Supercharge Your Innovation With Domain-Expert AI Agents!

Process for preparing a biphenyl-2-ylcarbamic acid

A technology of methyltetrahydrofuran and compound, applied in the preparation of the crystalline free base of this ester, the preparation of intermediates that can be used for synthesizing the ester and the crystalline free base, and can solve the problem of low yield, difficult to scale up, and aldehyde intermediates. instability, etc.

Active Publication Date: 2013-03-06
THERAVANCE BIOPHARMA R&D IP LLC
View PDF6 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, although this procedure performs well at small scale, the aldehyde intermediate is difficult to scale up due to its instability and low yields are often observed

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for preparing a biphenyl-2-ylcarbamic acid
  • Process for preparing a biphenyl-2-ylcarbamic acid
  • Process for preparing a biphenyl-2-ylcarbamic acid

Examples

Experimental program
Comparison scheme
Effect test

example

[0095] The following Preparations and Examples are provided to illustrate specific examples of the invention. However, unless expressly stated otherwise, the specific examples are not intended to limit the scope of the invention in any way. Unless otherwise stated, the following abbreviations have the following meanings, and any other abbreviations used herein and not defined have their standard meanings:

[0096] AcOH acetic acid

[0097] EtOAc ethyl acetate

[0098] EtOH: ethanol

[0099] IPA isopropyl alcohol

[0100] iPrOAc isopropyl acetate

[0101] MeCN acetonitrile

[0102] MeOH Methanol

[0103] MTBE methyl tert-butyl ether

[0104] MeTHF 2-Methyltetrahydrofuran

[0105] NaHB(OAc) 3 Sodium triacetoxyborohydride

[0106] Any other abbreviations used herein but not defined have their accepted standard meanings. Reagents, starting materials, and solvents were purchased from commercial suppliers (eg, Sigma-Aldrich, Fluka, and the like) and used without further...

example 1

[0112] Step A: Benzyl (2,2-Dimethoxyethyl)methylcarbamate

[0113]

[0114] mixed K 2 CO 3 (13.8g, 100mmol, 1.76eq.) with H 2 O (46 mL) to form a homogeneous solution. The solution was cooled to 20°C. N-Methylaminoacetaldehyde dimethyl acetal (12.8 mL, 100 mmol, 1.8 eq) and MeTHF (50 mL) were added. The resulting mixture was cooled to 2°C. Benzylchloroformate (8.1 mL, 56.7 mmol, 1.0 eq.) was added via syringe over 10 minutes (addition was exothermic). The mixture was maintained at room temperature until the reaction was complete. The layers were separated and the organic layer was washed with 1N HCl (50 mL) and used directly in the next step.

[0115] Step B: Benzyl Methyl-(2-oxoethyl)carbamate

[0116]

[0117] The mixture from the previous step was combined with 3N HCl solution (70 mL) and the resulting mixture was stirred at 22 °C for 18 hours to yield a clear homogeneous pale yellow solution. Solid NaHCO 3 added to the solution to neutralize the pH. The la...

example 2

[0127] All volumes and molar equivalents are given relative to biphenyl-2-yl-piperidin-4-ylcarbamate.

[0128] Step A: Benzyl (2,2-Dimethoxyethyl)methylcarbamate

[0129] Will K 2 CO 3 (8.4kg, 60mol, 1.8eq.) and H 2 O (49.3 kg, 2.6 vol) was placed in the reaction vessel and stirred. N-Methylaminoacetaldehyde dimethyl acetal (6.5 kg, 54 mol, 1.6 eq) and MeTHF (20.2 kg, 2.9 vol) were added. The resulting mixture was cooled to 5°C. Benzyl chloroformate (6.8 kg, 37.6 mol, 1.1 eq.) was added over a period of about 30 minutes while maintaining the temperature below 10°C. The feed tube was flushed with MeTHF (4.3 kg). The mixture was then maintained at 5°C and stirred for 1 hour. The layers were separated and the organic layer was washed with 1N HCl (14.3 kg, 11.7 mol, 1.4 vol) and used directly in the next step.

[0130] Step B: Benzyl Methyl-(2-oxoethyl)carbamate

[0131] The mixture from the previous step was combined with water (23.4 kg, 2.9 vol) and 30% hydrochloric aci...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a process of preparing an intermediate useful in the synthesis of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester, and a process of preparing a crystalline freebase of the ester.

Description

technical field [0001] The present invention relates to the preparation of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidine- Process for 4-yl esters. The invention additionally relates to a process for preparing the crystalline free base of this ester. The present invention also relates to a process for the preparation of intermediates useful in the synthesis of said esters and said crystalline free base. Background technique [0002] US Patent No. 7,228,657 to Mammen et al. discloses novel biphenyl compounds that are expected to be useful in the treatment of pulmonary diseases such as chronic obstructive pulmonary disease and asthma. Specifically, the compound biphenyl-2-ylcarbamate 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piper The pyridin-4-yl esters are specifically described in this application as having muscarinic receptor antagonist or anticholinergic activity and are represented b...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D211/46
CPCC07D211/46C07D401/12A61P11/00C07D211/44A61K31/4545
Inventor 皮埃尔-让·科尔松
Owner THERAVANCE BIOPHARMA R&D IP LLC
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com