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US 9,238,604 B2Granted
Process and intermediates for preparing macrolactams
AssigneeMerck Sharp & Dohme Corp.
InventorsFeng Xu, Guy Humphrey, Tao Pei, Zhiguo Jake Song, Tao Wang, Laura Artino
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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.
Claims8
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 R5 is either hydrogen, aryl, halogen, C1-6 alkyl, O—C1-6 alkyl or C3-C8 cycloalkyl, and wherein any of Compounds 11, 12, 13, 14, 15, 16, 21, and 18 independently may be provided as salts.
14 more elements
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.
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.
Dependencies are inferred from the claim text.