US20080269517A1 - Process for the preparation of acid halides - Google Patents

Process for the preparation of acid halides Download PDF

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Publication number
US20080269517A1
US20080269517A1 US12/105,339 US10533908A US2008269517A1 US 20080269517 A1 US20080269517 A1 US 20080269517A1 US 10533908 A US10533908 A US 10533908A US 2008269517 A1 US2008269517 A1 US 2008269517A1
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US
United States
Prior art keywords
formula
process according
compound
preparation
alkylamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/105,339
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English (en)
Inventor
Ursula Hoffmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Assigned to F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY reassignment F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOFFMANN, URSULA
Assigned to HOFFMANN-LA ROCHE, INC. reassignment HOFFMANN-LA ROCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Publication of US20080269517A1 publication Critical patent/US20080269517A1/en
Priority to US12/418,902 priority Critical patent/US7977509B2/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part

Definitions

  • the present invention is directed to a process for the preparation of acid halides which are useful as intermediates in the preparation of pharmaceutically active compounds, and in particular, for the preparation of compounds that inhibit cholesterylester transfer protein (CETP) such as those as described in EP 1,020,439.
  • CETP cholesterylester transfer protein
  • CETP is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between lipoproteins. It has been demonstrated that the inhibition of CETP increases the levels of high density lipoprotein (HDL).
  • the present invention provides an improved production process for intermediates in the preparation of pharmaceutically active compounds and, in particular, for the preparation of intermediates used in the preparation of CETP inhibitors.
  • the present invention provides a process for the preparation of a compound of formula I
  • R 1 , R 2 and R 3 have the above meanings; with thionylchloride in the presence of a tri-C 1 -C 5 alkylamine and an aliphatic hydrocarbon solvent.
  • the compounds of formula I may be used as intermediates in the synthesis of valuable pharmaceutical compounds, e.g. those as described in e.g. EP 1,020,439.
  • the present invention provides a process comprising the synthetic steps represented in the following scheme:
  • the process comprises reacting a compound of formula I with bis(2-aminophenyl)disulfide to acylate the amino groups of the (2-aminophenyl)disulfide, reducing the amino-acylated disulfide product with a reducing agent such as triphenylphosphine, zinc or sodium borohydride to yield the thiol product, and acylating the thiol group in the thiol product with R 4 C(O)Cl.
  • a reducing agent such as triphenylphosphine, zinc or sodium borohydride
  • the additional steps may be performed, e.g., according to the procedures described in Shinkai et al., J. Med. Chem. 43:3566-3572 (2000).
  • C 1 -C 8 alkyl examples include methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl, e.g. CH 2 CH(CH 2 CH 3 ) 2 , heptyl and octyl.
  • R 1 C 1 -C 8 alkyl is preferably CH 2 CH(CH 2 CH 3 ) 2 .
  • C 1 -C 8 alkyl is preferably isopropyl.
  • C 2 -C 8 alkenyl examples include unsaturated carbon chains containing one or more double bonds at any possible position, e.g. vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
  • tri-C 1 -C 5 alkylamine denotes a compound of formula R 4 N(R 5 )R 6 wherein R 4 , R 5 and R 6 independently are a C 1 -C 8 alkyl, and includes triethylamine, tributylamine, di-ethyl-methylamine, dimethyl-ethylamine and methylethylbutylamine.
  • aliphatic hydrocarbon refers to a branched, straight or cyclic hydrocarbon chain, such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, or mixtures thereof.
  • the most preferred aliphatic hydrocarbon is heptane.
  • the process may take place at a temperature in the range from 20 to 60° C., e.g. in a range from 40 to 55° C.
  • the acylating steps of the present invention are preferably conducted in the presence of a base.
  • Preferred bases include organic bases with N-Methylmorpholine being a preferred organic base.
  • the amount of thionylchloride in relation to the compound of formula II, in the reaction mixture may be in the range from 1.0 to 2.0 equivalents of thionylchloride, e.g. from 1.0 to 1.2 equivalents, e.g. 1.2 equivalents.
  • the amount of the tri-C 1 -C 5 alkylamine in relation to the amount of the compound of formula 11 may be at a ratio of from 5 mol % to 0.1 mol %, e.g. from 0.3 mol % to 0.5 mol %, e.g. 0.3 mol %.
  • continuously adding denotes the addition of thionylchloride to a solution of compound II in an aliphatic hydrocarbon solvent, during a period of time from 10 minutes to 5 hours, depending on the batch size.
  • the solution of compound II is heated to the desired temperature prior to the addition of thionylchloride. This method is different from the batch mode where all components are mixed at RT and the mixture is heated to the desired temperature.
  • the present invention provides a process for the preparation of a compound of formula I wherein R 1 is —CH 2 CH(CH 2 CH 3 ) 2 .
  • the present invention provides a process for the preparation of a compound of formula I wherein the tri-C 1 -C 5 alkylamine is triethylamine or tributylamine.
  • the present invention provides a process for the preparation of a compound of formula I wherein the tri-C 1 -C 5 alkylamine is tributylamine. When using tributylamine no precipitation of the hydrochloride salt of the tertiary amine occurs.
  • the compounds of formula II are commercially available or can be prepared by procedures known to the skilled person.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US12/105,339 2007-04-25 2008-04-18 Process for the preparation of acid halides Abandoned US20080269517A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/418,902 US7977509B2 (en) 2007-04-25 2009-04-06 Process for the preparation of acid halides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07106893 2007-04-25
EP07106893.6 2007-04-25

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/418,902 Continuation US7977509B2 (en) 2007-04-25 2009-04-06 Process for the preparation of acid halides

Publications (1)

Publication Number Publication Date
US20080269517A1 true US20080269517A1 (en) 2008-10-30

Family

ID=39595819

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/105,339 Abandoned US20080269517A1 (en) 2007-04-25 2008-04-18 Process for the preparation of acid halides
US12/418,902 Active US7977509B2 (en) 2007-04-25 2009-04-06 Process for the preparation of acid halides

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/418,902 Active US7977509B2 (en) 2007-04-25 2009-04-06 Process for the preparation of acid halides

Country Status (11)

Country Link
US (2) US20080269517A1 (zh)
EP (1) EP2150520B1 (zh)
JP (1) JP5314671B2 (zh)
CN (1) CN101663260B (zh)
AR (1) AR066259A1 (zh)
CA (1) CA2684067A1 (zh)
CL (1) CL2008001188A1 (zh)
ES (1) ES2395167T3 (zh)
PE (1) PE20090735A1 (zh)
TW (1) TW200911749A (zh)
WO (1) WO2008132044A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105164276B (zh) 2013-03-27 2020-01-14 豪夫迈·罗氏有限公司 用于预测对于治疗的响应性的遗传标记
ES2825675T3 (es) 2014-07-30 2021-05-17 Hoffmann La Roche Marcadores genéticos para predecir la reactividad al tratamiento con un agente que aumenta las HDL o que imita las HDL

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899458A (en) * 1959-08-11 Process for producing oxy aromatic
US4129595A (en) * 1978-03-29 1978-12-12 Chevron Research Company Preparation of chloroacetyl chloride
US20030009278A1 (en) * 2001-05-18 2003-01-09 Robert Mallet Surface traffic movement system and method
US20070100154A1 (en) * 2005-10-31 2007-05-03 Ursula Hoffmann Process for the production of acid chlorides
US20080154059A1 (en) * 2006-12-20 2008-06-26 Ursula Hoffmann Process for the preparation of cetp(1)

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2007A (en) * 1841-03-16 Improvement in the mode of harvesting grain
JPS5740432A (en) * 1980-08-25 1982-03-06 Mitsubishi Chem Ind Ltd Production of carboxylic acid chloride
JPS57163342A (en) * 1981-03-30 1982-10-07 Seitetsu Kagaku Co Ltd Preparation of 3,4,5-trimethoxybenzoic acid halide
JPS6420439A (en) 1987-07-15 1989-01-24 Yamatake Honeywell Co Ltd Humidity sensible element
DE3903623A1 (de) * 1989-02-08 1990-08-09 Basf Ag Verfahren zur herstellung von anthrachinonderivaten
JPH03255050A (ja) * 1990-03-01 1991-11-13 Mitsubishi Kasei Corp シス，シス―ムコン酸クロリドの製造方法
JPH07242593A (ja) * 1994-03-08 1995-09-19 Asahi Glass Co Ltd ２，３，４，５−テトラフルオロ安息香酸の製造方法
JP3290962B2 (ja) * 1997-02-12 2002-06-10 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
IT1292037B1 (it) * 1997-05-30 1999-01-25 Bracco Spa Processo per la preparazione di 5-(acetil 62,3-diidrossipropil)- ammino)-n,n'-bis(2,3-diidrossipropil)-2,4,6-triiodo-1,3-benzen-
JP2000026369A (ja) * 1998-07-10 2000-01-25 Sumikin Chemical Co Ltd ３−アセトキシ−２−メチル安息香酸クロライドの製造方法
JP2001278839A (ja) * 2000-01-25 2001-10-10 Kanegafuchi Chem Ind Co Ltd ２−位が置換された光学活性カルボン酸の製造法
JP2002069033A (ja) * 2000-06-16 2002-03-08 Japan Tobacco Inc １−置換−シクロヘキサンカルボニルハライド化合物の製造方法
US20030154059A1 (en) * 2001-11-30 2003-08-14 Jorg-Uwe Feldmann Simulation apparatus and simulation method for a system having analog and digital elements
GB0229803D0 (en) * 2002-12-20 2003-01-29 Syngenta Ltd Chemical process
GB0304132D0 (en) * 2003-02-24 2003-03-26 Syngenta Ltd Chemical process
ITMI20031333A1 (it) * 2003-06-30 2005-01-01 Erregierre Spa Processo di preparazione di raloxifene cloridrato.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899458A (en) * 1959-08-11 Process for producing oxy aromatic
US4129595A (en) * 1978-03-29 1978-12-12 Chevron Research Company Preparation of chloroacetyl chloride
US20030009278A1 (en) * 2001-05-18 2003-01-09 Robert Mallet Surface traffic movement system and method
US20070100154A1 (en) * 2005-10-31 2007-05-03 Ursula Hoffmann Process for the production of acid chlorides
US20080154059A1 (en) * 2006-12-20 2008-06-26 Ursula Hoffmann Process for the preparation of cetp(1)

Also Published As

Publication number Publication date
AR066259A1 (es) 2009-08-05
WO2008132044A1 (en) 2008-11-06
EP2150520B1 (en) 2012-10-31
CA2684067A1 (en) 2008-11-06
TW200911749A (en) 2009-03-16
EP2150520A1 (en) 2010-02-10
JP2010525006A (ja) 2010-07-22
JP5314671B2 (ja) 2013-10-16
CL2008001188A1 (es) 2008-12-26
US7977509B2 (en) 2011-07-12
US20090192333A1 (en) 2009-07-30
CN101663260A (zh) 2010-03-03
ES2395167T3 (es) 2013-02-08
PE20090735A1 (es) 2009-06-24
CN101663260B (zh) 2013-02-13

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AS Assignment

Owner name: HOFFMANN-LA ROCHE, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:F. HOFFMANN-LA ROCHE AG;REEL/FRAME:020944/0900

Effective date: 20080313

Owner name: F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY, SWITZERL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HOFFMANN, URSULA;REEL/FRAME:020991/0152

Effective date: 20080312

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION