# US 5,344,990 A · Process for the preparation of a renin inhibiting compound

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- Number: US 5,344,990 A
- Document ID: US5344990A
- Status: Granted
- Kind: A
- Application number: 08/131,837
- Filed: 1993-10-05
- Granted: 1994-09-06
- Earliest claimed: 1990-05-11
- Assignees: Abbott Laboratories
- Inventors: William R. Baker; Stephen L. Condon
- Web page: https://patentgrep.com/patent/US5344990A

## CPC

- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 295/26: Sulfur atoms
- C07K 5/06078: {and aromatic or cycloaliphatic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Intermediates and a process for their preparation are disclosed which are useful for the preparation of a renin inhibiting compound of the formula: ##STR1## wherein R is a nitrogen-containing heterocycle which is bonded via a nitrogen atom to the sulfonyl group, R.sub.6 is hydrogen, alkoxy, halogen or loweralkyl, R.sub.7 is loweralkyl having 2 to 7 carbon atoms, and R.sub.8 is loweralkyl, cycloalkyl, or aryl or a pharmaceutically acceptable acid addition salt thereof.

## Claims

### Claim 1

A process for the preparation of a substantially pure compound of the formula: ##STR6## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms and R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl wherein aryl is phenyl, naphthyl, tetrahydronaphthyl or indanyl wherein the aryl group is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or an acid addition salt thereof, comprising:
(a) hydrogenating a compound of the formula: ##STR7## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms, R.sub.7a is --CH.dbd.C(R.sub.7a1)(R.sub.7a2) wherein R.sub.7a1 and R.sub.7a2 are independently selected from hydrogen and loweralkyl, R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl as defined above and R" is benzyl, substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or (R'").sub.2 N-- wherein R"' is loweralkyl and
(b) removing the acetonide protecting group.

### Claim 2

A process for the preparation of a substantially pure compound of the formula: ##STR8## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms and R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl wherein aryl is phenyl, naphthyl, tetrahydronaphthyl or indanyl wherein the aryl group is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or an acid addition salt thereof, comprising:
(a) reacting a compound of the formula: ##STR9## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms, R.sub.7a is --CH.dbd.C(R.sub.7a1)(R.sub.7a2) wherein R.sub.7a1 and R.sub.7a2 are independently selected from hydrogen and loweralkyl and R" is benzyl, substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or (R"').sub.2 N-- wherein R"' is loweralkyl with an organometallic reagent of the formula R.sub.8 CH.sub.2 M wherein M is lithium or a magnesium halide and R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl as defined above to give a compound of the formula: ##STR10## (b) hydrogenating the product of step (a) and (c) removing the acetonide protecting group.

### Claim 3

A process for the preparation of a substantially pure compound of the formula: ##STR11## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms and R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl wherein aryl is phenyl, naphthyl, tetrahydronaphthyl or indanyl wherein the aryl group is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or an acid addition salt thereof, comprising:
(a) reacting a compound of the formula: ##STR12## wherein R.sub.7 is loweralkyl having 2 to 7 carbon atoms and R.sub.7a is --CH.dbd.C(R.sub.7a1)(R.sub.7a2) wherein R.sub.7a1 and R.sub.7a2 are independently selected from hydrogen and loweralkyl with R"NH.sub.2 wherein R" is benzyl, substituted benzyl wherein the phenyl ring of the benzyl group is substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide; or (R"').sub.2 N-- wherein R"' is loweralkyl to give a compound of the formula: ##STR13## (b) reacting the product of step (a) with an organometallic reagent of the formula R.sub.8 CH.sub.2 M wherein M is lithium or a magnesium halide and R.sub.8 is loweralkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl as defined above to give a compound of the formula: ##STR14## (c) hydrogenating the product of step (b) and (d) removing the acetonide protecting group.

### Claim 4 (depends on 1)

The process of claim 1 wherein R" is benzyl or (CH.sub.3).sub.2 N--, R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2 and R.sub.8 is cyclohexyl.

### Claim 5 (depends on 2)

The process of claim 2 wherein R" is benzyl or (CH.sub.3).sub.2 N--, R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2 and R.sub.8 is cyclohexyl.

### Claim 6 (depends on 3)

The process of claim 3 wherein R" is benzyl or (CH.sub.3).sub.2 N--, R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2 and R.sub.8 is cyclohexyl.

### Claim 7

A process for the preparation of a substantially pure compound of the formula: ##STR15## wherein R.sub.7 is isobutyl and R.sub.8 is cyclohexyl; or an acid addition salt thereof, comprising:
(a) hydrogenating a compound of the formula: ##STR16## wherein R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2, R.sub.8 is cyclohexyl and R" is benzyl or (CH.sub.3).sub.2 N-- and
(b) removing the acetonide protecting group.

### Claim 8

A process for the preparation of a substantially pure compound of the formula: ##STR17## wherein R.sub.7 is isobutyl and R.sub.8 is cyclohexyl; or an acid addition salt thereof, comprising:
(a) reacting a compound of the formula: ##STR18## wherein R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2 and R" is benzyl or (CH.sub.3).sub.2 N-- with an organometallic reagent of the formula R.sub.8 CH.sub.2 M wherein M is lithium or a magnesium halide and R.sub.8 is cyclohexyl to give a compound of the formula: ##STR19## wherein R.sub.7, R.sub.7a, R.sub.8 and R" are defined as above; (b) hydrogenating the product of step (a) and
(c) removing the acetonide protecting group.

### Claim 9

A process for the preparation of a substantially pure compound of the formula: ##STR20## wherein R.sub.7 is isobutyl and R.sub.8 is cyclohexyl; or an acid addition salt thereof, comprising:
(a) reacting a compound of the formula: ##STR21## wherein R.sub.7 is isobutyl and R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2 with R"NH.sub.2 wherein R" is benzyl or (CH.sub.3).sub.2 N-- to give a compound of the formula: ##STR22## wherein R.sub.7, R.sub.7a and R" are defined as above; (b) reacting the product of step (a) with an organometallic reagent of the formula R.sub.8 CH.sub.2 M wherein M is lithium or a magnesium halide and R.sub.8 is cyclohexyl to give a compound of the formula: ##STR23## wherein R.sub.7 is isobutyl, R.sub.7a is --CH.dbd.C(CH.sub.3).sub.2, R.sub.8 is cyclohexyl and R" is benzyl or (CH.sub.3).sub.2 N--;
(c) hydrogenating the product of step (b) and
(d) removing the acetonide protecting group.