Process and intermediates for preparing macrolactams

Patent metadata

Field	Value
Publication number	US-9238604-B2
Application number	US-201214239393-A
Country	US
Kind code	B2
Filing date	Aug 16, 2012
Priority date	Aug 19, 2011
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams from the intermediates. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.

First claim

What is claimed is:

1. A method of making Compound A or a salt thereof:

comprising
the steps of:
(i) reacting

 with

 by SNAR replacement to form Compound 13 and deprotecting

 to form

 wherein Compound 13 is not isolated prior to deprotection, and PG is a protecting group;
(ii) coupling Compound 14 with

 to produce

(iii) without isolating Compound 16, hydrogenating Compound 16 to produce

(iv) without isolating Compound 21, lactamizing Compound 21 to produce

(v) converting Compound 18 to

(vi) coupling
 or salt thereof, to

 or salt thereof,

wherein the coupling of step (vi) comprises the use of a coupling reagent and a compound selected from the group consisting of

 wherein R 5 is either hydrogen, aryl, halogen, C 1-6 alkyl, O—C 1-6 alkyl or C 3 -C 8 cycloalkyl, and wherein any of Compounds 11, 12, 13, 14, 15, 16, 21, and 18 independently may be provided as salts.

2. The method of claim 1 , wherein said coupling reagent is EDC, and the method comprises the use of at least 10 equivalents of pyridine and the use of acetonitrile as solvent.

3. The method of claim 1 , wherein said coupling reagent is EDC, and the method comprises the use of THF-DMAc as solvent and a temperature range of −10° C. to 50° C.

4. A compound selected from the group consisting of: a MeCN solvate of a methylsulfonic acid salt of

wherein said solvate is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2Θ values in degrees of about 5.3, 12.0, and 14;

or a salt thereof.

5. The compound of claim 4 , wherein said compound is a MeCN solvate of a Compound 14 methylsulfonic acid salt, wherein said solvate is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2Θ values in degrees of about 5.3, 12.0, and 14.

6. A method of making a compound of claim 4 , wherein the compound is Compound 16, said method comprising the step of:

wherein Compounds 14, 15, and 16 may be provided as a salt.

7. A method of making a compound of claim 4 , wherein the compound is Compound 17, said method comprising the steps of:

wherein Compounds 14, 15, 16, and 17 may be provided as a salt, and Compound 16 is not isolated prior to lactamization.

8. A compound selected from the group consisting of
a hydrate of Compound 19

wherein said hydrate of Compound 19 is characterized by either (i) an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2Θ values in degrees of about 8.7, 22.2, and 23.5; or (ii) a solid state carbon−13 CPMAS NMR comprising peaks at about 174.7, 172.0, 161.4, 156.8, 156.3, 149.5, 142.1, 133.9, 128.2, 121.3, 105.0, 76.9, 60.7, 57.5, 55.1, 53.5, 35.8, 34.7, 33.4, 32.4, 29.5, 27.8, 24.0, and20.2 ppm.

Assignees

• Xu Feng
• Humphrey Guy
• Pei Tao
• Song Zhiguo Jake
• Wang Tao
• Artino Laura
• Merck Sharp & Dohme

Inventors

• Xu Feng
• Humphrey Guy
• Pei Tao
• Song Zhiguo Jake
• Wang Tao
• Artino Laura

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07K5/0808 Primary

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07C271/34

  with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• A61K38/00

  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) · CPC title

• C07C69/12

  Acetic acid esters · CPC title