Patent ID: 6316656
Filing Date: 2001-11-13
Classification: B01J,C07C

Abstract:
A process comprising the steps of:treating a compound of the formula (II or II.sub.1): ##STR15##wherein R.sub.1 is hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group;R.sub.2 is CH.sub.2 R.sub.9 wherein R.sub.9 is(a) hydrogen,(b) C.sub.1 -C.sub.4 alkyl optionally substituted with one or more hydroxyl, C.sub.1 -C.sub.3 alkoxy, chloro or fluoro,(c) phenyl optionally substituted with one to three of C.sub.1 -C.sub.4 alkyl, halogen where halogen is fluoro, chloro, bromo or iodo, hydroxyl, nitro, C.sub.1 -C.sub.3 alkoxy, or --CO--N(R.sub.7).sub.2 wherein R.sub.7 is, independently, H or C.sub.1 -C.sub.4 alkyl,(d) a 5-7 member heteroxycle such as pyridyl, furyl, indolyl or benzisoxazolyl,(e) C.sub.3 -C.sub.7 cycloalkyl, or(f) naphthyl;R'.sub.3 isR.sub.6 --C--R'.sub.8 or R'.sub.8 --C--R.sub.6wherein R.sub.6 is(1) hydrogen;(2) alkyl of from 1 to 6 carbons optionally substituted by one or two hydroxyl, chloro or fluoro;(3) cycloalkyl of from 3 to 7 ring carbons;(4) Ar.sub.4 which is a phenyl group, or a phenyl group substituted by one to three substituent(s) consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(5) Ar.sub.5 is a tolyl group;(6) Ar.sub.6 is a tolyl group substituted by one to three substituents consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(7) Ar.sub.7 which is naphthyl or naphthyl substituted by one to three substituents consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(8) Ar.sub.8 which is indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl;(9) NHA wherein A is(a) trityl,(b) hydrogen,(c) alkyl of from one to six carbons,(d) R.sub.10 CO wherein R.sub.10 is (A) hydrogen, (B) alkyl of from one to six carbons optionally substituted with hydroxyl, chloro, or fluoro, (C) phenyl or naphthyl unsubstituted or substituted with one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons, or (D) a 5 to 7 member heterocycle such as indolyl, pyridyl, furyl or benzisoxazolyl;(e) phthaloyl wherein the aromatic ring is optionally substituted by one to three of (A) alkyl of from to three carbons, (B) halogen where halogen is F, Cl, Br, or I, (C) hydroxy, (D) nitro, (E) alkoxy of from one to three carbons, (F) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons,(f) R.sub.12 (R.sub.13 R.sub.14 C).sub.m CO wherein m is one to three and R.sub.12, R.sub.13, and R.sub.14 are independently (A) hydrogen, (B) chloro or fluoro, (C) alkyl of from one to three carbons optionally substituted by chloro, fluoro, or hydroxy, (D) hydroxy, (E) phenyl or naphthyl optionally substituted by one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons, (F) alkoxy of from one to three carbons, (G) 5 to 7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl, or (H) R.sub.12 R.sub.13, and R.sub.14 are independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is a cycloalkyl of from three to six carbons, except that only one of R.sub.12, R.sub.13 and R.sub.14 can be hydroxy or alkoxy on the same carbon and can not by hydroxy, chloro or fluoro when m is one;(g) R.sub.12 (R.sub.13 R.sub.14 C).sub.m W wherein m is independently 1 to 3 and W is OCO or SO.sub.2 and R.sub.12, R.sub.13, and R.sub.14 are independently as defined above;(h) R.sub.20 W wherein R.sub.20 is a 5 to 7 member heterocycle;(i) R.sub.21 W wherein R.sub.21 is phenyl or naphthyl unsubstituted or substituted by one to three substituents of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons;(j) R.sub.12 (R.sub.13 R14C).sub.m P(O)(OR.sub.22) wherein R.sub.22 is alkyl of from one to four carbons or phenyl;(k) R.sub.20 P(O)(OR.sub.22) wherein R.sub.22 is as defined above; or(l) R.sub.21 P(O)(OR.sub.22) wherein R.sub.22 is as defined above; N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above;(10) R.sub.12 (R.sub.13 R.sub.14 C).sub.m V wherein V is 0 or NH and R.sub.12 (R.sub.13 R.sub.14 are independently as defined above;(11) N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above;(12) NR.sub.15 NR.sub.16 wherein R.sub.15 and R.sub.16 are joined to form a 4 to 6 membered saturated nitro containing heterocycle which is (i) azetidinyl, (ii) pyrrolidinyl, (iii) piperidinyl, or (iv) morpholinyl(13) R.sub.17 OCH.sub.2 O wherein R.sub.17 is(a) alkyl of from one to six carbons,(b) R.sub.21 wherein R.sub.21 is independently defined as above; or(c) CH.sub.2 Q.sub.1 wherein Q.sub.1 is phenyl, naphthyl or a 5 to 7 membered heterocycle,;(14) R.sub.17 OCH.sub.2 CH.sub.2 OCH.sub.2 wherein R.sub.17 is independently as defined above;(15) alkynyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; or(16) alkenyl of from two to six carbons optionally substituted with R.sub.21 wherein in R.sub.21 is independently as defined above; andR'.sub.8 is hydrogen, C.sub.1 -C.sub.4 alkyl or cycloalkyl; andR'.sub.4 is hydrogen, an amino acid radical or a protecting group such as a substituted or unsubstituted acyl;R'.sub.5 is hydrogen,with hydrogen in the presence of rhodium (R,R)-(1,2-ethanediyl)bis{(ortho-methoxyphenyl)phenylphosphine}(H.sub.2 RhDiPAMP) in a deoxygeneated solvent; anddeprotecting the nitrogen to obtain a compound of the formula (I or I.sub.1): ##STR16##wherein R.sub.1 and R.sub.2 are as previously described,wherein R.sub.3 is R.sub.6 --CH--R.sub.8 wherein one of R.sub.6 and R.sub.8 is hydrogen and the other is(1) hydrogen;(2) alkyl of from 1 to 6 carbons optionally substituted by one to two hydroxyl, chloro or fluoro;(3) cycloalkyl of from 3 to 7 ring carbons;(4) Ar.sub.4 is a phenyl group, or a phenyl group substituted by one to three substituent(s) consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(5) Ar.sub.5 is a tolyl group;(6) Ar.sub.6 is a tolyl group substituted by one to three substituents consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(7) Ar.sub.7 is naphthyl or a naphthyl substituted by one to three substituents consisting of(a) alkyl of from one to four carbons,(b) halogen consisting of fluoro, chloro, bromo, or iodo,(c) alkoxy of from one to three carbons,(d) nitro,(e) amido,(f) mono- or di- alkyl (of from one to four carbons) amido, or(g) hydroxy;(8) Ar.sub.8 is indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl;(9) NHA wherein A is(a) trityl,(b) hydrogen,(c) alkyl of from one to six carbons,(d) R.sub.10 CO wherein R.sub.10 is (A) hydrogen, (B) alkyl of from one to six carbons optionally substituted with hydroxyl, chloro, or fluoro, (C) phenyl or naphthyl unsubstituted or substituted with one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons, or (D) a 5 to 7 member heterocycle such as indolyl, pyridyl, furyl or benzisoxazolyl;(e) phthaloyl wherein the aromatic ring is optionally substituted by one to three of (A) alkyl of from to three carbons, (B) halogen where halogen is F, Cl, Br, or I, (C) hydroxy, (D) nitro, (E) alkoxy of from one to three carbons, (F) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons,(f) R.sub.12 (R.sub.13 R.sub.14 C).sub.m CO wherein m is one to three and R.sub.12, R.sub.13, and R.sub.14 are independently (A) hydrogen, (B) chloro or fluoro, (C) alkyl of from one to three carbons optionally substituted by chloro, fluoro, or hydroxy, (D) hydroxy, (E) phenyl or naphthyl optionally substituted by one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, or (vi) CON(R.sub.11).sub.2 wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons, (F) alkoxy of from one to three carbons, (G) 5 to 7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl, or (H) R.sub.12 R.sub.13, and R.sub.14 are independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is a cycloalkyl of from three to six carbons, except that only one of R.sub.12, R.sub.13 and R.sub.14 can be hydroxy or alkoxy on the same carbon and can not be hydroxy, chloro or fluoro when m is one;(g) R.sub.12 (R.sub.13 R.sub.14 C).sub.m W wherein m is independently 1 to 3 and W is OCO or SO.sub.2 and R.sub.12, R.sub.13, and R.sub.14 are independently as defined above;(h) R.sub.20 W wherein R.sub.20 is a 5 to 7 member heterocycle;(i) R.sub.21 W wherein R.sub.21 is phenyl or naphthyl unsubstituted or substituted by one to three substituents of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R.sub.11) wherein R.sub.11 is independently hydrogen or alkyl of from one to four carbons;(j) R.sub.12 (R.sub.13 R.sub.14 C).sub.m P(O)(OR.sub.22) wherein R.sub.22 is alkyl of from one to four carbons or phenyl;(k) R.sub.20 P(O)(OR.sub.22) wherein R.sub.22 is as defined above; or(l) R.sub.21 P(O)(OR.sub.22) wherein R.sub.22 is as defined above; N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above;(10) R.sub.12 (R.sub.13 R.sub.14 C).sub.m V wherein V is O or NH and R.sub.12, R.sub.13, and R.sub.14 are independently as defined above;(11) N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above;(12) NR.sub.15 NR.sub.16 wherein R.sub.15 and R.sub.16 are joined to form a 4 to 6 membered saturated nitrogen containing heterocycle which is (a) azetidinyl, (b) pyrrolidinyl, (d) piperidinyl, or (d) morpholinyl;(13) R.sub.17 OCH.sub.2 O wherein R.sub.17 is(a) alkyl of from one to six carbons,(b) R.sub.21 wherein R.sub.21 is independently defined as above; or(c) CH.sub.2 Q.sub.1 wherein Q.sub.1 is phenyl, naphthyl or a 5 to 7 membered heterocycle,;(14) R.sub.17 OCH.sub.2 CH.sub.2 OCH.sub.2 wherein R.sub.17 is independently as defined above;(15) alkynyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; or(16) alkenyl of from two to six carbons optionally substituted with R.sub.21 wherein in R.sub.21 is independently as defined above;R.sub.4 is hydrogen, an amino acid radical or a protecting group;R.sub.5 is independently hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group.