# US 7,411,074 B2 · Process and intermediates for the preparation of the thienopyrrole derivatives

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- Number: US 7,411,074 B2
- Document ID: US7411074B2
- Status: Granted
- Kind: B2
- Application number: 10/528,974
- Filed: 2003-09-29
- Published: 2006-02-16
- Granted: 2008-08-12
- Earliest claimed: 2002-10-03
- Assignees: AstraZeneca AB
- Inventors: Paul Murray; Jeremy Stephen Parker; Paul Schofield; Andrew Stocker
- Web page: https://patentgrep.com/patent/US7411074B2

## CPC

- C07D 495/04: Ortho-condensed systems
- C07D 333/36: Nitrogen atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A process for preparing a compound of formula (I) where R4 and R5 are as defined in the specification; and R6 is hydrogen or a protecting group, which process comprises cyclisation of a compound of formula (II) where R4, R5 and R6 are as defined in relation to formula (I), and R7 is nitrogen-protecting group, and removing the group R7—, and thereafter if desired or necessary, removing any protecting group R6 to obtain the corresponding carboxylic acid. Novel intermediates and the use of the products in the preparation of pharmaceutical compounds is also described and claimed.

## Claims

### Claim 1

A process for preparing a compound of formula (I)
wherein
R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N—(C1-6alkyl)sulphamoyl, N,N,—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, and C1-6alkylsulphonyl-N—(C1-6alkyl)amino; and
R6 is hydrogen or a protecting group,
which process comprises cyclisation of a compound of formula (II)
wherein
R4, R5, and R6 are as defined in relation to formula (I); and
R7 is a nitrogen protecting group; and
removing protecting group R7, and thereafter if desired or necessary, removing any protecting group R6 to obtain the corresponding carboxylic acid.

### Claim 2 (depends on 1)

A process according to claim 1, wherein the protecting group R7 is removed during the cyclisation.

### Claim 3 (depends on 1)

A process according to claim 1, wherein in a structure of formula (II), R7 is a group of sub-formula (i)
wherein R8 is a straight chain alkyl group of from 1 to 6 carbon atoms.

### Claim 4 (depends on 1)

A process according to claim 1, wherein R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, and C1-4alkanoyloxy.

### Claim 5 (depends on 1)

A method according to claim 1, for the production of a second compound of formula (I) where R6 is hydrogen, further comprising reacting a first compound of formula (I) with an amine of formula (Xl),
where R14 is selected from hydrogen and C1-8alkyl;
m is an integer of from 0 to 4;
each R15 is the same or different and is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N—(C1-6alkyl)amino, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, aryl, arylC1-6alkyl, heterocyclic group, and (heterocyclic group)C1-6alkyl; wherein R15 may be optionally substituted on carbon with one or more P groups, and if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted with an R group;
each R16 is the same or different and is selected from hydrogen and C1-6alkyl;
R17 is selected from hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-4alkyl)2carbamoyl, N—(C1-6alkyl)-N—(C1-6alkoxy)carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, sulphamoylamino, N—(C1-6alkyl)sulphamoylamino, N,N—(C1-6alkyl)2sulphamoylamino, C1-6alkylsulphonylamino, C1-6alkylsulphonylaminocarbonyl, C1-6alkylsulphonyl-N—(C1-6alkyl)amino, and a group -E-F-G-H;
E and G are independently selected from a direct bond, —O—, —S—, —SOS—, —SO2—, —OC(O)—, —C(O)O—, —C(O)—, —NRa—, —NRaC(O)—, —C(O)NRa—, —SO2NRa—, —NRaSO2—, —NRaC(O)NRb—, —OC(O)NRa—, —NRaC(O)O—, —NRaSO2NRb—, —SO2NRaC(O)—, and —C(O)NRaSO2—; Ra and Rb are independently selected from hydrogen and C1-6alkyl which is optionally substituted with a V group;
F is C1-6alkylene optionally substituted by one or more Q or a direct bond;
H is selected from aryl, C3-8cycloalkyl, and heterocyclic group; wherein H may be optionally substituted on carbon with one or more S groups, and if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted with a T group;
P, S, and Q are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N—(C1-6alkyl)amino, N,N—(C1-6alkyl)2amino, C1-6alkanoylamino, N—(C1-6alkyl)carbamoyl, N,N—(C1-6alkyl)2carbamoyl, N—(C1-6alkyl)-N—(C1-6alkoxy)carbamoyl, C1-6alkylS(0)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N—(C1-6alkyl)sulphamoyl, N,N—(C1-6alkyl)2sulphamoyl, C1-6alkylsulphonylamino, C1-6alkylsulphonyl-N—(C1-6alkyl)amino, C3-8cycloalkyl, aryl, and heterocyclic group; wherein P, S, and Q may be optionally independently substituted on carbon with one or more V groups and if said heterocyclic group contains an —NH— moiety, that nitrogen may be optionally substituted by a U group;
V is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methyithia, ethyithia, methylsuiphinyl, ethylsuiphinyl, mesyl, ethylsuiphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl, N-methyl-N-ethylsulphamoyl, morpholino, morpholinocarbonyl, N- benzylcarbamoyl, and 4-hydroxypiperidinocarbonyl;
R, T, and U are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, carbamoyl, N—(C1-4alkyl)carbamoyl, N,N—(C1-4alkyl)carbamoyl, phenyl, benzyl, benzyloxycarbonyl, benzoyl, and phenylsulphonyl; wherein R, T, and U may be optionally independently substituted on carbon with one or more V groups; to produce a compound of formula (XII)
where R4, R5, R15, R16, R17, and m are as defined above, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.