Patent EA-002724-B1 (EA)
Title: Process for the preparation of azacycloalkylalkanoyl pseudotetrapeptides
Inventor: MENCEL JAMES J
IPC: C07K5/072
Filed: 1998-10-09
Abstract: 1. A process for preparing a pseudotetrapeptide compound of formula   or a salt or prodrug thereof wherein   is optionally amino protected 4-8 membered azaheterocyclyl;   is a single or double bond; q is 1-5; B is C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkylC1-C20alkyl, C1-C20alkylC3-C10cycloalkyl, C1-C20alkylC3-C10cycloalkylC1-C20alkyl, C6-C10aryl, C6-C10arC1-C20alkyl, C1-C20alkylC6-C10aryl or C1-C20alkylC6-C10arC1-C20alkyl; Q2 is H or a carboxy protecting group; J is -H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkylC1-C20alkyl, C1-C20alkylC3-C10cycloalkyl, C1-C20alkylC3-C10cycloalkylC1-C20alkyl, C6-C10aryl, substituted C6-C10aryl, C6-C10arC1-C20alkyl or substituted C6-C10arC1-C20alkyl; L is OR<1>, or NR<1>R<2>, where R<1> and R<2> are independently -H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl C1-C20alkyl,C1-C20alkyl C3-C10cycloalkyl, C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl, C6-C10aryl, C6-C10ar C1-C20alkyl,C1-C20alkyl C6-C10aryl, or C1-C20alkyl C6-C10ar C1-C20alkyl, and p is 1 or 2, comprising (a) coupling an azaheterocyclyl pseudodipeptide of formula   or a salt thereof wherein K is OH or an acyl activating group, with a carboxylic acid substituted dipeptide of formula   or a salt thereof; (b) optionally removing the amino protecting group or carboxylic acid protecting group and (c) optionally converting the pseudotetrapeptide to the salt or prodrug. 2. The process of Claim 1 wherein   is a group of formula   wherein m is 1 to 5, preferably 3; n is 2-6, preferably 3 or 4; and P1 is an amino protecting group, wherein  Q2 is a carboxy protecting group; wherein B is C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkylC1-C20alkyl, C1-C20alkyl C3-C10cycloalkyl, or C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl, J is -H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl C1-C20alkyl,C1-C20alkyl C3-C10cycloalkyl, or C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl. 3. The process of Claim 2 wherein B is C1-C20alkyl, J is C1-C20alkyl, C3-C10cycloalkyl, or C3-C10cycloalkyl C1-C20alkyl, R<1> and R<2> are independently -H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl C1-C20alkyl, C1-C20alkyl C3-C10cycloalkyl, C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl or C6-C10ar C1-C20alkyl, m is 3, n is 3 or 4, and p is 1. P1 is benzyloxycarbonyl and Q2 is H or benzyl, L is -NR<1>R<2>. 4. The process of Claim 1 wherein the salt of the azaheterocyclyl pseudodipeptide is coupled with the salt of the carboxylic acid substituted dipeptide or wherein a base addition salt of the azaheterocyclyl pseudodipeptide is coupled with an acid addition salt of the carboxylic acid substituted dipeptide or wherein the dicyclohexylamine salt of the azaheterocyclyl pseudodipeptide is coupled with the trifluoroacetate salt of the carboxylic acid substituted dipeptide. 5. The process of Claim 1 comprising (a) coupling a azaheterocyclyl pseudodipeptide of formula   or a base addition salt thereof, wherein P1 is an amino protecting group; and B is C1-C20alkyl, with a carboxylic acid substituted dipeptide of formula   or an acid addition salt thereof wherein Q2 is H or a carboxylic acid protecting group; J is C1-C20alkyl, C3-C10cycloalkyl, or C3-C10cycloalkyl C1-C20alkyl; and L is OR<1> or NR<1>R<2>, where R<1> and R<2> are independently H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl C1-C20alkyl, C1-C20alkyl C3-C10cycloalkyl, C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl or ar C1-C20alkyl, to prepare a pseudotetrapeptide of formula   (b) optionally removing the amino protecting group or carboxylic acid protecting group and (c) optionally converting the pseudotetrapeptide its salt or prodrug. 6. The process of Claim 5 wherein P1 is benzyloxycarbonyl, Q2 is a benzyl, B is ethyl, J is cyclohexylmethyl and L is NH2. 7. The process of Claim 5 wherein P1 is benzyloxycarbonyl, Q2 is H, B is ethyl, J is cyclohexylmethyl and L is NH2. 8. A process for preparing a cyclohexylmethyl substituted peptide of formula   wherein Q2 is H or a carboxylic acid protecting group; and Q3 is H or an amino protecting group; comprising (a) reducing a phenylmethyl substituted peptide of formula   and (b) optionally removing the amino protecting group or carboxylic acid protecting group. 9. The process of Claim 8 wherein the reducing is carried out by catalytic hydrogenation, preferably using a platinum catalyst, such as platinum oxide or platinum on alumina. 10. A process for preparing an amido dipeptide of formula   wherein Q2 is H or a base addition salt, or a carboxylic acid protecting group; and Q3 is H or a amino protecting group; comprising amidating a peptide ester of formula   wherein R<3> is C1-C10alkyl. 11. The process of Claim 10 wherein the amidating is carried out using ammonia in alcohol such as C1-C4alcohol, or ammonia in a C1-C4alcohol-C1-C3glycol solvent mixture, which comprises methanol and ethylene glycol. 12. A process for preparing a protected aspartame compound of formula   wherein Q2 is H or a carboxylic acid protecting group; Q3 is an amino protecting group; and R<3> is C1-C10alkyl; comprising introducing an amino protecting group to an aspartame compound of formula   13. The process of Claim 12 wherein Q3 is benzyloxycarbonyl or tret-butyloxycarbonyl. Q2 is H. 14. A process for preparing an amido dipeptide of formula   wherein Q3 is an amino protecting group; and Q2 is H, comprising (a) adding base and an amino protecting agent to a solution of aspartame in a solvent to form a solution of a compound of formula   wherein Q3 is H or a base addition salt, and (b) introducing ammonia into the resultant solution of step (a). 15. The process of Claim 14 wherein Q3 is tert-butyloxycarbonyl or benzyloxycarbonyl, the solvent is C1-C3alcohol, or C1-C3alcohol-C1-C3glycol mixture. 16. The process of Claim 15 wherein the solvent is methanol or a methanol-ethylene glycol mixture. 17. A process for preparing a cyclohexylmethyl substituted dipeptide of formula   or an acid addition salt thereof, comprising (a) preparing a mixture of a catalyst and a phenylmethyl substituted peptide of formula   wherein Q3 is tert-butyloxycarbonyl in a solvent, (b) treating the mixture with hydrogen, (c) removing the catalyst from the mixture, and (c) introducing gaseous HCl into the mixture. 18. The process of Claim 17 wherein the solvent is acetic acid. 19. A process for preparing an azaheterocyclyl substituted acid compound of formula   wherein R<4> is H or C1-C10alkyl and P1 is an amino protecting group, comprising (a) decarboxylating a 2-pyridylethyl-di(C1-C10alkyl) malonate of formula   wherein R<5> is C1-C10alkyl to prepare a pyridyl acid of formula:   (b) hydrogenating the pyridyl acid with hydrogen in the presence of a catalyst to prepare a piperidine acid of formula   (c) optionally removing the catalyst; (d) amino protecting the piperidine acid to prepare amino protected piperidine acid of formula   (e) coupling the amino protected piperidine acid with a N-ethylglycine compound of formula   to prepare the azaheterocyclyl substituted acid compound; and (f) optionally deesterifying the azaheterocyclyl substituted compound wherein R<4> is C1-C10alkyl. 20. The process of Claim 19 wherein P1 is benzyloxycarboxyl and R<4> is H, wherein the decarboxylating is carried out by heating the 2-pyridylethyl-di(C1-C10alkyl)malonate in an aqueous acid solution, wherein the hydrogenating is carried out in an aqueous acid solution, and wherein the amino protecting is carried out in an aqueous base solution. 21. The process of Claim 20 wherein the aqueous acid on the stage of decarboxylating and hydrogenating is aqueous HCl. 22. The process of Claim 20 wherein (a) a solution in aqueous acid of the 2-pyridylethyl-di(C1-C10alkyl) malonate is heated to prepare a solution of the pyridyl acid in aqueous acid; (b) a catalyst is added to the solution of pyridyl acid and the mixture is treated with hydrogen with to form a mixture of catalyst and the piperidine acid; (c) the catalyst is separated from the mixture to prepare an aqueous solution of piperidine acid; and (d) a base and amino protecting agent are added to the aqueous solution to prepare the amino protected piperidine acid. 23. A process for preparing a pseudotetrapeptide of formula   or a salt or prodrug thereof wherein m is 3; n is 2-6; B is C1-C20alkyl; p is 1 or 2: J is cyclohexylmethyl: and L is OR<1> or NR<1>R<2> wherein R<1> and R<2> are independently -H, C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkylC1-C20alkyl, C1-C20alkyl C3-C10cycloalkyl or C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl, comprising (a) reducing a pseudotetrapeptide compound of formula   wherein   is pyridyl or   wherein m is 3 and P1 is H or amino protecting group; Q2 is H or a carboxylic acid protecting group; J is phenylmethyl; (b) optionally removing the amino protecting group or carboxylic acid protecting group; and (c) optionally converting the pseudotetrapeptide to the salt or prodrug. 24. The process of Claim 23 wherein the reducing is by catalytic hydrogenation. 25. The process of Claim 24 wherein   is   wherein m is 3 P1 is amino protecting group, preferably unsteady to hydrogenation; n is 3; p is 1; and Q2 is a carboxylic acid protecting group, preferably unsteady to hydrogenation. 26. The process of Claim 25 wherein the catalytic reduction effects simultaneous reduction and removal of P1 and Q2. 27. The process of Claim 24 wherein   is pyridyl; and Q2 is a carboxylic acid protecting group, preferably unsteady to hydrogenation. 28. The process of Claim 27 wherein the catalytic reduction effects simultaneous reduction and removal of Q2. 29. A pseudotetrapeptide compound of formula   or a salt thereof wherein P1 is amino protecting group; B is C1-C20alkyl, C3-C10cycloalkyl, C3-C10cycloalkyl C1-C20alkyl,C1-C20alkyl C3-C10cycloalkyl, C1-C20alkyl C3-C10cycloalkyl C1-C20alkyl, C6-C10aryl, C6-C10ar C1-C20alkyl, C1-C20alkyl C6-C10aryl or C1-C20alkyl C6-C10ar C1-C20alkyl; and R<4> is H or C1-C10alkyl. 30. The pseudodipeptide compound of Claim 29 wherein P1 is amino protecting group,