# US 7,608,614 B2 · Process for preparing macrocyclic compounds

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- Number: US 7,608,614 B2
- Document ID: US7608614B2
- Status: Granted
- Kind: B2
- Application number: 11/276,573
- Filed: 2006-03-06
- Published: 2006-09-14
- Granted: 2009-10-27
- Earliest claimed: 2005-03-08
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Carl Alan Busacca; Fabrice Gallou; Nizar Haddad; Azad Hossain; Suresh R. Kapadia; Jianxiu Liu; Chris Senanayake; Xudong Wei; Nathan K. Yee
- Web page: https://patentgrep.com/patent/US7608614B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/04: Ortho-condensed systems
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Intermediates of the formula QUIN: and methods for their preparation are described. The intermediate compounds are useful for preparing active agents for the treatment of hepatitis C virus (HCV) infection.

## Claims

### Claim 1

A compound of the following formula QUIN:
wherein:
L0 selected from H, —OH, —OCH3, —OC2H5, —OC3H7, —OCH(CH3)2, —NHCH3, —NHC2H5, —NHC3H7, —NHCH(CH3)2, —N(CH3)2, —N(CH3)C2H5, —N(CH3)C3H7 and —N(CH3)CH(CH3)2,
L1 and L2 are each independently selected from hydrogen, fluorine, chlorine, bromine, —CH3, —C2H5, —C3H7, —CH(CH3)2, —OCH3, —OC2H5, —OC3H7 and —OCH(CH3)2,
R2 is C1-6 thioalkyl, C1-6 alkoxy, or Het, where Het is selected from the following:
wherein R6 is H, C1-6 alkyl, NH—R7, NH—C(O)—R7, or NH—C(O)—NH—R7,
wherein each R7 is independently: H, C1-6 alkyl, or C3-6 cycloalkyl;
or R6 is NH—C(O)—OR8, wherein R8 is C1-6 alkyl;
and R is a C6 or C10 aryl group.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein:
L0 is selected from H, —OH, —OCH3 and —N(CH3)2;
one of L1 and L2 is —CH3, —F, —Cl or —Br and the other of L1 and L2 is H, or both L1 and L2 are H;
R2is
wherein R6 NH—R7 NH—C(O)—
R7, wherein R7 is independently: C1-6 alkyl, or C3-6 cycloalkyl;
and R is a C6 or C10 aryl group.

### Claim 3 (depends on 2)

A compound according to claim 2, having the following formula:
wherein:
L0 is —OCH3;
L1 is —CH3, —F, —Cl or —Br and L2 is H, or both L1 and L2 are H;
R6 is NH—R7 or NH—C(O)—R7, wherein R7 is independently: C1-6 alkyl or C3-6 cycloalkyl;
and R is a C6 or C10 aryl group.

### Claim 4 (depends on 1)

A process for preparing a compound of formula QUIN according to claim 1, said process comprising:
reacting a compound II with a halogenating agent to obtain a compound of formula III wherein X is a halogen atom, and then reacting a compound of formula III with a sulfinate salt RSO2M, wherein M is an alkali metal, to obtain a compound QUIN, and wherein L0, L1, L2, R2 and R are as defined in claim 1.

### Claim 5 (depends on 4)

A process according to claim 4, wherein the halogenating agent is selected from POX3 and PX5, where X═F, Cl, Br or I, and wherein the sulfinate salt RSO2M is PhSO2Na.

### Claim 6 (depends on 1)

A process for preparing a compound of formula QUIN according to claim 1, said process comprising:
reacting a compound II with an arene sulfonylchloride compound RASO2Cl, wherein RA is a neutral or electron rich arene group, in the presence of a suitable base in a suitable solvent, and then reacting the resulting compound in the presence of an acid with a sulfinate salt RSO2M,
wherein M is an alkali metal, to obtain a compound QUIN, and wherein L0, L1, L2, R2 and R are as defined in claim 1.

### Claim 7 (depends on 6)

A process according to claim 6, wherein in the first step the arene sulfonylchloride compound RASO2Cl is benzenesulfonyl chloride or tosyl chloride, the base is N-methylpyrrolidine or diisopropylethylamine, and the solvent is selected from acetonitrile, THF, toluene and DMF; and in the second step the acid is acetic acid, trifluoroacetic acid or hydrochloric acid and the sulfinate salt RSO2M is PhSO2Na, PhSO2K or PhSO2Cs.

### Claim 8 (depends on 7)

A process according to claim 7, wherein the arene sulfonylchloride compound RASO2Cl is benzenesulfonyl chloride, the base is N-methylpyrrolidine, the solvent is acetonitrile, the acid is acetic acid and sulfinate salt RSO2M is PhSO2Na.

### Claim 9 (depends on 1)

A compound according to claim 1, which is selected from the compounds of the following formula:
wherein Ph is phenyl and L0, L1, L2 and R2 are:
Cpd #
L2
L0
L1
R2
301
H
—OMe
Me
302
H
—OMe
Me
303
H
—OMe
Me
304
H
—OMe
Me
305
H
—OMe
Br
306
H
—OMe
Br
307
H
—OMe
Cl
308
H
—OMe
Cl
309
Me
—OMe
Me
310
Me
—OMe
Me
311
H
—OMe
F
312
H
—OMe
F
313
H
—OMe
Cl
314
H
—OMe
Br
315
H
—OMe
Br
316
H
—OMe
Br

### Claim 10 (depends on 1)

A compound according to claim 1, which is selected from the compounds of the following formula:
wherein Ph is phenyl and R2 is:
Cpd #
R2
401
402
403
404
OEt;
405
OEt;
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
OEt;
421
422
423
and 424

### Claim 11 (depends on 9)

A compound according to claim 9, which is Cpd #301.

### Claim 12 (depends on 9)

A compound according to claim 9, which is Cpd #302.

### Claim 13 (depends on 9)

A compound according to claim 9, which is Cpd #303.

### Claim 14 (depends on 9)

A compound according to claim 9, which is Cpd #304.

### Claim 15 (depends on 9)

A compound according to claim 9, which is Cpd #305.

### Claim 16 (depends on 9)

A compound according to claim 9, which is Cpd #306.

### Claim 17 (depends on 9)

A compound according to claim 9, which is Cpd #307.

### Claim 18 (depends on 9)

A compound according to claim 9, which is Cpd #308.

### Claim 19 (depends on 9)

A compound according to claim 9, which is Cpd #309.

### Claim 20 (depends on 9)

A compound according to claim 9, which is Cpd #310.

### Claim 21 (depends on 9)

A compound according to claim 9, which is Cpd #311.

### Claim 22 (depends on 9)

A compound according to claim 9, which is Cpd #312.

### Claim 23 (depends on 9)

A compound according to claim 9, which is Cpd #313.

### Claim 24 (depends on 9)

A compound according to claim 9, which is Cpd #314.

### Claim 25 (depends on 9)

A compound according to claim 9, which is Cpd #315.

### Claim 26 (depends on 9)

A compound according to claim 9, which is Cpd #316.