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WO1998011061A1 - Nouveaux intermediaires pour la preparation de derives du verapamil - Google Patents

Nouveaux intermediaires pour la preparation de derives du verapamil Download PDF

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Publication number
WO1998011061A1
WO1998011061A1 PCT/GB1997/002430 GB9702430W WO9811061A1 WO 1998011061 A1 WO1998011061 A1 WO 1998011061A1 GB 9702430 W GB9702430 W GB 9702430W WO 9811061 A1 WO9811061 A1 WO 9811061A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
enantiomerically
verapamil
reduction
formula
Prior art date
Application number
PCT/GB1997/002430
Other languages
English (en)
Inventor
Robin Mark Bannister
Graham Robert Evans
Original Assignee
Darwin Discovery Limited
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 Darwin Discovery Limited filed Critical Darwin Discovery Limited
Priority to EP97939074A priority Critical patent/EP0925277A1/fr
Priority to CA002263116A priority patent/CA2263116A1/fr
Priority to AU41295/97A priority patent/AU714440B2/en
Priority to JP10513356A priority patent/JP2001500151A/ja
Publication of WO1998011061A1 publication Critical patent/WO1998011061A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton

Definitions

  • This invention relates to novel compounds and their use in the manufacture of enantiomerically-enriched verapamil and related compounds.
  • Verapamil (I) is presently in clinical use as the racemate and is used extensively for the treatment of hypertension.
  • the opposite enantiomers of verapamil have different biological activities.
  • the (s) -enantiomer levoverapamil
  • the (J?)- enantio er differs in having sodium channel and other cell-pump actions in addition to higher bioavailability, with slower clearance rate.
  • These differences may be of clinical significance, for example, the [R) -enantiomer may be of benefit for the reversal of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 4j5: 113); in this case hypotensive action by admixture with the (S) -enantiomer would be undesirable.
  • Literature methodology for the conversion of enantiomerically-enriched (II) to verapamil (I) , and corresponding processes for analogues invariably entails reduction of (II) to either the enantiomerically-enriched alcohol (III) or the enantiomerically-enriched aldehyde (IV) .
  • Proceeding via alcohol (III) involves conversion to either an O-sulphonyl derivative or an alkyl halide, and subsequent a ination to verapamil (I) , which may require elevated temperatures (see GB 1367677) , prolonged reaction times (see Theodore and Nelson, as above) , or the use of the hazardous solvent hexamethylphosphoramide (see US-A- 4940780) .
  • a novel compound optionally in enantiomerically-enriched form (J? or S) has the formula (V) , below, wherein Ar and Ar are independently selected from optionally-substituted aromatic or heteroaro atic groups having upto 20 C atoms, Ak is C,. 20 alkyl, and R is H or C.,. 20 alkyl.
  • a process for the preparation of a compound of formula (VI) , below, optionally in enantiomerically-enriched form (R or S) comprises chemoselective reduction of a compound of formula (V) , as defined above.
  • the compounds of formula (V) may be prepared by reaction of a suitable carboxylic acid with a suitable primary or secondary amine, under standard reaction conditions.
  • R is alkyl
  • R it may be the same or different to the Ak group.
  • both R and Ak are independently selected from c,. 12 alkyl, and R is more preferably methyl.
  • verapamil (I) is prepared by reduction of compound (V) in which Ar 1 and Ar 2 are both 3,4- dimethoxyphenyl , Ak is isopropyl, and R is methyl.
  • verapamil is prepared by reduction of compound (V) in which Ar 1 and Ar 2 are both 3 ,4-dimethoxyphenyl, Ak is isopropyl, and R is H, followed by W-methylation; omission of the N-methylation step provides a route to norverapamil, optionally in enantiomerically-enriched form.
  • a number of reagents are suitable for effecting the desired chemoselective reduction of compound (V) , including metal hydride reagents and borane-based reagents. Suitable metal hydride reagents include aluminohydride reagents such as lithium aluminium hydride.
  • Suitable borane-based reagents include preformed complexes of borane with either dimethyl sulphide or tetrahydrofuran. Alternatively, and more economically, borane may be generated in situ , typically by the reaction of sodium borohydride with an acidic reagent such as hydrogen chloride.
  • coupling of compounds (II) and (VII) to prepare an amide (VI) may be achieved by condensation under mild conditions in which approximately equimolar quantities of reactants can be used.
  • the present invention is further illustrated by the following Examples. Examples. Examples
  • Example 2 Using the procedure of Example 1, 5.0 g of 4-cyano-4- (3,4-dimethoxyphenyl) -5-methyl hexanoic acid (0.0172 mol) and 3.35 g, 3.17 ml of N-methylhomoveratrylamine (0.0172 mol) were coupled in the presence of 30 mg of 3-nitro- phenylboronic acid (- l mol %) . This gave after work-up 7.17 g (89.1%) of a yellow/orange coloured oil. Addition of lOmls of TBME and 5mls petrol (60-80) effected crystallisation to give 5.81 g (72.2%) of a beige coloured solid. Mp ⁇ 92.1°C. IR (KBr disc).
  • reaction mixture was then worked up by addition of water (500 ml) and then adjustment of pH to 1.5 with hydrochloric acid (35%, ca 20 ml), to remove unreacted amine.
  • the lower aqueous phase was separated, and the organics given a wash at pH 1.5, then an alkaline wash (pH 11) , to remove unreacted verapamilic acid (4.8 g of 47% w/w NaOH required).
  • an alkaline wash pH 11
  • verapamilic acid 4.8 g of 47% w/w NaOH required
  • Example 4 Reduction of 4-cvano-4-(3 , 4-dimethoxyphen ⁇ l) - 5.N-dimethyl-N-f2-phenyleth ⁇ l)hexanamide 1.50 g (3.68 mmol) 4-cyano-4- (3 , 4-dimethoxyphenyl) - 5,N-dimethyl-N-(2-phenylethyl)hexanamide was taken up in 10 ml of dry THF under nitrogen at 0°C To this solution was added 0.350 g, 0.440 ml of borane dimethyl sulphide complex (4.60 mmol) dropwise over a 5 minute period.
  • Example 5 Reduction of 4-c ⁇ ano-4-f3 , 4-dimethoxyphen ⁇ l) -N- r2- (3 , 4-di ethoxyphenyl . ethy 1 -5.N-dimethylhexanamide: Using the procedure of Example 4, 2 eq of BH 3 .DMS, 1.0 g of 4-cyano-4- (3 , 4-dimethoxyphenyl) -N-[2- (3 , 4-dimethoxy- phenyl) ethyl]-5,N-dimethyl-hexanamide (2.14 mmol) was taken up in 10 ml of dry THF at 0°C under nitrogen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention se rapporte à un procédé de préparation d'un composé représenté par la formule (VI), éventuellement sous forme enrichie en énantiomères (R ou S). Ledit procédé consiste en une réduction chimiosélective d'un nouveau composé représenté par la formule (V), dans laquelle Ar?1 et Ar2¿ sont sélectionnés indépendamment parmi des groupes hétéro-aromatiques ou aromatiques éventuellement substitués comportant jusqu'à 20 atomes de carbone, Ak est alkyle C¿1-20?, et R est H ou alkyle C1-20.
PCT/GB1997/002430 1996-09-10 1997-09-09 Nouveaux intermediaires pour la preparation de derives du verapamil WO1998011061A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97939074A EP0925277A1 (fr) 1996-09-10 1997-09-09 Nouveaux intermediaires pour la preparation de derives du verapamil
CA002263116A CA2263116A1 (fr) 1996-09-10 1997-09-09 Nouveaux intermediaires pour la preparation de derives du verapamil
AU41295/97A AU714440B2 (en) 1996-09-10 1997-09-09 New intermediates for the preparation of verapamil derivates
JP10513356A JP2001500151A (ja) 1996-09-10 1997-09-09 ベラパミル誘導体製造のための新規中間体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9618835.4A GB9618835D0 (en) 1996-09-10 1996-09-10 Process
GB9618835.4 1996-09-10

Publications (1)

Publication Number Publication Date
WO1998011061A1 true WO1998011061A1 (fr) 1998-03-19

Family

ID=10799667

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/002430 WO1998011061A1 (fr) 1996-09-10 1997-09-09 Nouveaux intermediaires pour la preparation de derives du verapamil

Country Status (7)

Country Link
EP (1) EP0925277A1 (fr)
JP (1) JP2001500151A (fr)
AU (1) AU714440B2 (fr)
CA (1) CA2263116A1 (fr)
GB (1) GB9618835D0 (fr)
WO (1) WO1998011061A1 (fr)
ZA (1) ZA978146B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582461B2 (en) 2003-07-29 2009-09-01 Life Technologies Corporation Kinase and phosphatase assays
US7619059B2 (en) 2003-07-29 2009-11-17 Life Technologies Corporation Bimolecular optical probes
US8945884B2 (en) 2000-12-11 2015-02-03 Life Technologies Corporation Methods and compositions for synthesis of nucleic acid molecules using multiplerecognition sites
US9534252B2 (en) 2003-12-01 2017-01-03 Life Technologies Corporation Nucleic acid molecules containing recombination sites and methods of using the same

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9950995B2 (en) * 2014-10-29 2018-04-24 Center Laboratories, Inc. Crystal forms of verapamil hydrochloride

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4948421A (fr) * 1972-09-10 1974-05-10
GB1367677A (en) * 1970-12-05 1974-09-18 Knoll Ag Optically active basically substituted phenylacetonitriles
EP0165322A1 (fr) * 1984-06-15 1985-12-27 LUDWIG HEUMANN & CO GMBH Méthode de préparation de phénylacétonitrile substitué par un radical basique
US4940780A (en) * 1986-12-11 1990-07-10 Basf Aktiengesellschaft Basically substituted phenylacetonitriles, their preparation and drugs containing these compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1367677A (en) * 1970-12-05 1974-09-18 Knoll Ag Optically active basically substituted phenylacetonitriles
JPS4948421A (fr) * 1972-09-10 1974-05-10
EP0165322A1 (fr) * 1984-06-15 1985-12-27 LUDWIG HEUMANN & CO GMBH Méthode de préparation de phénylacétonitrile substitué par un radical basique
US4940780A (en) * 1986-12-11 1990-07-10 Basf Aktiengesellschaft Basically substituted phenylacetonitriles, their preparation and drugs containing these compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 82, no. 23, 9 June 1975, Columbus, Ohio, US; abstract no. 155900, YASUDA, KIKUO ET AL: "Aminoalkylphenylacetonitriles" XP002031564 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9309520B2 (en) 2000-08-21 2016-04-12 Life Technologies Corporation Methods and compositions for synthesis of nucleic acid molecules using multiple recognition sites
US8945884B2 (en) 2000-12-11 2015-02-03 Life Technologies Corporation Methods and compositions for synthesis of nucleic acid molecules using multiplerecognition sites
US7582461B2 (en) 2003-07-29 2009-09-01 Life Technologies Corporation Kinase and phosphatase assays
US7619059B2 (en) 2003-07-29 2009-11-17 Life Technologies Corporation Bimolecular optical probes
US9534252B2 (en) 2003-12-01 2017-01-03 Life Technologies Corporation Nucleic acid molecules containing recombination sites and methods of using the same

Also Published As

Publication number Publication date
GB9618835D0 (en) 1996-10-23
AU4129597A (en) 1998-04-02
EP0925277A1 (fr) 1999-06-30
CA2263116A1 (fr) 1998-03-19
ZA978146B (en) 1998-09-10
JP2001500151A (ja) 2001-01-09
AU714440B2 (en) 2000-01-06

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