GOLCONDANE | ORGANIC CHEMISTRY SELECT

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Synthesize 7-azanorbornane on an industrial scale

Synthesize 7-azanorbornane on an industrial scale

Patent Number:	US 8404865
Title:	Process for preparing azabicyclic compounds
Inventor(s):	Ambhaikar, Narendra Bhalchandra; Bear, Brian Richard; Fanning, Lev T. D.; Hughes, Robert; Littler, Benjamin
Patent Assignee(s):	Vertex Pharmaceuticals Incorporated, USA
Source:	U.S. Pat. Appl. Publ., 8pp. CODEN: USXXCO
Language:	English
Abstract:The present invention relates to a process for prepg. azabicyclic compds. that are useful intermediates for synthesizing pharmaceutical compds. or salts thereof.  Thus, azabicyclo[2.2.1]heptane hydrochloride (I·HCl) was prepd. from trans-4-aminocyclohexanol via N-protection with Boc2O in CH2Cl2 contg. Et3N; mesylation with MsCl in CH2Cl2 contg. Et3N; N-deprotection with CF3CO2H; cyclization with aq. NaOH; and treatment with http://www.google.com.mx/patents/US8404865 view patent 7-azabicyclo[2.2.1]heptanes are useful intermediates in the synthesis of pharmaceutical compounds and salts thereof. For example, see U.S. Pat. Nos. 6,117,889 and 6,060,473, each of which is hereby incorporated by reference in its entirety

 Despite the title of N. B. Ambhaikar and co-inventors’ patent, “Process for preparing azabicyclic compounds”, it only describes a process for preparing 7-azanorbornane (5) and its HCl salt (6). The inventors state that compound 5 is an intermediate in the synthesis of pharmaceutical compounds, but they do not mention any.

The patent’s examples describe the preparation of 5 and its precursors on a kilogram scale. The first step is protecting the amino group in 1 by converting it to tert-butoxycarbonyl (BOC) derivative 2 with the anhydride (BOC)2O in the presence of Na2CO3. The product is isolated in 88.8% yield. The reaction can also be carried out with K2CO3, but the yield is not reported.

In the second step, 2 is treated with methanesulfonyl chloride (MsCl) in the presence of Et3N to form methanesulfonate 3 in 96.6% isolated yield. In step three, the BOC group is removed by adding CF3CO2H in two batches. The product is amine salt 4. The recovered salt contains excess CF3CO2H; and as a result, the yield appears to be >100%.

In the final stage, the CF3CO2H salt is treated with NaOH to cyclize it to the desired compound. Azanorbornane 5 is recovered by fractional distillation; treating the fractions with concd HCl gives hydrochloride salt 6. The salt is recovered as a solid, dried, and recrystallized from MeOH and MeOH–THF. Although the examples contain significant detail, the product’s final yield and purity are not reported.

The process is an efficient method for preparing 7-azanorbornane and its salt. It is clearly suitable for large-scale production. (Vertex Pharmaceuticals [Cambridge, MA]. US Patent 8,404,865, March 26, 2013; Keith Turner)

NMR

 7-azanorbornane HCl salt (6). 

¹HNMR (DMSO-d⁶) ppm 8.02-8.04 (d); 7.23-7.31 (m); 4.59 (s); 3.31 (s); 2.51-3.3 (m); 1.63-1.75 (m); 1.45-1.62 (m).

In one aspect, the invention includes a process for preparing Compound 7-azanorbornane

PL IGNORE NUMBER 7

• • or a pharmaceutically acceptable salt thereof, comprising contacting trans-4-aminocyclohexanol with Boc anhydride to produce a compound of formula A

• • contacting a compound of formula A with methanesulfonic acid to produce a compound of formula B

• • contacting a compound of formula B with trifluoroacetic acid to produce a compound of formula C

• • contacting a compound of formula C with hydroxide to produce a compound of formula 

In some embodiments, the invention includes a method of producing a compound of formula 7-azanorbornane Hydrocloride salt

• • The TFA salt of trans-4-aminocyclohexylmethanesulfonate (200 g, 650.9 mmol) was introduced into a 3-necked flask followed by the addition of water (2.200 L, 11 vol). NaOH (78.11 g, 1.953 mol, 3 eq) was slowly added, keeping the temperature of the reaction mixture below 25° C. and the mixture was stirred overnight. DCM (1.4 L, 7 vol) was then added and the mixture stirred, and the organic layer was separated. The aqueous layer was then extracted a second time with DCM (1.4 L, 7 vol), and the DCM layers were combined. HCl (108.5 mL, 12M, 1.3020 mol, 2 eq) was then added, the mixture was stirred for 30 min and then concentrated on a rotary evaporator to dryness. Acetonitrile (10 vol) was added and the mixture concentrated. This was repeated 3 times until all trace water was azeotropically removed, to provide 7-azabicyclo[2.2.1]heptane hydrochloride. The crude product was recrystallized from acetonitrile (10 vol) to provide 7-azabicyclo[2.2.1]heptane hydrochloride as a colorless crystalline solid.

Home ANTHONY CRASTO MEDICINAL CHEMISTRY (A.M.CRASTO MEDICINAL CHEMISTRY)

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PATENT EXPIRY DATES « New Drug Approvals

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Microwave-assisted synthesis of N-heterocycles in medicinal chemistry

Med. Chem. Commun., 2013, 4,1323-1343
DOI: 10.1039/C3MD00152K, Review Article

Davide Garella, Emily Borretto, Antonella Di Stilo, Katia Martina, Giancarlo Cravotto, Pedro Cintas
Microwave-assisted synthesis of heterocycle libraries has given an impressive contribution to drug discovery and development.http://pubs.rsc.org/en/Content/ArticleLanding/2013/MD/C3MD00152K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

 

Microwave-assisted synthesis of N-heterocycles in medicinal chemistry

 

 

 The syntheses of almost all N-heterocycles have now been successfully performed under microwave irradiation and have provided significant improvements in the reaction time and efficiency. The peculiar properties of dielectric heating give it the ability to strongly promote cyclocondensation, cycloaddition and selective N-heterocycle functionalisation and it has, therefore, very much caught the attention of the medicinal chemistry community. In this work, we present an overview of recent literature and technical advances in this research field with the aim of providing insight into the applications of microwave-assisted synthesis in the preparation of the main drug categories that contain N-heterocycle scaffolds.

A Novel Solid-Phase Synthesis of Quinolines

Short Paper | Regular issue | Vol 85, No. 3, 2012, pp.667-676
Published online: 26th January, 2012

DOI: 10.3987/COM-11-12411

■ A Novel Solid-Phase Synthesis of Quinolines

E Tang,* Deshou Mao, Wen Li, Zhangyong Gao, and Pengfei Yao

*School of Chemical Science and Technology, Yunnan University, No. 2 Green Lake North Road, Kunming 650091, China

Abstract

A method for synthesizing substituted-quinolines using TMSOTf-catalyzed polystyrene-supported succinimidyl selenide-induced intramolecular seleno-arylation of tethered alkenes as a key step has been developed. The catalytic process provides an efficient method for the stereoselective and regioselective synthesis of tetrahydroquinoline possessing a seleno-functionality, followed by deprotection of tosyl group and syn-elimination of selenoxides to provide quinolines in good yields and purities.

 http://www.heterocycles.jp/newlibrary/payments/form/22246/fulltext

Efficient Synthesis of 2,4-Diarylquinolines via Fe(III) Trifluoroacetate Catalyzed Three-Component Reactions under Solvent-Free Conditions

 

 

Paper | Regular issue | Vol 85, No. 3, 2012, pp.639-649
Published online: 9th February, 2012

DOI: 10.3987/COM-12-12433

■ Efficient Synthesis of 2,4-Diarylquinolines via Fe(III) Trifluoroacetate Catalyzed Three-Component Reactions under Solvent-Free Conditions

Min Zhang,* Ting Wang, Biao Xiong, Fengxia Yan, Xiaoting Wang, Yuqiang Ding, and Qijun Song

*School of Chemistry and Materials Engineering, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu Province, 214122, China

Abstract

A convenient and efficient one-pot synthesis of 2,4-diarylquinolines is described by using Fe(CF3CO2)3 as a catalyst for the first time. In this method, three-component coupling of arylaldehydes, arylamines and arylacetylenes furnished the corresponding products in good to excellent yields. The work features the use of cheap and eco-friendly catalyst, excellent functional group tolerance and solvent-free conditions. A variety of new products were afforded effectively.

http://www.heterocycles.jp/newlibrary/payments/form/22272/fulltext

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Photosynthesis: Turning CO2 into O2 – or maybe not. | DownHouseSoftware

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GSK and Genmab seek alternative approval for leukaemia drug Arzerra « New Drug Approvals

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Catalyst Calls The Shots - Organic Synthesis: Iron-based catalyst controls selectivity in C–H oxidations

 

Iron catalysts selectively oxidize different C–H bonds (yellow and green) in the same isoleucine substrate, reactions that would otherwise require independent synthetic routes from different starting materials.

http://cen.acs.org/articles/91/i40/Catalyst-Calls-Shots.html

Chemists have developed a new catalyst that accelerates oxidation of C–H bonds selectively in nonaromatic compounds such as terpenes, rather than relying on the inherent properties of the reactant molecules. The catalyst could boost the versatility with which organic compounds can be synthesized for drug discovery and other applications.

read all at

http://cen.acs.org/articles/91/i40/Catalyst-Calls-Shots.html

Download BRITISH PHARMACOPOEIA 2009 - All Volumes - Single File in PDF

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