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WO1998047870A1 - Procede de synthese du 4-phenoxyphenylester de l'acide 4-[6-(hexylcarbamoyloxy) hexylcarbamoyloxy]-piperidine-1- carboxylique - Google Patents

Procede de synthese du 4-phenoxyphenylester de l'acide 4-[6-(hexylcarbamoyloxy) hexylcarbamoyloxy]-piperidine-1- carboxylique Download PDF

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Publication number
WO1998047870A1
WO1998047870A1 PCT/US1998/006513 US9806513W WO9847870A1 WO 1998047870 A1 WO1998047870 A1 WO 1998047870A1 US 9806513 W US9806513 W US 9806513W WO 9847870 A1 WO9847870 A1 WO 9847870A1
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WO
WIPO (PCT)
Prior art keywords
hexylcarbamoyloxy
piperidine
benzyl
phenoxyphenyl
methyl
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.)
Ceased
Application number
PCT/US1998/006513
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English (en)
Inventor
Ivo Jirkovsky
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.)
Wyeth LLC
Original Assignee
American Home Products Corp
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 American Home Products Corp filed Critical American Home Products Corp
Priority to AU69469/98A priority Critical patent/AU6946998A/en
Publication of WO1998047870A1 publication Critical patent/WO1998047870A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids

Definitions

  • This invention is concerned with a new and improved process for the large scale production of 4-[6-(hexylcarbamoyloxy)hexylcarbamoyloxy]-piperidine-l-carboxylic acid 4- phenoxyphenyl ester, disclosed in European Patent Application 0635 501 Al, published January 25, 1995, a compound that inhibits cholesterol ester hydrolase (CEH) and acyl- coenzyme A cholesterol acyltransferase (ACAT), both enzymes that are implicated in the reesterification and absorption of exogenous cholesterol, thereby reducing cholesterol absorption. Reduction in cholesterol absorption may be useful for in the treatment of hypercholesterolemia, hyperlipidemia, and atherosclerosis.
  • CEH cholesterol ester hydrolase
  • ACAT acyl- coenzyme A cholesterol acyltransferase
  • the invention provides a new process for the large scale production of 4- [6- (hexylcarbamoyloxy)hexylcarbamoyloxy]-piperidine-l-carboxyUc acid 4-phenoxyphenyl ester of the formula (1) as outlined in Scheme II.
  • the sequence of steps begins with reacting l-substituted-4-hydroxypiperidines (7) with a carbonylating reagent such as carbonyl diimidazole (CDI), disuccinimidyl carbonate, 2,2'- carbonyl-bis(3,5-dioxo- 1 ,2,4-oxazolidine) or 3,3 ' -carbonyl- bis[5-phenyl- 1 ,3,4-oxadiazole- 2(3H)thione], preferably carbonyl diimidazole, and subsequently coupling the reactive intermediate thus formed with 6-aminohexanol provides intermediate hydroxycarbamates (8) that are in turn subjected to carbonylation and coupling with hexylamine.
  • a carbonylating reagent such as carbonyl diimidazole (CDI), disuccinimidyl carbonate, 2,2'- carbonyl-bis(3,5-dioxo- 1 ,2,4-oxazol
  • R benzyl or methyl
  • CCR coupling carbonylation reagent, e.g., N, N' -carbonyldiimidazole
  • reaction of hydroxypiperidines (7) with CDI and 6-aminohexanol, as well as the reaction of (8) with CDI and hexylamine are carried out in an aprotic solvent such as tetrahydrofuran, toluene, methylene chloride, or ethyl acetate at from about 0 °C to about 70 °C or to the boiling point of the solvent used if lower than 70 °C in the absence or presence of a tertiary amine, preferably triethylamine.
  • triethylamine causes a substantial decrease in the reaction time, and the carbamates (8 and 9) are obtained in higher yield and purity.
  • acceptable yields are achieved only in the presence of triethylamine.
  • the penultimate intermediate carbamates (9) can be recrystallized from a variety of solvent systems, for example, acetone, acetone/heptane, ethyl acetate, aqueous tetrahydrofuran, or ether. Cleavage of tertiary amines by reaction with chloroformates is well known. The superiority of phenyl chloroformate over methyl chloroformate and ethyl chloroformate has been reported (J.Chem.Soc.(C) 1967, 2015), the development of this reaction has been reviewed (Synthesis 1989, 1-7), and an application of the method to 1,2,5,6- tetrahydropyridines has been described (Liebigs Ann.Chem.
  • the requisite 4-phenoxyphenyl chloroformate (10) is heretofore an unknown compound. It is conveniently prepared by a procedure analogous to the prior art method (J. Org. Chem. 1967, 21, 300; Japanese patent JP 76-27090; Czechoslovakia patent CS 202458) l o which comprises reaction of phosgene with 4-phenoxyphenol in the presence of N,N-dimethyl or N,N-diethylaniline, preferably in toluene.
  • To quantify 4-phenoxyphenyl chloroformate formed an aliquot sample is treated with isopropanol and the content of the corresponding mixed carbonate is determined by GC or HPLC methods.
  • Comparative TLC confirmed that the product was identical to the intermediate carbamate prepared according to Example 1.
  • the material was redissolved in methylene chloride (110 mL) and added to a stirred suspension of N,N' -carbonyldiimidazole (53.50 g, 0.33 mol) in the same solvent (250 mL).
  • the resulting solution was kept for 1 hr. at RT, and then mixed with a solution of hexylamine (60 mL, approx. 1.5 eq.) in methylene chloride (60mL).
  • the reaction mixture was stirred overnight at RT, washed with water, dried over magnesium sulfate, filtered, and evaporated to give waxy, semi-solid residue.
  • Example 2 in toluene (16 mL), and the reaction mixture was heated at 100°C for 4 hrs. A mild vacuum was applied intermittently during the final 2 hrs. to distill off some 20 ml of toluene.
  • Example 4 was added to a solution of the biscarbamate (9)(2.23 g, 5.80 mmol) prepared in Example 6) in the same solvent (15 mL). The resultant milky solution was refluxed for 5 hrs.using a Dean-Stark separator, and eventually more toluene was removed under mild vacuum. After cooling, the reaction mixture was diluted with toluene, washed successively with IN HCl, IN NaOH, water, and brine. The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to obtain a solid residue (3.1 g, 91.9%; m.p. 78-79°C).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un nouveau procédé amélioré, qui permet de produire en grandes quantités le 4-phénoxyphénylester de l'acide 4-[6-(hexylcarbamoyloxy)hexylcarbamoyloxy]-pipéridine-1-carboxylique, décrit dans le brevet EP 0 635 501 A1, publié le 25 janvier 1995, composé qui inhibe la cholestérol ester hydrolase (CEH) et l'acyl-coenzyme A cholestérol acyltransférase (ACAT). Selon le procédé de l'invention, on fait réagir la 1-benzyl-4-hydroxypipéridine ou la 1-méthyl-4-hydroxypipéridine avec un agent carbonylant, tel que le carbonyldi-imidazole (CDI) et le 6-aminohexanol, de façon à former la 1-benzyl(ou méthyl)-4-(6-hydroxyhexylcarbamoyloxy)pipéridine intermédiaire. La réaction dudit intermédiaire avec le CDI et l'hexylamine donne la 1-benzyl(ou méthyl)-4-[6-(hexylcarbamoyloxy)-hexylcarbamoyloxy]pipéridine correspondante. On élimine le groupe N-benzyle ou méthyle et on le remplace par le groupe 4-phénoxyphényloxycarbonyle en utilisant le 4-phénoxyphénylchloroformate. Le procédé peut être mis en oeuvre, depuis le matériau de départ jusqu'au produit final, sans isolement d'intermédiaires, sans changement de solvant, et le rendement et la pureté du produit final restent plus que satisfaisants. Cette modification apportée par le présent procédé est nettement moins exigeante en travail et en temps que la voie de synthèse présentée dans le brevet EP 0 635 501 A1.
PCT/US1998/006513 1997-04-24 1998-03-31 Procede de synthese du 4-phenoxyphenylester de l'acide 4-[6-(hexylcarbamoyloxy) hexylcarbamoyloxy]-piperidine-1- carboxylique Ceased WO1998047870A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69469/98A AU6946998A (en) 1997-04-24 1998-03-31 Process for the synthesis of 4-{6-(hexylcarbamoyloxy) hexylcarbamoyloxy}-piperidine-1- carboxylic acid 4-phenoxyphenyl ester

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84556597A 1997-04-24 1997-04-24
US08/845,565 1997-04-24

Publications (1)

Publication Number Publication Date
WO1998047870A1 true WO1998047870A1 (fr) 1998-10-29

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Country Status (3)

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AU (1) AU6946998A (fr)
WO (1) WO1998047870A1 (fr)
ZA (1) ZA983399B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002518405A (ja) * 1998-06-12 2002-06-25 バイオテック・オーストラリア・ピーティーワイ・リミテッド ビタミンｂ１２誘導体及びそれらの製造方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3244594A1 (de) * 1982-12-02 1984-06-07 Hoechst Ag, 6230 Frankfurt 1-phenylisochinolinderivate und verfahren zu ihrer herstellung, diese verbindung enthaltende pharmazeutische praeparate und deren anwendung
EP0216162A2 (fr) * 1985-08-23 1987-04-01 Sandoz Ltd. Procédé de préparation d'indoles et de dérivés de l'indole couplés par les positions 4,5,6 ou 7, composés ainsi obtenus et leur utilisation
EP0550007A2 (fr) * 1991-12-31 1993-07-07 AESCULAPIUS FARMACEUTICI S.r.l. Dérivés de l'eseroline ayant une activité anti-cholinesterase, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0635501A1 (fr) * 1993-07-21 1995-01-25 American Home Products Corporation Esters d'acides tris-carbamiques: inhibiteurs de l'absorption du cholestérol; inhibiteurs de l'ACAT et CEH
WO1996032375A1 (fr) * 1995-04-10 1996-10-17 Yukong Limited O-carbamoylphenylalaninol ayant un substituant au niveau du cycle benzenique, ses sels utiles sur le plan pharmaceutique et son procede de preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3244594A1 (de) * 1982-12-02 1984-06-07 Hoechst Ag, 6230 Frankfurt 1-phenylisochinolinderivate und verfahren zu ihrer herstellung, diese verbindung enthaltende pharmazeutische praeparate und deren anwendung
EP0216162A2 (fr) * 1985-08-23 1987-04-01 Sandoz Ltd. Procédé de préparation d'indoles et de dérivés de l'indole couplés par les positions 4,5,6 ou 7, composés ainsi obtenus et leur utilisation
EP0550007A2 (fr) * 1991-12-31 1993-07-07 AESCULAPIUS FARMACEUTICI S.r.l. Dérivés de l'eseroline ayant une activité anti-cholinesterase, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0635501A1 (fr) * 1993-07-21 1995-01-25 American Home Products Corporation Esters d'acides tris-carbamiques: inhibiteurs de l'absorption du cholestérol; inhibiteurs de l'ACAT et CEH
WO1996032375A1 (fr) * 1995-04-10 1996-10-17 Yukong Limited O-carbamoylphenylalaninol ayant un substituant au niveau du cycle benzenique, ses sels utiles sur le plan pharmaceutique et son procede de preparation

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CAMPBELL ET AL.: "The mild and selective N-debenzylation of tertiary alkylamines using beta-trimethylsilylethyl chloroformate", TETRAHEDRON LETTERS., vol. 28, no. 21, 1987, OXFORD GB, pages 2331 - 2334, XP002071549 *
CHEMICAL ABSTRACTS, vol. 102, no. 1, 1985, Columbus, Ohio, US; abstract no. 6344m, KOBAYASHI ET AL.: "Studies on the synthesis of antiulcer agents" XP002071553 *
CHEMICAL ABSTRACTS, vol. 113, no. 1, 1990, Columbus, Ohio, US; abstract no. 6255k, AVRAMOVA: "N-Dealkylation of substituted morpholines" XP002071552 *
FARMATSIYA, vol. 39, no. 5, 1989, pages 1 - 5 *
JOURNAL OF THE CHEMICAL SOCIETY, SECTION C: ORGANIC CHEMISTRY., 1967, LETCHWORTH GB, pages 2015 - 2017, XP002071550 *
YAKUGAKU ZASSHI, vol. 104, no. 6, 1984, pages 659 - 679 *
ZABIK ET AL.: "Product and rate studies on the reactions of selected aryl chloroformates with silver nitrate", JOURNAL OF ORGANIC CHEMISTRY., vol. 32, 1967, EASTON US, pages 300 - 307, XP002071551 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002518405A (ja) * 1998-06-12 2002-06-25 バイオテック・オーストラリア・ピーティーワイ・リミテッド ビタミンｂ１２誘導体及びそれらの製造方法
JP4794735B2 (ja) * 1998-06-12 2011-10-19 バイオエー・ピーティーワイ・リミテッド ビタミンｂ１２誘導体及びそれらの製造方法

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AU6946998A (en) 1998-11-13
ZA983399B (en) 1999-10-22

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