4)-aLlcyl, or (n) -NHSO2R 12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
2 5 i) -OH, ii) -NR7R 12 iii) -cooR7 ~
iv) -CoNHR7, or v) -CoNR7R 12, or 3 û (c) Cl, or F;
R12 iS
(a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
W O 97~1693 PCT~US96~9782 i) -oR7, ii) -NLR7]2, iii) -NH2, iv) -CooR7, v) -N[CH2CH232Q, vi) -CF3, or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which i~ unsubstituted or substituted with I () one or two substituents selected from the group consisting of:
i) (C 1 -c4)-alkyl~
ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v) -CooR7, vi) -NH2, vii) -NH[(C 1 -C4)-alkyl], viii) -N[(Cl-C4)-alkyl]2, or 2 0 ix) -CONICH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is a~ defined above, (d) (C3-C7)-cycloalkyl, N--N
(e) N--N, or 2 5 (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl; and 3 () Q is O, S or-NR7.
CA 02238960 l998-05-28 W O 97/21693 PCT~US96/19782 An embodiment of thi~; aspect of the invention is a compound of formula:
X
o wherein:
Rc is selected from the group con.sisting of:
\ , Ra is (Cl-C6)-alkyl, phenyl or cyclohexyl;
I O R13 is (Cl-C6)-aLkyl, phenyl or cyclohexyl; and R 14 and R 15 are independently: (C I -C 1 o)-alkyl, or R 14 and R 15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperadinyl or 1 5 pyrrolidinyl.
Another embodiment of this a,spect of the invention is a compound of formula:
X
R~ Rc 2 û wherein:
X is Br or I;
CA 02238960 1998-0~-28 WO 97/21693 PCT/US96~19782 RC is:
~~r C H
3 ; and R is ethyl, phenyl or 3,4-methylenedioxyphenyl.
The alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl-substituents denote alkyl groups as described above which are modified so that each cont~ins a carbon to carbon I û double bond such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The aL~oxy substituent represents an allcyl group as de,scribed above attached through an oxygen bridge.
The heteroaryl i~s defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
2 0 The lactamide chiral auxiliary is synthesized from (R)- or (S)-ethyl lactate under Weinreb amidation conditions employing trimethylaluminum and pyrrolidine. [See (a) Nahm, S.; Weinreb, S.M.
Tetra~edron Letf. l9gl, 22, 3~15. (b) Basha, A.; Lipton, M.;
Weinreb, S.M. Tetrahedr~n Letf. 1977, 28, 4171.] The reaction is 2 5 complete in less than 2 hours with no detectable loss in the enantiopurity. The product is obtained in ~0% yield with the lactamide formed being ,suitable for use without further purification. The lactamide esters of the racemic oc-halo acids were prepared via DCC
coupling with comrnercially available acid~ or upon reaction with 3 0 commercially available acid halides according to literature procedure.
CA 02238960 1998-0~-28 W O 97/21693 PCT~US96tl9782 [See (a) Durst, T.; Koh, K. Tet~ahedron Lctt. 1992, 33, 6799. (b) Harpp, D.N.; Bao, L.Q.; Black, C.J.; Gleason, J.G.; Smith, R.A.; J.
Org~. Chem. 1975, 40, 3420.]
The coupling reaction was conducted by adding a 5 preformed solution of aryloxide to a THF solution of halide, with or without tricaprylmethylammonium iodide, at the desired temperature (Table 1). The reactions were found to proceed at a much faster rate than with conventional ester auxiliaries. A reaction performed at -35 ~C~ with ,sodium 4-methoxyphenoxide wa.s completed in 0.5h with a I 0 diastereoselectivity of 92% (entry 1). A similar reaction utilizing ethyl lactate as the auxiliary required a reaction time of 24h at 0 ~C Product was also obtained with a dimini~ht d diastereoselectivity of 60%. This o~servation also holds true for the ethyl lactate auxiliary. The fact that coupling reactions involvin~ pyrrolidine lactamide auxiliaries proceed 1 5 at a more rapid rate than their ester counterparts allows for the use of alternative phenoxide salts.
WO97/21693 PCT~US96~19782 Table 1 O-M+
~OMe \~ J~N,~ OMe ~
EntryTemp ~~C)Metal ~M+) XTime (h)Yield (%) DR
-35 Na B r 0.5 7~ 96:4 2* -35 Na B r 0.5 ~$4 95 :5 3 RT Li B r 6 83 94:6 4 0 Li Br ~ ~s0 95:5 -15 Li Br 24 82 95:5 6* RT Li B r 6 79 95:5 7* 0 Li Br 8 83 95:5 8* -15 Li Br 24 ~6 96:4 9 RT Li I 0.25 87 98:2 0 Li I 0.~ ~s9 99:1 * Reaction conducted in the presence of 20 mol% ~icaprylmethyl-ammonium iodi~e.
A method for the stereoselective preparation of a compound of formula:
p~3 ~
R~ RC
o 5 wherein:
~ designates a stereogenic center;
Rc is: a chiral auxiliary;
R is (a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
1 5 R 1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -N02, (d) -NH2, 2 0 (e) -NH~C1-C4)-alkyl, (f) -N[(Cl -C4)-alkyl]2, (g) -S02NHR7, (h) -CF3, (i) (Cl-C6)-alkyl, 2 5 (j) -oR7, (k) -S (O)n-(C 1 -C4)-alkyl, (I) -NHCO-(C 1 -C4)-alkyl, (m) -NHCO-O(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 (n) -CH20-(C 1 -C4)-alkyl, (O) -o-(CH2)m-oR7 (P) -CoNR7R 12, (q) -CooR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
' ~;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R 1 O)(R 1 0)] s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, 2 0 (h) -C(R 1 O)(R 1 O)-C(R 1 O)(R 10) y or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
nisO, I or2;
mi~s2,30r4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, WO 97/21693 PC'r,~JS96~19782 (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (C l -C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (Cl-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituent~ selected from the group consisting of:
i) -OH, ii) -O-(C 1 -C4)-alkyl, iii) -S(O)n-(C 1 -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 vii) -CoNHR7 viii) -oCoR12, or ix) -CoNR7R 12, 2 0 (c) (c3-c7)-cycloalk (d) F, Cl, Br, I, (e) CF3, (f) -CooR7, (g) -CoNR7R 12, 2 5 (h) -NR7R 12, (i) -NR7CoNR7R 12, (j) -NR7CooR 12 (k) -S02NR7R 12, (1) -O-(C 1 -C4)-alkyl, 3 0 (m) -S(O)n-(Cl-C4)-alkyl, or (n) -NHSO2R 12;
R10 is:
(a) H, CA 02238960 1998-0~-28 W O 97/21G93 PCTrUS96/19782 (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R 12, iii) -CooR7~
iv) -CoNHR7, or v) -CoNR7R 12, or (c~ Cl, or F;
I () R 1 2 is (a) (C1-C6)-alkyl, un~ubstituted or substituted with a substituent selected from the group consisting of:
i) -oR7, ii) -N[R7]2, iii) -NH2, iv) -CooR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CoN(R7)2;
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) (Cl-C4)-alkyl, 2 5 ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v) -CooR7, vi) -NH2, 3 () vii) -NH[(Cl-C4)-alkyl], viii) -N[(Cl-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(Cl-C4)-alkylaryl, wherein aryl is as defined above, WO 97/21693 PCT/US9~i~19782 (d) (C3-C7)-cycloalkyl, R,7 N--N
(e) N N, or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or-NlR7;
which comprises alkylating a halo derivative X
R~f RC
o wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
R2 R~
R3 ,r~
1 5 O-M+, wherein M+ is Na+, K+, l_i+, or N(R16)4+; and R16 is H or (Cl-C6)-alkyl;
in an organic solvent at a temperature range of about -60 ~C to about 30 ~C for about 30 minutes to about 30 hours to give an alkylated 2 0 derivative bearing the chiral auxiliary:
~0 R~ Rc A method for the preparation of a compound of formula:
R3 ~' R~OH
S wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary;
I O Ris (a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and 1 5 R6;
R 1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, 2 0 (c) -N02, (d) -NH2, (e) -NH(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 (f) -N[(C 1 -C4)-alkYl]2 (g) -S02NHR7, (h) -CF3, (i) (Cl-C6)-alkyl, s (j) -oR7, (k) -S(O)n-(C 1 -C4)-alkyl, (1) -NHCO-(C 1 -C4)-alkyl, (m) -NHCO-O(C 1 -C4)-aLkyl, (n) -CH20-(C 1 -C4)-alkyl, (o) -0-(CH2)m 0R7 (P) -CoNR7R 12, (q) -CooR7, or (r) -phenyl;
1 5 R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
2 O A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R I O)(R 10)~s -Y-2 5 (e) -Y-C(R~)(R8)-C(R~)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, ~ (h) -C(R 1 O)(R I O)-C(R 1 O)(R 10) -y or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
nisO, 1 or2;
W O 97/21693 PCT~US96/19782 m is 2, 3 or 4;
,s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R~S and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, 2 () ii) -O-(C 1 -C4)-alkyl, iii) -S(O)n-(C 1 -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 2 5 vii) -CoNHR7~
viii) -oCoR12, or ix) -CoNR7R 12~
(c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, 3 0 (e) CF3, (f) -CooR7, (g) -CoNR7R 12, (h) -NR7R 12, (i) -NR7CoNR7R 12, WO 97/21693 PCT~US96~197~2 (i ) -NR7CooR 12 (k) -So2NR7R 12, (I) -O-(C 1 -C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R 12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R 12 iii) -cooR7~
iv) -CoNHR7, or 1 5 v) -CoNR7R 12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a 2 0 substituent selected from the group consisting of:
i) -oR7, ii) -N[R7]2, iii) -NH2, iv) -CooR7, 2 5 v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with 3 0 one or two substituents selected from the group consisting of:
i) (C 1 -C4)-alkyl, ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v ) -CooR7, vi) -NH2, vii) -NH[(C 1 -C4)-alkyl], viii) -N[(C I -C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -~C1-C4)-alkylaryl, wherein aryl is as defined above, (d~ (C3-C7)-cycloalkyl, R,7 N~N
(e) N N, or (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or-NR7;
comprising the steps of:
2 0 1 ) alkylating a halo derivative X
R~f RC
o wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
R ~ R
R3 r~
O-M+, wo 97nl693 PC'r~US96~9782 wherein M+ is Na+, K+, Li+, or N(R16)4+; and R ~ 6 is H
or (Cl-C6)-alkyl;
in an organic solvent at a temperature range of about -60 ~C to about 30 ~C for about 30 minutes to about 30 hours to give an alkylated derivative bearing the chiral auxiliary:
R3 ~' ,J RC
R *~
~ ; and 2) hydrolyzing the chiral auxiliary of the alkylated derivative with an inorganic base and peroxide in an aqueou~s solvent I 0 mixture to give a ,salt of the acid:
R3 ~' ,~O-M+
O
and wherein M+ is Na+, K+, or Li+;
3) neutralizing the salt of the acid with an acidic solution to give 1 5 an acid:
R3 ~
O
CA 02238960 l998-0~-28 The alkylation step can be carried out in organic solvents such as tetrahydrofuran, toluene, xylenes, or dimethylforamide. The alkylation step requires the addition of a solution of the salt of the phenoxide generally prepared by the addition of the salt of t-butoxide to S a tetrahydrofuran solution of the phenol. Phenoxide salts having counterions, such as potassium, sodium, lithium or amrnonium [N(R 16)4+, where R 16 is defined as H or (Cl -C6)-alkyl], are useful in thi.s alkylation step. Thus, the organic solvent is often a mixture of, for example, tetrahydrofuran and t-butanol. The preferred temperature 1 0 range for the alkylation step is 60 ~C to about room temperature (25 ~C).
The hydrolysis step can be carried out using an inorganic base, such as LiOH, KOH, NaOH, KOCH3, NaOCH3, LiOCH3, KOC2H5, NaOC2H5, LiOC2H5, etc. The hydrolysis step also requires 1 5 the presence of a peroxide such as hydrogen peroxide. The aqueous solvent mixtures useful in the hydrolysis .step are tetrahydrofuran-water, toluene-water, dimethylformamide-water or alternatively a polar organic solvent such as methanol, ethanol, or t-butanol.
An acidic solution, such as saturated amrnonium chloride 2 0 solution is useful in the neutralization step.
A chiral auxilary is defined as an easily removable chiral group which is attached at a position near the site of alkylation and i,~;
capable of influencing the direction of nucleophilic attack. Some of the chiral auxiliarie.s useful in this method are:
O O O
~OR, ~N , ~O;
Ra Ra R15 CH3~/
wherein:
Ra is (Cl-C6)-alkyl, phenyl, or cyclohexyl;
R13 is (Cl-C6)-alkyl, phenyl or cyclohexyl;
R 1 4 and R l 5 are independently: (C l -C 1 o)-alkyl, or R 1 4 and R 1 5 3 0 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
A preferred chiral auxiliary useful in this invention S wherein RC is ~ O
An aspect of this invention is a compound of formula:
\
Ra R15 1 0 wherein:
Ra is (Cl-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (Cl-Clo)-alkyl or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring 1 5 selected from the group consisting of piperadinyl or pyrrolidinyl .
Another aspect of this invention is a compound of formula:
X
R~f RC
O
2 0 wherein:
X is Cl, Br, I, Omesylate, Otosylate, Otriflate;
Rc is: a chiral auxiliary;
WO 97/21693 PCT~US96/19782 R is:
(a) (C 1 -C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naph~yl unsubstituted or substituted with one, two or three sub~titutents defined as R4, R5 and R6;
F~4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -N02, (d) -NH2, (e) -NH(C 1 -C4)-alkyl, 1 5 (f) -NL(Cl -C4)-alkYl]2 (g) -S02NHR7, (h) -CF3, (i) (C 1 -C6)-alkyl, (i) -oR7, 2 0 (k) -s(o)n-(cl-c4)-alkyl~
(1) -NHCO-~C 1 -C4)-alkyl, (m) -NHCO-O(C I -C4)-alkyl, (n) -cH2o-(c 1 -C4)-alkyl, (O) -o-(CH2)m-oR7 2 5 (P) -CONR7R12, (q) -CooR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to 3 0 form a ring ~tructure:
W O 97121693 PCT~US96/19782 A represents:
(a) -Y-C(R~)=C(R9)-, (b) -Y-c(R8)=N
(c) -Y-N=C(R8)-, (d) -Y-[C(R 1 0)(R 10)] s -Y-, (e) -Y-C(R8)(R8~-C(R8)(R~)-, (f) -C(R8)=C(R9)-Y -, (g) -N=C(R~s)-Y-, 1 0 (h) -C(R 1 0)(R 1 0)-C(R 1 0)(R 10) y or (i) -C(R~)=C(R9)-C(R~)=C(R9)-;
nis0, 1 or2;
1 5 m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C 1 -C6)-alkyl, (c) phenyl, (d) (Cl-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R~ and R9 are independently:
(a) H, 3 0 (b) (Cl-C6)-aLkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consi.sting of:
i) -OH, ii) -O-(C 1 -C4)-alkyl, W O 97/21693 PCT~US96/19782 iii) -S(O)n-(C l -C4)-alkyl, iv) -NR7-(C 1 -C4)-alkyl, v) -NHR7, vi) -cooR7 vii) -CoNHR7~
viii) ocoR 12~ or ix) -CoNR7R 12~
(c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -CooR7, (g) -CoNR7R 12, (h) -NR7R 12?
(i) -NR7CoNR7R 12, I S (i ) -NR7~ooR 12 (k) -S02NR7R 12, (l) -O-(C 1 -C4)-alkyl, (m) -S(O)n-(Cl-C4)-aLlcyl, or (n) -NHSO2R 12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
2 5 i) -OH, ii) -NR7R 12 iii) -cooR7 ~
iv) -CoNHR7, or v) -CoNR7R 12, or 3 û (c) Cl, or F;
R12 iS
(a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
W O 97~1693 PCT~US96~9782 i) -oR7, ii) -NLR7]2, iii) -NH2, iv) -CooR7, v) -N[CH2CH232Q, vi) -CF3, or vii) -CoN(R7)2;
(b) aryl, wherein aryl is defined as phenyl or naphthyl which i~ unsubstituted or substituted with I () one or two substituents selected from the group consisting of:
i) (C 1 -c4)-alkyl~
ii) -O-(C 1 -C4)-alkyl, iii) -Co[NR7]2, iv) F, Cl, Br or I, v) -CooR7, vi) -NH2, vii) -NH[(C 1 -C4)-alkyl], viii) -N[(Cl-C4)-alkyl]2, or 2 0 ix) -CONICH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is a~ defined above, (d) (C3-C7)-cycloalkyl, N--N
(e) N--N, or 2 5 (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl; and 3 () Q is O, S or-NR7.
CA 02238960 l998-05-28 W O 97/21693 PCT~US96/19782 An embodiment of thi~; aspect of the invention is a compound of formula:
X
o wherein:
Rc is selected from the group con.sisting of:
\ , Ra is (Cl-C6)-alkyl, phenyl or cyclohexyl;
I O R13 is (Cl-C6)-aLkyl, phenyl or cyclohexyl; and R 14 and R 15 are independently: (C I -C 1 o)-alkyl, or R 14 and R 15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperadinyl or 1 5 pyrrolidinyl.
Another embodiment of this a,spect of the invention is a compound of formula:
X
R~ Rc 2 û wherein:
X is Br or I;
CA 02238960 1998-0~-28 WO 97/21693 PCT/US96~19782 RC is:
~~r C H
3 ; and R is ethyl, phenyl or 3,4-methylenedioxyphenyl.
The alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl-substituents denote alkyl groups as described above which are modified so that each cont~ins a carbon to carbon I û double bond such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The aL~oxy substituent represents an allcyl group as de,scribed above attached through an oxygen bridge.
The heteroaryl i~s defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
2 0 The lactamide chiral auxiliary is synthesized from (R)- or (S)-ethyl lactate under Weinreb amidation conditions employing trimethylaluminum and pyrrolidine. [See (a) Nahm, S.; Weinreb, S.M.
Tetra~edron Letf. l9gl, 22, 3~15. (b) Basha, A.; Lipton, M.;
Weinreb, S.M. Tetrahedr~n Letf. 1977, 28, 4171.] The reaction is 2 5 complete in less than 2 hours with no detectable loss in the enantiopurity. The product is obtained in ~0% yield with the lactamide formed being ,suitable for use without further purification. The lactamide esters of the racemic oc-halo acids were prepared via DCC
coupling with comrnercially available acid~ or upon reaction with 3 0 commercially available acid halides according to literature procedure.
CA 02238960 1998-0~-28 W O 97/21693 PCT~US96tl9782 [See (a) Durst, T.; Koh, K. Tet~ahedron Lctt. 1992, 33, 6799. (b) Harpp, D.N.; Bao, L.Q.; Black, C.J.; Gleason, J.G.; Smith, R.A.; J.
Org~. Chem. 1975, 40, 3420.]
The coupling reaction was conducted by adding a 5 preformed solution of aryloxide to a THF solution of halide, with or without tricaprylmethylammonium iodide, at the desired temperature (Table 1). The reactions were found to proceed at a much faster rate than with conventional ester auxiliaries. A reaction performed at -35 ~C~ with ,sodium 4-methoxyphenoxide wa.s completed in 0.5h with a I 0 diastereoselectivity of 92% (entry 1). A similar reaction utilizing ethyl lactate as the auxiliary required a reaction time of 24h at 0 ~C Product was also obtained with a dimini~ht d diastereoselectivity of 60%. This o~servation also holds true for the ethyl lactate auxiliary. The fact that coupling reactions involvin~ pyrrolidine lactamide auxiliaries proceed 1 5 at a more rapid rate than their ester counterparts allows for the use of alternative phenoxide salts.
WO97/21693 PCT~US96~19782 Table 1 O-M+
~OMe \~ J~N,~ OMe ~
EntryTemp ~~C)Metal ~M+) XTime (h)Yield (%) DR
-35 Na B r 0.5 7~ 96:4 2* -35 Na B r 0.5 ~$4 95 :5 3 RT Li B r 6 83 94:6 4 0 Li Br ~ ~s0 95:5 -15 Li Br 24 82 95:5 6* RT Li B r 6 79 95:5 7* 0 Li Br 8 83 95:5 8* -15 Li Br 24 ~6 96:4 9 RT Li I 0.25 87 98:2 0 Li I 0.~ ~s9 99:1 * Reaction conducted in the presence of 20 mol% ~icaprylmethyl-ammonium iodi~e.
5 ** Diastereomenc ratios detennined via HPL~ u~lizing a Chiracel OD column and via 300MHz lH NMR integration of the diastereomeric methyl doublets.
Lithium 4-methoxyphenoxide, although unreactive at -35 ~C, readily undergoes reaction with the cc-bromoester at temperatures ranging from -15 ~C to ambient (entries 3-6). No temperature effect is 10 observed, with diastereoselectivities obtained at room temperature rivaling those obtained with the sodium salt at -35 ~C (entries 6-8).
However, conducting the coupling reaction utilizing the cc-iodoester leads to significant increases in diastereoselection (entries 9 & 10). [The oc-iodoester was prepared by treating the a-bromoester with Nal in W O 97/21693 PCT~US96/19782 acetone.] Reactions performed at ambient temperature and 0 ~C showed enhanced dia,stereomeric ratios of 9g:2 and 99:1 respectively.
The generality of the reaction was assessed by studying a variety of diastereomeric halides and substituted phenols (Table 2).
Table 2 R~ ~N~ o L ~ R' J~N~
THF, RT ~ 4 -Entry R R2 Rl Time (h) Yield (~o3 DR*
Et H nPr 8 76 95:5 2 Ph H H 0.25 78 97 :3 3 Ph H nPr 0.25 77 97:3 4 Ph OMe H 0.25 88 98:2 5** Ph OMe H 0.l0 ~7 99:1 * Diastereomeric ratio (DR) de~lll,illed via HPLC Il~ili7.in~ either a Supelcosil LC CN
colulTm or a Chiracel OD column. Diastereoselec~ivi~ies could also be obtained via 300MH~ IH NMR.
1 () ** Reaction conducted utilizing the a-iodoester.
The substitution pattern about the phenol has minim~l influence on the diastereoselectivity of the reaction. The sterically demanding 2-propylphenol gives similar diastereomeric ratios to 15 unencumbered phenols (entries 1, 2-4). Again, diastereoselectivities ob.served are on the order of 5-15% higher than those obtained utilizing either ethyl lactate or pantolactone as the chiral auxiliary.
Diastereomeric ratios of 99:1 can be obtained at room temperature through utilization of the oc-iodoester (entry 5). The reaction is 2 û complete upon addition of the phenoxide and excellent yields are obtained.
WO 97/21693 PCT~US9C/197~82 The absolute configuration of the newly formed stereogenic center was determined by first hydrolyzing the coupled product to remove the chiral auxiliary, followed by converting the acid to the corresponding R- or S- methyl mandelate. [See Corey, EJ.; Link, J.O.
Tetrahedron Lett. 1992,33, 3431.]
The instant invention can be understood further by the following examples, which do not constitute a limitation of the invention.
<0~3 + ~OEt CH2CI2 <o-~CO2Et To a slurry of alllminllm chloride (150 g, 1.13 mole) in methylene chloride (800 ml) at -55 ~C was added ethyl oxalyl chloride (100 ml, 0.89 moles) over 5 min. The reaction exothermed to -48 ~C
1 5 and was cooled back down to -55 ~C over 15 min. 1,3-Benzodioxole (100 g, 94 ml, 0.~2 moles) was added over 15 min while the reaction temperature was maintained between -45 ~C and-55 ~C using dry ice /
acetone. The red solution was aged for 20 min. The batch was carefully quenched into 700 ml of ice water and the mixture agitated for 2 0 10 min. The layers were separated and the organic layer was washed with water (500 ml). Concentration in vacuo provided the product as a brown oil (1~S4 g) which was used in the next step without purification.
Synthe,sis of Ketoacid O O
o_~CO2Et NaOH <O~ ~CO2H
To a solution of ketoester 3 (182 g, 0.82 mole) in methanol (800 ml) was added a mixture of 5N sodium hydroxide (300 ml) and water (300 ml) while maintaining the temperature below 35 ~C using an I () ice bath. The batch was aged for 20 min. during which time a precipitate formed. Methylene chloride (500 ml) was added and the mixture was acidified to pH 3.0 using concentrated HCl. The layers were separated and the organic phase was concentrated in vacuo to 100 ml. Toluene (300 ml) was added and concentration was continued to a 15 final volume of 300 ml. The resulting slurry was aged for lh and filtered. The wet cake was washed with hexane and air dried to provide 120 g of ketoacid as a tan solid.
Lactate Ester Formation O O O
o~OH 1. oxalyl chloride O~ 'OEt < _~ 2. ethyl-(S)-Iactate <O I~J O
To a slurry of ketoacid (~0 g, 0.41 moles) in methylene 2 5 chloride (~S00 ml) at 20-25 ~C was added DMF (3 ml). Oxalyl chloride (37 ml, 0.42 moles, d=1.45 g/ml) was added over 10 min.
CA 02238960 l998-05-28 W O 97/21693 PCT~US96J19782 Within 20 min the reaction mixture turned to a clear solution. NMR assay of a small sample indicated <5% ketoacid rem~ining. The reaction mixture was then added via cannula over 15 min to a solution of et,hyl-(S)-lactate (44 ml, 0.39 mole, d=1.042 g/ml), and TEA (143 ml, d = 0.72 g/ml) in methylene chloride (600 ml) while m~int~ining the temperature <30 ~C using an ice bath. The mixture was aged for lh. The batch was quenched into water (500 ml) and the layers separated. The organic layer was washed with water (500 ml) and then with sat'd sodium bicarbonate (2x300 ml). Concentration in 1 0 vacu~ provided 100 g of product as an oil. The material is used in the next step without purification.
EX~MPLE 4 1 5 Lactate ester Reduction O O OH O
<o~ ~OEt NaBH4~ <O~
To a solution of lactate ester (100 g, 0.34 mole) in THF
(600 ml) at 10-15 ~C was added water (65 ml). Sodium borohydride (5 g, 0.14 mole) was added in 5 portions over 25 min. The reaction 2 () temperature was m~int~ined < 25 ~C using an ice bath. The mixture was aged for 20 min and poured into brine (300 ml) and ethyl acetate (600 ml). The layers were cut and the aqueous was back extracted with ethyl acetate (300 ml). The combined organic extracts were washed with water (200 ml) and the layers were separated. Concentration i~1 2 5 vacuo yielded 100 g of product as an oil which was used in the next step without purification.
W O 97/21693 PCT~US96/19782 - 2~ -Preparation of Bromide OH O Br O
<~_~O~Jl~OEt PBr3. <O~O~Jl~OEt To a solution of the hydroxyester (100 g, 0.34 mole) in methylene chloride (500 ml) at 10-15 ~C was added phosphorous tribromide (12.8 ml, 0.13 moles, d=2.85 g/ml) over 5 min. The mixture was allowed to warm to 20 ~C and aged for 1.5 h. The batch 1 0 was quenched into water (250 ml) and the organic layer was washed with aqueous sodium bicarbonate (250 ml). Concentration of the organic layer in vacuo provided 111 g of bromide as a dark oil which was used in the next ,step without purification.
I 5 l~XAMPLE 6 Phenoxide Coupling MeO2C ~
<O~-~O~OEt ~:,M~ <O~O~OEt ONa To a solution of methyl 4- hydroxy-3-n-propylbenzoate 2 ~1 (23.7 g, 0.12 mole) in T~F (175 ml) at 5-10 ~(~ was added ~sodium t-butoxide (11.7 g, 0.12 mole) in 3 portions over 15 min while maintaining the temperature <20 ~C using an ice bath. The mixture was aged for 20 min and then added via a cannula to a ,solution of the bromide (55.0 g, 0.15 mole) in THF (400 ml) at -35 ~C. The reaction WO 97/21693 PCT~rJS96~19782 was aged at -35 ~C for 20 h. The mixture was poured into a mixture of brine (200 ml), water (200 ml), and ethyl acetate (400 ml). The layers were cut and the organic layer was concentrated in VCIC~o to yield 69.0 g of product as an oil.
s HPLC assay Column: Zorbax Rx-C8 4.6mm x 25cm; Solvent: CH3CN:H2O(0.1 H3PO4) 60:40, Flow Rate: 1 ml/min; Wavelength: 220 nm; Column Temperature 25 ~C; Retention Times: Major isomer: 20.2 min; Minor 10 isomer:l8.~ min; and bromide: 7.~S min.
EXAMPLl~ 7 Lactate E~ter Hydrolysis MeO2C ~ MeO2C
~ O LiOH, H2O2 <~ ~¢~'~ .~OEt <O ~ OH
Hydrogen peroxide (3.5 1, 133.~ mole) was added to a solution of lithium hydroxide (709 g, 16.9 mole) in water (3.5 1) and the mixture was aged for 20 min at 20-25 ~C. This solution was then 2 0 slowly added over 30 min to a cold (0-5 ~~) solution of lactate ester g (3.1 kg, 6.76 mole) in THF (2~ 1). The reaction mixture was aged for 30 min, cooled to 0-5 ~C and ~luenched with sat'd aqueous sodium bisulfite (6 1). Saturated aqueous ammonium chloride (41) and methyl t-butyl ether (36 1) was added and after agitation the layers were 2 5 separated. The organic layer was dried over MgSO4 (1 kg) and then concentrated in vacuo to yield 2.6 kg of crude product as a dark oil which was used without futher purification.
W O 97/21693 PCT~US96/19782 EXAMPLE P~
o~ ~,OH2( )2 , CH3 O OCH2CI2 DMF Et3N
O O
<~--~~~ N~
To a solution of the ketoacid (29.1 g) in methylene chloride (375 ml) was added 3 ml of DMF. Oxalyl chloride (13.1 ml) was added dropwise and the mixture stirred for 30 minutes. The mixture was cooled to 0 ~C and the hydroxyamide (20.4 g) was added. Triethyl amine (42 ml) was added drowise and the mixture aged for 30 minutes.
I () The reaction was quenched with water (200 ml) and the organic layer was washed with saturated sodium bicarbonate (200 ml), dried with MgSO4 and concentrated to yield 44.4 g of product as an oil.
CA 02238960 l998-05-28 ~XAMPLE 9 ~ O ~
olC~ ~ N~ NaBH4 OH O
~ ~~ ~~ N~
To a solution of ketoester (44.4 g) in THF (300 ml) was 5 added in water (30 ml). Sodium borohydride (2.1 g) was added in portion~ over 15 minlltes and the mixture was aged for 30 minute~. The reaction wa,s quenched with brine (200 ml) and the phases separated.
The aqueous phase wals extracted with ethyl acetate and the combined organics were dried over MgSO4 and concentrated to yield 44.4 g of I () the product as an oil.
<0~ ~ CH3 O ~ ~O J~
1 5 To a solution of alcohol (8.1 g) in methylene chloride (60 ml) at 0 ~C was added P13r3 (0.96 ml) over 5 minutes. The mixture was aged for 30 minutes and quenched with 50 ml of saturated ~sodium bicarbonated. The layers were separated and the a~lueous was extracted with methylene chloride (100 ml). The combined organics were dried 2 û over MgSO4 and concentrated to provide 7.3 g of product a.s an oil.
W O 97/21693 PCT~US96/19782 EXAMPLE 1 l Phenoxide Couplin~:
<~ ~b~ ~J~N,~ 5O
O-Li+
2 r MeO2C~
O O
< ~ J~ N~
To a solution of methyl4-hydroxy-3-n-propylbenzoate (122 mg, 0.62 mmol) in THF (2 ml) at ambient temperature was added lithium t-butoxide (0.63 ml of a lM solution, 0.63 mmol) in one portion. The lithium salt thus formed was added via cannula to a THF
I û (3 ml) solution of bromide 1 (220 mg, 0.~7 mmol). The reaction was stirred for I h at room temperature at which time HPLC assay indicated <1% bromide rem;~ining. The reaction was quenched with water (10 ml) and EtOAc (10 ml) was added. The phases were separated and the aqueous phase was extracted with EtOAc (lx10 ml). The combined I S organic phase~s were washed with brine (lx10 ml) and concentrated in vacuo to give 290 mg of crude material. The product was isolated as a 9g:2 mixture of diastereomers (determined by HPLC) and was used without further purification.
W O g7121693 PC~US96~19782 HPLC assay:
Column: Supelcosil LC-CN 250 mm x 4.6 mm; Solvent: Hexane:IPA
98:2; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column Temperature: 25 ~C; Retention times: major isomer: 14.4 min; minor isomer: 17.2 min; and bromide: 13.2 min., 15.5 min.
MeO2C ~ MeO2C
LiOH, H2~2 THF o~OH
I 0 To a solution of 4.1 g of ester in 33 ml TH~ at 0 ~C was added a mixture of 696 mg of LiOH and hydrogen peroxide (6.~ ml).
The reaction was aged for 1 hour and quenched with 20 ml of saturated sodium bisulfite. The phases were separated and the aqueous phase was extracted with 50 ml CH2C12. The combined organic pha~e were dried 1 5 over MgSO4 and concentrated to yield 5.1 g of acid.
W O 97/21693 PCTnUS96/19782 o t THF, RT ~
Example R R2Rl Time (h3 Yield( % ) DR*
13 Et H nPr 8 76 95:5 14 Ph H H 0.2~ 7~s 97:3 Ph H nPr 0.25 77 97:3 16 Ph OMe H 0.25 88 98:2 1 7t Ph OMe H 0.10 87 99:1 5 * Diastereomeric ratio (DR) determined via HPLC utilizing either a Supelcosil LC CN
column or a Chiracel OD column. Diastereoselectivities could also be obtained via 300MHz I H NMR.
t Reaction conducted utilizing the oc-iodoester.
Following the procedures described hereinabove the 10 aLlcylated compound 4 (wherein R, Rl and R2 are a~ defined above), was prepared.
Lithium 4-methoxyphenoxide, although unreactive at -35 ~C, readily undergoes reaction with the cc-bromoester at temperatures ranging from -15 ~C to ambient (entries 3-6). No temperature effect is 10 observed, with diastereoselectivities obtained at room temperature rivaling those obtained with the sodium salt at -35 ~C (entries 6-8).
However, conducting the coupling reaction utilizing the cc-iodoester leads to significant increases in diastereoselection (entries 9 & 10). [The oc-iodoester was prepared by treating the a-bromoester with Nal in W O 97/21693 PCT~US96/19782 acetone.] Reactions performed at ambient temperature and 0 ~C showed enhanced dia,stereomeric ratios of 9g:2 and 99:1 respectively.
The generality of the reaction was assessed by studying a variety of diastereomeric halides and substituted phenols (Table 2).
Table 2 R~ ~N~ o L ~ R' J~N~
THF, RT ~ 4 -Entry R R2 Rl Time (h) Yield (~o3 DR*
Et H nPr 8 76 95:5 2 Ph H H 0.25 78 97 :3 3 Ph H nPr 0.25 77 97:3 4 Ph OMe H 0.25 88 98:2 5** Ph OMe H 0.l0 ~7 99:1 * Diastereomeric ratio (DR) de~lll,illed via HPLC Il~ili7.in~ either a Supelcosil LC CN
colulTm or a Chiracel OD column. Diastereoselec~ivi~ies could also be obtained via 300MH~ IH NMR.
1 () ** Reaction conducted utilizing the a-iodoester.
The substitution pattern about the phenol has minim~l influence on the diastereoselectivity of the reaction. The sterically demanding 2-propylphenol gives similar diastereomeric ratios to 15 unencumbered phenols (entries 1, 2-4). Again, diastereoselectivities ob.served are on the order of 5-15% higher than those obtained utilizing either ethyl lactate or pantolactone as the chiral auxiliary.
Diastereomeric ratios of 99:1 can be obtained at room temperature through utilization of the oc-iodoester (entry 5). The reaction is 2 û complete upon addition of the phenoxide and excellent yields are obtained.
WO 97/21693 PCT~US9C/197~82 The absolute configuration of the newly formed stereogenic center was determined by first hydrolyzing the coupled product to remove the chiral auxiliary, followed by converting the acid to the corresponding R- or S- methyl mandelate. [See Corey, EJ.; Link, J.O.
Tetrahedron Lett. 1992,33, 3431.]
The instant invention can be understood further by the following examples, which do not constitute a limitation of the invention.
<0~3 + ~OEt CH2CI2 <o-~CO2Et To a slurry of alllminllm chloride (150 g, 1.13 mole) in methylene chloride (800 ml) at -55 ~C was added ethyl oxalyl chloride (100 ml, 0.89 moles) over 5 min. The reaction exothermed to -48 ~C
1 5 and was cooled back down to -55 ~C over 15 min. 1,3-Benzodioxole (100 g, 94 ml, 0.~2 moles) was added over 15 min while the reaction temperature was maintained between -45 ~C and-55 ~C using dry ice /
acetone. The red solution was aged for 20 min. The batch was carefully quenched into 700 ml of ice water and the mixture agitated for 2 0 10 min. The layers were separated and the organic layer was washed with water (500 ml). Concentration in vacuo provided the product as a brown oil (1~S4 g) which was used in the next step without purification.
Synthe,sis of Ketoacid O O
o_~CO2Et NaOH <O~ ~CO2H
To a solution of ketoester 3 (182 g, 0.82 mole) in methanol (800 ml) was added a mixture of 5N sodium hydroxide (300 ml) and water (300 ml) while maintaining the temperature below 35 ~C using an I () ice bath. The batch was aged for 20 min. during which time a precipitate formed. Methylene chloride (500 ml) was added and the mixture was acidified to pH 3.0 using concentrated HCl. The layers were separated and the organic phase was concentrated in vacuo to 100 ml. Toluene (300 ml) was added and concentration was continued to a 15 final volume of 300 ml. The resulting slurry was aged for lh and filtered. The wet cake was washed with hexane and air dried to provide 120 g of ketoacid as a tan solid.
Lactate Ester Formation O O O
o~OH 1. oxalyl chloride O~ 'OEt < _~ 2. ethyl-(S)-Iactate <O I~J O
To a slurry of ketoacid (~0 g, 0.41 moles) in methylene 2 5 chloride (~S00 ml) at 20-25 ~C was added DMF (3 ml). Oxalyl chloride (37 ml, 0.42 moles, d=1.45 g/ml) was added over 10 min.
CA 02238960 l998-05-28 W O 97/21693 PCT~US96J19782 Within 20 min the reaction mixture turned to a clear solution. NMR assay of a small sample indicated <5% ketoacid rem~ining. The reaction mixture was then added via cannula over 15 min to a solution of et,hyl-(S)-lactate (44 ml, 0.39 mole, d=1.042 g/ml), and TEA (143 ml, d = 0.72 g/ml) in methylene chloride (600 ml) while m~int~ining the temperature <30 ~C using an ice bath. The mixture was aged for lh. The batch was quenched into water (500 ml) and the layers separated. The organic layer was washed with water (500 ml) and then with sat'd sodium bicarbonate (2x300 ml). Concentration in 1 0 vacu~ provided 100 g of product as an oil. The material is used in the next step without purification.
EX~MPLE 4 1 5 Lactate ester Reduction O O OH O
<o~ ~OEt NaBH4~ <O~
To a solution of lactate ester (100 g, 0.34 mole) in THF
(600 ml) at 10-15 ~C was added water (65 ml). Sodium borohydride (5 g, 0.14 mole) was added in 5 portions over 25 min. The reaction 2 () temperature was m~int~ined < 25 ~C using an ice bath. The mixture was aged for 20 min and poured into brine (300 ml) and ethyl acetate (600 ml). The layers were cut and the aqueous was back extracted with ethyl acetate (300 ml). The combined organic extracts were washed with water (200 ml) and the layers were separated. Concentration i~1 2 5 vacuo yielded 100 g of product as an oil which was used in the next step without purification.
W O 97/21693 PCT~US96/19782 - 2~ -Preparation of Bromide OH O Br O
<~_~O~Jl~OEt PBr3. <O~O~Jl~OEt To a solution of the hydroxyester (100 g, 0.34 mole) in methylene chloride (500 ml) at 10-15 ~C was added phosphorous tribromide (12.8 ml, 0.13 moles, d=2.85 g/ml) over 5 min. The mixture was allowed to warm to 20 ~C and aged for 1.5 h. The batch 1 0 was quenched into water (250 ml) and the organic layer was washed with aqueous sodium bicarbonate (250 ml). Concentration of the organic layer in vacuo provided 111 g of bromide as a dark oil which was used in the next ,step without purification.
I 5 l~XAMPLE 6 Phenoxide Coupling MeO2C ~
<O~-~O~OEt ~:,M~ <O~O~OEt ONa To a solution of methyl 4- hydroxy-3-n-propylbenzoate 2 ~1 (23.7 g, 0.12 mole) in T~F (175 ml) at 5-10 ~(~ was added ~sodium t-butoxide (11.7 g, 0.12 mole) in 3 portions over 15 min while maintaining the temperature <20 ~C using an ice bath. The mixture was aged for 20 min and then added via a cannula to a ,solution of the bromide (55.0 g, 0.15 mole) in THF (400 ml) at -35 ~C. The reaction WO 97/21693 PCT~rJS96~19782 was aged at -35 ~C for 20 h. The mixture was poured into a mixture of brine (200 ml), water (200 ml), and ethyl acetate (400 ml). The layers were cut and the organic layer was concentrated in VCIC~o to yield 69.0 g of product as an oil.
s HPLC assay Column: Zorbax Rx-C8 4.6mm x 25cm; Solvent: CH3CN:H2O(0.1 H3PO4) 60:40, Flow Rate: 1 ml/min; Wavelength: 220 nm; Column Temperature 25 ~C; Retention Times: Major isomer: 20.2 min; Minor 10 isomer:l8.~ min; and bromide: 7.~S min.
EXAMPLl~ 7 Lactate E~ter Hydrolysis MeO2C ~ MeO2C
~ O LiOH, H2O2 <~ ~¢~'~ .~OEt <O ~ OH
Hydrogen peroxide (3.5 1, 133.~ mole) was added to a solution of lithium hydroxide (709 g, 16.9 mole) in water (3.5 1) and the mixture was aged for 20 min at 20-25 ~C. This solution was then 2 0 slowly added over 30 min to a cold (0-5 ~~) solution of lactate ester g (3.1 kg, 6.76 mole) in THF (2~ 1). The reaction mixture was aged for 30 min, cooled to 0-5 ~C and ~luenched with sat'd aqueous sodium bisulfite (6 1). Saturated aqueous ammonium chloride (41) and methyl t-butyl ether (36 1) was added and after agitation the layers were 2 5 separated. The organic layer was dried over MgSO4 (1 kg) and then concentrated in vacuo to yield 2.6 kg of crude product as a dark oil which was used without futher purification.
W O 97/21693 PCT~US96/19782 EXAMPLE P~
o~ ~,OH2( )2 , CH3 O OCH2CI2 DMF Et3N
O O
<~--~~~ N~
To a solution of the ketoacid (29.1 g) in methylene chloride (375 ml) was added 3 ml of DMF. Oxalyl chloride (13.1 ml) was added dropwise and the mixture stirred for 30 minutes. The mixture was cooled to 0 ~C and the hydroxyamide (20.4 g) was added. Triethyl amine (42 ml) was added drowise and the mixture aged for 30 minutes.
I () The reaction was quenched with water (200 ml) and the organic layer was washed with saturated sodium bicarbonate (200 ml), dried with MgSO4 and concentrated to yield 44.4 g of product as an oil.
CA 02238960 l998-05-28 ~XAMPLE 9 ~ O ~
olC~ ~ N~ NaBH4 OH O
~ ~~ ~~ N~
To a solution of ketoester (44.4 g) in THF (300 ml) was 5 added in water (30 ml). Sodium borohydride (2.1 g) was added in portion~ over 15 minlltes and the mixture was aged for 30 minute~. The reaction wa,s quenched with brine (200 ml) and the phases separated.
The aqueous phase wals extracted with ethyl acetate and the combined organics were dried over MgSO4 and concentrated to yield 44.4 g of I () the product as an oil.
<0~ ~ CH3 O ~ ~O J~
1 5 To a solution of alcohol (8.1 g) in methylene chloride (60 ml) at 0 ~C was added P13r3 (0.96 ml) over 5 minutes. The mixture was aged for 30 minutes and quenched with 50 ml of saturated ~sodium bicarbonated. The layers were separated and the a~lueous was extracted with methylene chloride (100 ml). The combined organics were dried 2 û over MgSO4 and concentrated to provide 7.3 g of product a.s an oil.
W O 97/21693 PCT~US96/19782 EXAMPLE 1 l Phenoxide Couplin~:
<~ ~b~ ~J~N,~ 5O
O-Li+
2 r MeO2C~
O O
< ~ J~ N~
To a solution of methyl4-hydroxy-3-n-propylbenzoate (122 mg, 0.62 mmol) in THF (2 ml) at ambient temperature was added lithium t-butoxide (0.63 ml of a lM solution, 0.63 mmol) in one portion. The lithium salt thus formed was added via cannula to a THF
I û (3 ml) solution of bromide 1 (220 mg, 0.~7 mmol). The reaction was stirred for I h at room temperature at which time HPLC assay indicated <1% bromide rem;~ining. The reaction was quenched with water (10 ml) and EtOAc (10 ml) was added. The phases were separated and the aqueous phase was extracted with EtOAc (lx10 ml). The combined I S organic phase~s were washed with brine (lx10 ml) and concentrated in vacuo to give 290 mg of crude material. The product was isolated as a 9g:2 mixture of diastereomers (determined by HPLC) and was used without further purification.
W O g7121693 PC~US96~19782 HPLC assay:
Column: Supelcosil LC-CN 250 mm x 4.6 mm; Solvent: Hexane:IPA
98:2; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column Temperature: 25 ~C; Retention times: major isomer: 14.4 min; minor isomer: 17.2 min; and bromide: 13.2 min., 15.5 min.
MeO2C ~ MeO2C
LiOH, H2~2 THF o~OH
I 0 To a solution of 4.1 g of ester in 33 ml TH~ at 0 ~C was added a mixture of 696 mg of LiOH and hydrogen peroxide (6.~ ml).
The reaction was aged for 1 hour and quenched with 20 ml of saturated sodium bisulfite. The phases were separated and the aqueous phase was extracted with 50 ml CH2C12. The combined organic pha~e were dried 1 5 over MgSO4 and concentrated to yield 5.1 g of acid.
W O 97/21693 PCTnUS96/19782 o t THF, RT ~
Example R R2Rl Time (h3 Yield( % ) DR*
13 Et H nPr 8 76 95:5 14 Ph H H 0.2~ 7~s 97:3 Ph H nPr 0.25 77 97:3 16 Ph OMe H 0.25 88 98:2 1 7t Ph OMe H 0.10 87 99:1 5 * Diastereomeric ratio (DR) determined via HPLC utilizing either a Supelcosil LC CN
column or a Chiracel OD column. Diastereoselectivities could also be obtained via 300MHz I H NMR.
t Reaction conducted utilizing the oc-iodoester.
Following the procedures described hereinabove the 10 aLlcylated compound 4 (wherein R, Rl and R2 are a~ defined above), was prepared.
Claims (19)
1. A process for the preparation of a compound of formula:
wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary selected from the group consisting of:
, or ;
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2, (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii)-OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CONR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (j) -NR7COOR12, (k) -SO2NR7R12, (l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, , or (e) (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or -NR7;
R 13 is (C1-C6)-alkyl, phenyl or cyclohexyl;
R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl;
which comprises alkylating a halo derivative wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
, wherein M+ is Na+, K+, Li+, or N(R16)4+; and R16 is H or (C1-C6)-alkyl;
in an organic solvent at a temperature range of about -60 °C to about 30 °C for about 30 minutes to 30 hours to give an alkylated derivative bearing the chiral auxiliary:
.
wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary selected from the group consisting of:
, or ;
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2, (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii)-OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CONR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (j) -NR7COOR12, (k) -SO2NR7R12, (l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, , or (e) (f) CF3;
R7 and R 12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or -NR7;
R 13 is (C1-C6)-alkyl, phenyl or cyclohexyl;
R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl;
which comprises alkylating a halo derivative wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
, wherein M+ is Na+, K+, Li+, or N(R16)4+; and R16 is H or (C1-C6)-alkyl;
in an organic solvent at a temperature range of about -60 °C to about 30 °C for about 30 minutes to 30 hours to give an alkylated derivative bearing the chiral auxiliary:
.
2. A method for the preparation of a compound of formula:
wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary selected from the group consisting of:
,or Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2, (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii) -OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CoNR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (i) -NR7COOR12, (k) -SO2NR7R12, (l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-c4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, (e) , or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or -NR7;
R13 is (C1-C6)-alkyl, phenyl or cyclohexyl;
R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl;
comprising the steps of:
1) alkylating a halo derivative wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
, wherein M+ is Na+, K+, Li+, or N(R16)4+; and R16 is H
or (C1-C6)-alkyl;
in an organic solvent at a temperature range of about -60 °C to about 30 °C for about 30 minutes to about 30 hours to give an alkylated derivative bearing the chiral auxiliary:
; and 2) hydrolyzing the chiral auxiliary of the alkylated derivative with an inorganic base and peroxide in an aqueous solvent mixture to give a salt of the acid:
wherein M+ is Na+, K+, or Li+;
3) neutralizing the salt of the acid with an acidic solution to give an acid:
.
wherein:
* designates a stereogenic center;
Rc is: a chiral auxiliary selected from the group consisting of:
,or Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R1, R2, R3, R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2, (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s -Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii) -OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CoNR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (i) -NR7COOR12, (k) -SO2NR7R12, (l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-c4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, (e) , or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl, or Q is O, S or -NR7;
R13 is (C1-C6)-alkyl, phenyl or cyclohexyl;
R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl;
comprising the steps of:
1) alkylating a halo derivative wherein X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
with an aryloxy derivative:
, wherein M+ is Na+, K+, Li+, or N(R16)4+; and R16 is H
or (C1-C6)-alkyl;
in an organic solvent at a temperature range of about -60 °C to about 30 °C for about 30 minutes to about 30 hours to give an alkylated derivative bearing the chiral auxiliary:
; and 2) hydrolyzing the chiral auxiliary of the alkylated derivative with an inorganic base and peroxide in an aqueous solvent mixture to give a salt of the acid:
wherein M+ is Na+, K+, or Li+;
3) neutralizing the salt of the acid with an acidic solution to give an acid:
.
3. The method as recited Claim 2, wherein RC is:
.
.
4. The method as recited Claim 3, wherein the organic solvent in the alkylation step is tetrahydrofuran and t-butanol.
5. The method as recited Claim 4, wherein M+ in the alkylation step is Li+.
6. The method as recited Claim 5, wherein the reaction time in the alkylation step is about one hour.
7. The method as recited Claim 6. wherein the reaction temperature in the alkylation step is about room temperature.
8. The method as recited Claim 2, wherein Rc is:
.
.
9. The method as recited Claim 8, wherein the organic solvent in the alkylation step is tetrahydrofuran and t-butanol.
10. The method as recited Claim 9, wherein M+ in the alkylation step is Li+.
11. The method as recited Claim 10, wherein the reaction time in the alkylation step is about one hour.
12. The method as recited Claim 11, wherein the reaction temperature in the alkylation step is about room temperature.
13. The method as recited Claim 12, wherein the base in the hydrolysis step is lithium hydroxide.
14. The method as recited Claim 13, wherein the peroxide in the hydrolysis step is hydrogen peroxide.
15. The method as recited Claim 14, wherein the aqueous solvent in the hydrolysis step is tetrahydrofuran and water.
16. The method as recited Claim 15, wherein the acidic solution in the neutralization step is a saturated aqueous ammounium chloride solution.
17. A compound of formula:
wherein:
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperadinyl or pyrrolidinyl.
wherein:
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (C1-C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperadinyl or pyrrolidinyl.
18. A compound of formula:
wherein:
X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
Rc is: a chiral auxiliary selected from the group consisting of:
, or ;
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2 (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s-Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii) -OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CONR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (j) -NR7COOR12, (k) -SO2NR7R12;
(l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, (e) , or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl; and Q is O, S or -NR7;
R13 is (C1-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (C1-C10)-alkyl or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
wherein:
X is Cl, Br, I, Omesylate, Otosylate or Otriflate;
Rc is: a chiral auxiliary selected from the group consisting of:
, or ;
Ra is (C1-C6)-alkyl, phenyl or cyclohexyl;
R is (a) (C1-C6)-alkyl, (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substitutents defined as R4, R5 and R6;
R4, R5 and R6 are independently:
(a) H, (b) F, Cl, Br, or I, (c) -NO2 (d) -NH2, (e) -NH(C1-C4)-alkyl, (f) -N[(C1-C4)-alkyl]2, (g) -SO2NHR7, (h) -CF3, (i) (C1-C6)-alkyl, (j) -OR7, (k) -S(O)n-(C1-C4)-alkyl, (l) -NHCO-(C1-C4)-alkyl, (m) -NHCO-O(C1-C4)-alkyl, (n) -CH2O-(C1-C4)-alkyl, (o) -O-(CH2)m-OR7, (p) -CONR7R12, (q) -COOR7, or (r) -phenyl;
R4 and R5 on adjacent carbon atoms can be joined together to form a ring structure:
;
A represents:
(a) -Y-C(R8)=C(R9)-, (b) -Y-C(R8)=N-, (c) -Y-N=C(R8)-, (d) -Y-[C(R10)(R10)]s-Y-, (e) -Y-C(R8)(R8)-C(R8)(R8)-, (f) -C(R8)=C(R9)-Y-, (g) -N=C(R8)-Y-, (h) -C(R10)(R10)-C(R10)(R10)-Y-, or (i) -C(R8)=C(R9)-C(R8)=C(R9)-;
n is 0, 1 or 2;
m is 2, 3 or 4;
s is 1 or 2;
Y is -O-, -S(O)n- and -N(R12)-;
R7 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl, (d) (C1-C6)-alkylphenyl, or (e) (C3-C7)-cycloalkyl;
R8 and R9 are independently:
(a) H, (b) (C1-C6)-alkyl or (C2-C6)-alkenyl each of which is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) -OH, ii) -O-(C1-C4)-alkyl, iii) -S(O)n-(C1-C4)-alkyl, iv) -NR7-(C1-C4)-alkyl, v) -NHR7, vi) -COOR7, vii) -CONHR7, viii) -OCOR12, or ix) -CONR7R12, (c) (C3-C7)-cycloalkyl, (d) F, Cl, Br, I, (e) CF3, (f) -COOR7, (g) -CONR7R12, (h) -NR7R12, (i) -NR7CONR7R12, (j) -NR7COOR12, (k) -SO2NR7R12;
(l) -O-(C1-C4)-alkyl, (m) -S(O)n-(C1-C4)-alkyl, or (n) -NHSO2R12;
R10 is:
(a) H, (b) (C1-C4)-alkyl unsubstituted or substituted with one of the following substituents:
i) -OH, ii) -NR7R12, iii) -COOR7, iv) -CONHR7, or v) -CONR7R12, or (c) Cl, or F;
R12 is (a) (C1-C6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -OR7, ii) -N[R7]2, iii) -NH2, iv) -COOR7, v) -N[CH2CH2]2Q, vi) -CF3, or vii) -CON(R7)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) (C1-C4)-alkyl, ii) -O-(C1-C4)-alkyl, iii) -CO[NR7]2, iv) F, Cl, Br or I, v) -COOR7, vi) -NH2, vii) -NH[(C1-C4)-alkyl], viii) -N[(C1-C4)-alkyl]2, or ix) -CON[CH2CH2]2Q;
(c) -(C1-C4)-alkylaryl, wherein aryl is as defined above, (d) (C3-C7)-cycloalkyl, (e) , or (f) CF3;
R7 and R12 on the same nitrogen atom they can join together to form a ring selected from the group consisting of:
morpholinyl, piperazinyl, or pyrrolyl; and Q is O, S or -NR7;
R13 is (C1-C6)-alkyl, phenyl or cyclohexyl; and R14 and R15 are independently: (C1-C10)-alkyl or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
19. The compound, as recited in Claim 18, of the formula:
, wherein:
X is Br or I;
RC is:
; and R is ethyl, phenyl or 3,4 methylenedioxyphenyl.
, wherein:
X is Br or I;
RC is:
; and R is ethyl, phenyl or 3,4 methylenedioxyphenyl.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US875895P | 1995-12-12 | 1995-12-12 | |
| US60/008,758 | 1995-12-12 | ||
| GBGB9602833.7A GB9602833D0 (en) | 1996-02-13 | 1996-02-13 | Stereoselective process |
| US1328896P | 1996-03-12 | 1996-03-12 | |
| US60/013,288 | 1996-03-12 | ||
| GBGB9608928.9A GB9608928D0 (en) | 1996-04-29 | 1996-04-29 | Stereoselective process |
| GB9602833.7 | 1996-04-29 | ||
| GB9608928.9 | 1996-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2238960A1 true CA2238960A1 (en) | 1997-06-19 |
Family
ID=27451397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2238960 Abandoned CA2238960A1 (en) | 1995-12-12 | 1996-12-09 | Stereoselective process |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0869950A1 (en) |
| JP (1) | JP2000501737A (en) |
| AU (1) | AU703380B2 (en) |
| CA (1) | CA2238960A1 (en) |
| WO (1) | WO1997021693A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6699896B1 (en) | 1998-05-12 | 2004-03-02 | Wyeth | Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
| US6221902B1 (en) | 1998-05-12 | 2001-04-24 | American Home Products Corporation | Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
| CA2331056A1 (en) | 1998-05-12 | 1999-12-02 | Wyeth | 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia |
| US6232322B1 (en) | 1998-05-12 | 2001-05-15 | American Home Products Corporation | Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
| US6110963A (en) * | 1998-05-12 | 2000-08-29 | American Home Products Corporation | Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
| US6166069A (en) | 1998-05-12 | 2000-12-26 | American Home Products Corporation | Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
| US6451827B2 (en) | 1998-05-12 | 2002-09-17 | Wyeth | 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia |
| US6310081B1 (en) | 1999-05-10 | 2001-10-30 | American Home Products Corporation | Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
| JP2004521124A (en) | 2001-02-09 | 2004-07-15 | メルク エンド カムパニー インコーポレーテッド | 2-Aryloxy-2-arylalkanoic acids for diabetes and lipid disorders |
| JP5576791B2 (en) * | 2008-06-03 | 2014-08-20 | 株式会社カネカ | Method for producing optically active amino acid derivative |
-
1996
- 1996-12-09 AU AU12878/97A patent/AU703380B2/en not_active Ceased
- 1996-12-09 WO PCT/US1996/019782 patent/WO1997021693A1/en not_active Application Discontinuation
- 1996-12-09 CA CA 2238960 patent/CA2238960A1/en not_active Abandoned
- 1996-12-09 EP EP96943713A patent/EP0869950A1/en not_active Withdrawn
- 1996-12-09 JP JP09522200A patent/JP2000501737A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU1287897A (en) | 1997-07-03 |
| EP0869950A1 (en) | 1998-10-14 |
| WO1997021693A1 (en) | 1997-06-19 |
| AU703380B2 (en) | 1999-03-25 |
| JP2000501737A (en) | 2000-02-15 |
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