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WO2004080997A1 - Procede de preparation de loratadine - Google Patents

Procede de preparation de loratadine Download PDF

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Publication number
WO2004080997A1
WO2004080997A1 PCT/IN2003/000055 IN0300055W WO2004080997A1 WO 2004080997 A1 WO2004080997 A1 WO 2004080997A1 IN 0300055 W IN0300055 W IN 0300055W WO 2004080997 A1 WO2004080997 A1 WO 2004080997A1
Authority
WO
WIPO (PCT)
Prior art keywords
loratadine
reaction
formula
methyl
temperature
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/IN2003/000055
Other languages
English (en)
Inventor
Sanjay Suri
Jujhhar Singh
Syed Shawket Naim
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.)
Morepen Laboratories Ltd
Original Assignee
Morepen Laboratories Ltd
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 Morepen Laboratories Ltd filed Critical Morepen Laboratories Ltd
Priority to PCT/IN2003/000055 priority Critical patent/WO2004080997A1/fr
Priority to AU2003224421A priority patent/AU2003224421A1/en
Publication of WO2004080997A1 publication Critical patent/WO2004080997A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to an improved process for the production of Loratadine.
  • the present invention particularly relates to a process that results in the production of Loratadine with high yield and high purity.
  • the present invention also relates to a process for the manufacture of intermediates with high yield and purity useful in the production of Loratadine.
  • CNS central nervous system
  • cycloheptene derivatives which involve production of a tricyclic aromatic ketone which is reacted with a Grignard reagent such as N-methyl-4-piperidyl magnesium halide (or zinc halide) preferably chloride. Dehydration gives N-methyl product. The process is, however, hindered by the amount up to 30% of 1,6-addition product which is generated in the Grignard reaction causing problems in yield and purification.
  • a Grignard reagent such as N-methyl-4-piperidyl magnesium halide (or zinc halide) preferably chloride.
  • Cid et al have reported (tetrahedron, 1988, vol. 44, 6197-6200) cross coupling reactions between tricyclic ketone and a cyclic ketone using low valent titanium.
  • the low valent titanium has to be generated using lithium metal that is hazardous on industrial scale and is required to be used in high volumes to prevent the reaction
  • ES Patent No.2,040,177 advocates the use of trimethyl phosphite which makes the Process inconvenient from industrial viewpoint.
  • ES Patent Nos. 2,009,465 and 2,009,466 suggest the interchange in the order of last two reactions of the process disclosed in US Patent NO. 4,282,233.
  • Es Patent 2,080,700 and Canadian Patent No.2,134,128 teach the use of palladium- 5. catalysed condensation of an olefin an intermediate prepared through multi-step and complex reaction disclosed in ES Patent No. 2,080,699.
  • US Patent No. 6,093,827 advocates preparation of carbinol by reacting a dibenzosuberone with an aliphatic ketone in presence of low valent titanium generated in-situ by zinc. The process results in crude carbinol due to contamination with deoxygenated tricycle. Thus the reaction causes problems in yield and quality of the carbinol and subsequently the yield and quality of final product loratadine.
  • the main object of the present invention is to provide a process that obviates the drawbacks of the existing processes.
  • Another object of the present invention is to provide a process that gives enhanced yield and quality of the desired product- loratadine
  • Still yet another object of the present invention is to provide a process that results in to a product meeting ICH guidelines. 10.
  • the present invention also provides a process, which avoids use of hazardous reagents and stringent reaction conditions and yet produces a product with improved quality & yield.
  • the present invention provides a process for the production of loratadine, chemically known as 8-chloro-l l-(l-ethoxycarbonyl-4-piperidylidene)-6,ll-dihydro-
  • 5H-benzo [5,6]cyclohepta[l,2-b]pyridene which comprises reacting a tricyclic aromatic ketone with an organometallic compound containing Mg in presence of organic solvent then hydrolyzing and isolating loratadine by conventional methods wherein the reaction between cyclic ketone and the said organometallic compound is effected at a glacial temperature.
  • the tricyclic aromatic ketone used may be such as dibenzocycloheptene, particularly dibenzosuberone.
  • the said cyclic ketone may be of formula II and has chemical name 8-chloro-6,l l- dihydro->5H-benzo[5,6]cyclohepta[l,2-b]pyridine-l l-one
  • the cyclic ketone of formula II may be prepared according to US Patent No. 3,326,924 or to ES Patent No. 554 898.
  • the organometallic compound containing Mg may be N-methyl-piperidyl magnesium salt of formula III where in, z represents halogen. Particularly z may be chloro. N-methyl-piperidyl
  • magnesium chloride may be prepared by any standard method known in the art by reacting N-methyl-4-chloropiperidine with magnesium metal and dibromoethane in dry tetrahydrofuran.
  • the organic solvent used may be an inert solvent preferably ethereal solvent, more preferably tetrahydrofuran.
  • the reaction between the compound of formula II and of formula III may be effected at a temperature in the range of 0° to -95°C. The reaction may be carried out at a temperature between -80 and
  • reaction is conducted at -85 to -95°C.
  • a process of this invention also deals with the preparation of an intermediate carbinol of formula IV with increased yield and purity, which is further dehydrated and either demethylated or carboethosylated to give loratadine .
  • the process of the present invention is characterized by reacting tricyclic aromatic ketone of formula II with N-methyl-piperidyl magnesium chloride at a temperature in the range of -80 to-95 °C to get a carbinol of formula IV. It was noticed that the yield and purity of the carbinol is increased when produced by condensation at a low
  • the process has an advantage that magnesium is comparatively cheap and safe to use on industrial scale.
  • the invention provides an economical process for the preparation of carbinol.
  • the carbinol thus obtained is dehydrated by any known methods to N-methyl product (olefin)
  • the N-methyl product is further either demethylated or carbethxylated to get loratadine with enhanced purity & high yield.
  • the addition of reagents is carried out at a temperature ⁇ 30°C in US Pat. No. 6,093,827, the reaction was conducted at reflux temperature for the production of intermediate compound. This results in the production of crude product with around 89% yield. When further converted to loratadine it gives 68% yields and > 98% pure.
  • 6,084, 100 also teaches addition of reagents at a temperature in the range of o to -5°C. 5. However, the mixture was allowed to react for about 3hours before heating to around
  • N-methyl-piperidyl magnesium chloride prepared by addition of N-methyl-4- chloropiperidine (136 gm, 1.02 mole) to a stirred solution of magnesium metal (33.4 gm, 1.374 mole), dibromoethane (72.8 gm, 0.386 mole) and dry terahydrofuran (THF) (1.17 L) at 20 to 48°C, is added slowly to a cooled (-85 to -95°C) solution of 8- 20. chloro-6,1 l-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]-l 1-one (100 gm, 0.41 mole) in dry THF (530ml). The reaction mixture is stirred for 2-3 hours at the same temperature. The reaction mixture is quenched with 10% NH 4 CI (600ml)and extracted twice with
  • the reaction was carried out at a temperature of -25 to - 5°C following the steps as 10. described in Example 1.
  • the yield of isolated , 11 -(N-methyl-4-piperidinyl)- 11 -hydroxy- 8-chloro-6,l l-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine (carbinol) was 103 gm with a purity of 87.99% (ODB,HPLC) giving a yield of 73.2 %.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de production de loratadine dont le nom chimique est 8-chloro-11-(1-éthoxycarbonyl-4-pipéridylidène)-6,11-dihydro-5H-benzo[5,6]cycloheptal[1,2-B]pyridène. Ce procédé consiste à faire réagir un cétone aromatique tricyclique avec un composé organométallique contenant du Mg en présence d'un solvant organique, puis à hydrolyser et à isoler la loratadine à l'aide de méthodes classiques, la réaction entre le cétone cyclique et le composé organométallique étant effectuée à une température glaciale.
PCT/IN2003/000055 2003-03-13 2003-03-13 Procede de preparation de loratadine Ceased WO2004080997A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000055 WO2004080997A1 (fr) 2003-03-13 2003-03-13 Procede de preparation de loratadine
AU2003224421A AU2003224421A1 (en) 2003-03-13 2003-03-13 Process for the preparation of loratadine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000055 WO2004080997A1 (fr) 2003-03-13 2003-03-13 Procede de preparation de loratadine

Publications (1)

Publication Number Publication Date
WO2004080997A1 true WO2004080997A1 (fr) 2004-09-23

Family

ID=32982878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000055 Ceased WO2004080997A1 (fr) 2003-03-13 2003-03-13 Procede de preparation de loratadine

Country Status (2)

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AU (1) AU2003224421A1 (fr)
WO (1) WO2004080997A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102336739A (zh) * 2011-07-15 2012-02-01 海南灵康制药有限公司 一种氯雷他定化合物及其制法
CN113135893A (zh) * 2021-06-21 2021-07-20 北京鑫开元医药科技有限公司 苯并环庚烷并吡啶化合物、其制备方法及其用途
CN114085209A (zh) * 2022-01-10 2022-02-25 北京鑫开元医药科技有限公司 一种氯雷他定关键中间体的纯化方法
CN116179624A (zh) * 2023-03-16 2023-05-30 江苏广承药业有限公司 酶法催化地氯雷他定合成氯雷他定的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659716A (en) * 1984-02-15 1987-04-21 Schering Corporation Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines
ES2009465A6 (es) * 1988-12-21 1989-09-16 Inke Sa Procedimiento para la obtencion del 4-(8-cloro-5,6-dihidro-11h-benzo(5,6)ciclohepta(1,2-b)piridin-11-il-11ol)-1-piperdincarboxilato de etilo.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659716A (en) * 1984-02-15 1987-04-21 Schering Corporation Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines
ES2009465A6 (es) * 1988-12-21 1989-09-16 Inke Sa Procedimiento para la obtencion del 4-(8-cloro-5,6-dihidro-11h-benzo(5,6)ciclohepta(1,2-b)piridin-11-il-11ol)-1-piperdincarboxilato de etilo.

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PIWINSKI J J ET AL: "Dual antagonists of platelet activating factor and histamine.Identification of structural requirements for dual activity of N-acyl-4-(5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-y lidene)piperidines", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 1, 1991, pages 457 - 461, XP002169640, ISSN: 0022-2623 *
VILLANI F J ET AL: "DERIVATIVES OF 10,11-DIHYDRO-5H-DIBENZOUA,D CYCLOHEPTENE AND RELATED COMPOUNDS 6. AMINOALKYL DERIVATIVES OF THE AZA ISOSTERES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 15, no. 7, 1972, pages 750 - 754, XP000578364, ISSN: 0022-2623 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102336739A (zh) * 2011-07-15 2012-02-01 海南灵康制药有限公司 一种氯雷他定化合物及其制法
CN102336739B (zh) * 2011-07-15 2012-09-26 海南灵康制药有限公司 一种氯雷他定化合物及其制法
CN113135893A (zh) * 2021-06-21 2021-07-20 北京鑫开元医药科技有限公司 苯并环庚烷并吡啶化合物、其制备方法及其用途
CN114085209A (zh) * 2022-01-10 2022-02-25 北京鑫开元医药科技有限公司 一种氯雷他定关键中间体的纯化方法
CN116179624A (zh) * 2023-03-16 2023-05-30 江苏广承药业有限公司 酶法催化地氯雷他定合成氯雷他定的方法

Also Published As

Publication number Publication date
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