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Process for the preparation of cgrp antagonist

A technology of oxo and trifluoroethyl, applied in the field of preparation of CGRP antagonists, can solve the problems of low stability and bioavailability, low yield and optimal yield

Inactive Publication Date: 2009-04-29
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Finally, the existing process for the preparation of compound 1 using 4-nitrophenyl chloroformate as the carbonyl source resulted in suboptimal yields
The prior art further requires that the neutral form of the compound be isolated prior to conversion to the preferred salt form
In addition, previously laboratory-prepared forms of compound 1, including free base and salt forms, had less than ideal properties in terms of stability and bioavailability

Method used

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  • Process for the preparation of cgrp antagonist
  • Process for the preparation of cgrp antagonist
  • Process for the preparation of cgrp antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl ]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

[0082]

[0083] Into a 12 L 4-neck flask equipped with an overhead stirrer, thermocouple, and nitrogen inlet was charged caprolactam hydrochloride 2-MTBE solvate (412 g corrected for HCl salt; MTBE solvate typically contained 78-79 wt% hydrochloride ). Then, THF (4.1 L; 10 mL / g) was added at room temperature, followed by triethylamine (194 ml; 1.2 equiv). The slurry was aged at room temperature. Into a separate 22L 4-neck flask equipped with an overhead stirrer, thermocouple and nitrogen inlet was charged CDI (233g; 1.25 equiv) and THF (2.3L; 10ml / g relative to CDI). Allow the solution to stand at room temperature. Add the caprolactam slurry solution to the CDI solution over a period of 1 to 1.5 hours at room temperature, then allow it to stand at room temperature for 1 hour, and then assay the reaction to det...

Embodiment 2

[0085] N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl ]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

[0086]

[0087] Caprolactam 2 (8.23 kg (based on 68 wt% assay, 5.60 kg caprolactam hydrochloride)) was charged into inert vessel A with THF (66.4 L) and triethylamine (1.90 kg). Vessel B was charged with CDI (3.163 kg) and THF (30 L). The contents of container A were transferred to container B over a period of 1.5 hours, and the mixture in container B was left for 1 hour. At this point, HPLC analysis indicated that the formation of the caprolactam acylimidazole was nearly complete. Piperidine heterocycle 3 (5.0 kg) was charged into vessel B, followed by triethylamine (4.12 kg). When HPLC analysis indicated that the coupling was complete (3 solution (2 x 28L) for washing. At this point, the pH of the final aqueous phase was 9. The organic phase was washed with DI water (27 L) and the compound was assayed in MT...

Embodiment 3

[0089] N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl ]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium salt ethanolate

[0090]

[0091] A solution of Compound 1 (8.27 kg) in MTBE was charged through a 0.1 μm cartridge filter into an inert vessel and concentrated to 30 L using partial vacuum while maintaining T<40°C. Ethanol (116 L) was added, and the solution was re-concentrated to 30 L under vacuum at <40°C. Ethanol (116 L) was added, and the solution was analyzed for residual THF / MTBE content (not detected). Potassium tert-butoxide (1.720 kg), which would be a solid, was charged to the vessel and the mixture was warmed to 45°C to dissolve all solids. The batch was then concentrated to a final volume of 58 L (based on neutral 454, 7 ml / g) at <40°C. The resulting slurry was allowed to cool to room temperature overnight before filtering. The resulting filter cake was washed with cold ethanol (25 L) and ...

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Abstract

An efficient synthesis for the preparation of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide, by coupling (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride with 1,1'-carbonyldiimidazole ('CDI') as carbonyl source; and an efficient preparation of the potassium salt of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide.

Description

Background of the invention [0001] International Patent Applications PCT / US2004 / 010851 filed April 9, 2004 (published as WO2004 / 092166 on October 28, 2004) and PCT / US2004 / 011280 filed April 9, 2004 (published on October 2004 Published on October 29 as WO2004 / 092168) and U.S. Application Serial No. 10 / 838,835 (published on October 11, 2005 as U.S. Patent No. 6,953,790) disclose compounds useful in the treatment of diseases or conditions in humans or other species, the A disease or condition can be treated with an inhibitor, modulator or enhancer of calcitonin gene-related peptide (CGRP) receptor function. Such diseases or conditions include those mentioned in the references, and specifically include migraine and cluster headache. [0002] N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl ]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide, 1: [0003] [0004] Is a potent CGRP modulator. The laboratory preparation of Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04A61P25/06A61P43/00
Inventor K·贝利克N·赖弗拉
Owner MERCK & CO INC
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