[go: up one dir, main page]

EP1670742A1 - Procede de preparation de roflumilast - Google Patents

Procede de preparation de roflumilast

Info

Publication number
EP1670742A1
EP1670742A1 EP04769351A EP04769351A EP1670742A1 EP 1670742 A1 EP1670742 A1 EP 1670742A1 EP 04769351 A EP04769351 A EP 04769351A EP 04769351 A EP04769351 A EP 04769351A EP 1670742 A1 EP1670742 A1 EP 1670742A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkali metal
iodide
bromide
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.)
Withdrawn
Application number
EP04769351A
Other languages
German (de)
English (en)
Inventor
Prosenjit Bose
Yoginder Pal Sachdeva
Ramendra Singh Rathore
Yatendra Kumar
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1670742A1 publication Critical patent/EP1670742A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • PROCESS FOR THE PREPARATION OF ROFLUMILAST Field of the invention relates to a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I, and to the use of this compound as an intermediate for the preparation of roflumilast.
  • roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)benzamide of Formula VI, and is known from U.S. Patent No. 5,712,298.
  • FORMULA VI Roflumilast is an effective phosphodiesterase-4-inhibitor (PDE4-inhibitor), which can be used in the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney.
  • PDE4-inhibitor phosphodiesterase-4-inhibitor
  • U.S. Patent No. 5,712,298 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting 4-hydroxy-3- cyclopropylmethoxybenzaldehyde with dichlorofluoromethane followed by oxidation.
  • 6,712,274 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting dihydroxybenzaldehyde with tertiarybutyl difluorochloroacetate in the presence of lithium carbonate and reacting the obtained 4-difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethyl bromide in the presence of potassium carbonate followed by oxidation to yield 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid.
  • Summary of the Invention hi one general aspect there is provided a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid. The process includes reacting the compound of Formula II,
  • FORMULA V wherein X is a leaving group, in the presence of a base.
  • a novel compound 3- cyclopropylmethoxy-4-hydroxy benzoate of Formula II.
  • a novel compound of Formula III in another general aspect there is provided a process for the preparation of roflumilast. The process includes reacting compound of Formula I with 4-amino-3,5- dichloro pyridine.
  • a pharmaceutical composition that includes a therapeutically effective amount of roflumilast; and one or more pharmaceutically acceptable carriers, excipients or diluents. The details of one or more embodiments of the inventions are set forth in the description below.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tert- butyl groups.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl and hexenyl groups.
  • the substituted phenyl includes phenyl substituted by 1-3 substituents, which are independently bromine, chlorine, fluorine, - C 4 alkyl, C ⁇ -C alkoxy, and nitro groups.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • the substituted benzyl includes p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl, and 2,4,6-trimethyl benzyl groups.
  • the difluoro methylating agent which can be used for preparing 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I include difluorochloromethane (Freon-22 ® ), alkyl difluorochloroacetate such as methyl difluorochloroacetate, ethyl difluorochloro acetate and tertiarybutyl difluorochloroacetate.
  • the bases which can be used include organic and inorganic bases.
  • organic bases examples include trimethylamine, triethylamine, tributylamme, triisopropylami Le, diisopropylethylamine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]-non-5-ene), 4-dimethylamino pyridine and mixtures thereof.
  • inorganic bases include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof. Examples of alkali metal carbonates include lithium carbonate, sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • phase transfer catalysts include quaternary ammonium salts such as tetramethyl ammonium iodide, tetrabutyl ammonium iodide, benzyltributyl ammonium bromide, 1-methyl ⁇ yridinium iodide, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetrabutylammonium bromide and t-butylethyldimethylammonium bromide; quaternary phosphonium salts such as tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutyl phosphonium bromide;
  • the reaction of compound of Formula II with difluoromethylating agent may be carried out in the presence of a suitable solvent.
  • suitable solvents are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include alkyl ethers such as diethylether, diisopropylether and dimethoxyethane; nitriles such as acetonitrile and benzonitrile; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; esters such as ethylacetate and isopropylacetate; hydrocarbons such as benzene, xylene, toluene , hexane, cyclohexane, heptane and octane; dipolar aprotic solvents such as di
  • the reaction may be carried out at a temperature of from about 20°C to about 120°C, for example at a temperature of from about 25°C to about 50°C.
  • the compound of Formula HI is converted to the compound of Formula I by conventional methods including hydrolysis or hydrogenation, in case R is a benzylic group.
  • Examples of leaving group X, in the compound of Formula V, include chlorine, bromine, iodine, sulphate and tosylate.
  • the base, phase transfer catalyst and solvent, which may be used for preparing 3-cyclopropylmethoxy-4-hydroxy benzoate of Formula II from compound of Formula rv, can be the same as those which can be used in reaction of compound of Formula II with difluoromethylating agent.
  • roflumilast of Formula VI is prepared by reacting an activated derivative of the acid of Formula I, such as acid halide or a reactive ester, with 4-amino- 3,5-dichloro pyridine.
  • roflumilast can be prepared by reacting the corresponding acid chloride of the compound of Formula I with 4-amirro-3,5-dichloro pyridine in the presence of sodium hydride in tetrahydrofuran.
  • the resulting roflumilast may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. i these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage fonns may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the roflumilast can be administered for the treatment the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • Example 1 Preparation of 3 -Cvclopropylmethoxy-4-hvdroxy methyl benzoate 3,4-Dihydroxy methyl benzoate (50 g) was stirred with cyclopropylmethyl bromide (50.2 g) and potassium carbonate (82.1 g) in acetone (350 ml) for 18 hours at 40°C. The reaction mixture was filtered over a hyflo bed followed by concentration of the organic layer.
  • Example 2 Preparation of 3 -Cvclopropyhnethoxy-4-difluoromethoxy benzoic acid
  • the product obtained from Example 1 (10 g) was subjected, to difluoromethylation using difluorochloromethane, 35 % w/w sodium hydroxide aqueous solution (50 ml), tetrabutyl ammonium bromide (5.9 g) in toluene (100 ml) as solvent at 20 to 35° C.
  • the resulting product, 3-cyclopropylmethoxy-4-difluoromethoxy methyl benzoate was hydrolyzed in situ by adding 50 ml water and heating the reaction mixture to 50 to 55°C.
  • Example 3 Preparation of roflumilast The product obtained from Example 2 (lOg) was heated with thionyl chloride (5.8g) and catalytic amount of dimethylformamide (0.5ml) at 80 to 85°C for 1 hour. The solution was evaporated in vacuo and the oily residue was dissolved in dry tetrahydrofuran (50 ml). This was added dropwise at 0°C to a suspension prepared from sodium hydride (3.75 g, 60% suspension) and 4-amino-3,5-dichlorO pyridine (9.5g) in dry tetrahydrofuran (50 ml) with stirring. The reaction mixture was stirred for 30 minutes and then acidified to pH 2 with hydrochloric acid (1 N).
  • reaction mixture was extracted with ethyl acetate.
  • the extracted solvent was washed with sodium bicarbonate solution (5%) and water followed by evaporation in vacuum.
  • the residue was dissolved in methanol (45 ml) at 60°C and 5 ml of water was added to get precipitate.
  • the mixture was then cooled to 10°C and filtered to o " btain roflumilast.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation d'acide 3-cyclopropylméthoxy-4-difluorométhoxy benzoïque de formule structurale I, et l'utilisation de ce composé comme produit intermédiaire pour la préparation de roflumilast.
EP04769351A 2003-09-12 2004-09-13 Procede de preparation de roflumilast Withdrawn EP1670742A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1145DE2003 2003-09-12
PCT/IB2004/002959 WO2005026095A1 (fr) 2003-09-12 2004-09-13 Procede de preparation de roflumilast

Publications (1)

Publication Number Publication Date
EP1670742A1 true EP1670742A1 (fr) 2006-06-21

Family

ID=34308044

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04769351A Withdrawn EP1670742A1 (fr) 2003-09-12 2004-09-13 Procede de preparation de roflumilast

Country Status (2)

Country Link
EP (1) EP1670742A1 (fr)
WO (1) WO2005026095A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
ME00524B (me) 2003-03-10 2011-10-10 Astrazeneca Ab Novi postupak za dobijanje roflumilasta
EP1861074B1 (fr) 2005-03-16 2013-04-24 Takeda GmbH Forme de dosage cachant le goût comprenant du roflumilaste
CN102617457A (zh) * 2011-01-28 2012-08-01 天津药物研究院 一种制备罗氟司特的新方法
CN102690194B (zh) * 2011-03-24 2014-06-25 上海通远生物科技有限公司 3-环丙基甲氧基-4-二氟甲氧基苯甲酸的制备方法
WO2012147098A2 (fr) * 2011-04-28 2012-11-01 Glenmark Generics Limited Nouveau procédé de préparation de 3-(cyclopropylméthoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy) benzamide
CN102775345A (zh) * 2011-05-13 2012-11-14 上海特化医药科技有限公司 制备罗氟司特的方法及中间体
CN102276522B (zh) * 2011-06-15 2013-04-17 无锡泓兴生物医药科技有限公司 一种制备罗氟司特的方法及其中间体
WO2013072938A2 (fr) 2011-11-09 2013-05-23 Mylan Laboratories Ltd Procédé amélioré pour la préparation de roflumilast
CN102633631B (zh) * 2012-03-05 2014-02-26 山西仟源制药股份有限公司 3-环丙基甲氧基-4-二氟甲氧基苯甲酸的制备方法
CN102617339A (zh) * 2012-03-05 2012-08-01 山西仟源制药股份有限公司 3-环丙基甲氧基-4-卤代苯甲酸或其衍生物及应用
CN103319400A (zh) * 2012-03-21 2013-09-25 黑龙江福和华星制药集团股份有限公司 一种制备罗氟司特的方法
JP6153618B2 (ja) 2012-10-17 2017-06-28 インテルキム、ソシエダッド アノニマ ロフルミラストを調製するための方法
DK3293176T3 (da) * 2013-10-22 2021-02-15 Chiesi Farm Spa Krystalform af en pde4-inhibitor
CN104447245B (zh) * 2014-10-29 2017-06-06 成都森科制药有限公司 罗氟司特中间体、中间体制备方法及罗氟司特的制备方法
CN104447244B (zh) * 2014-10-29 2017-06-06 成都森科制药有限公司 罗氟司特中间体及罗氟司特的制备方法
CN106117133A (zh) * 2016-06-27 2016-11-16 成都欣捷高新技术开发股份有限公司 一种罗氟司特工艺杂质的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ290266B6 (cs) * 1993-07-02 2002-06-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Substituované benzamidy, způsob jejich výroby a farmaceutické prostředky s jejich obsahem
US6822114B1 (en) * 2002-10-08 2004-11-23 Albemarle Corporation Process for production of fluoroalkoxy-substituted benzamides and their intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005026095A1 *

Also Published As

Publication number Publication date
WO2005026095A1 (fr) 2005-03-24

Similar Documents

Publication Publication Date Title
EP1670742A1 (fr) Procede de preparation de roflumilast
JPH05213838A (ja) フルオキセチンの製法
JPH07108881B2 (ja) バルプロ酸または（ｅ）―２―バルプロ酸誘導体、それらの製造法ならびにそれらを含有する抗てんかん剤または抗けいれん剤
CN104892555A (zh) 曲前列尼尔中间体的制备方法
US12297193B2 (en) PTPN2/PTP1B degrader and therapeutic method thereof
JP3107613B2 (ja) ナフタレン誘導体
CA1183148A (fr) COMPOSES .beta.BLOQUANT A ACTION RAPIDE CONTENANT UN ESTER ET PROCEDE DE PREPARATION
WO1996031476A1 (fr) Hydroxyethers aromatiques
CN1105105C (zh) 制备作为杀虫剂中间体2－(吡啶－2－基氧基甲基)苯乙酸酯类化合物的方法
US8507696B2 (en) Intermediates in the synthesis zearalenone macrolide analogs
JP5257353B2 (ja) 置換ヒドロキシメチルフェノールの新規な合成
SK159297A3 (en) 4,4-(disubstituted)cyclohexan-1-ols-monomers and related compounds
CN114380783B (zh) 一种奥洛他定氘标记代谢物的制备方法
JP2000095741A (ja) アミド類の製造法
JP5102985B2 (ja) 含フッ素２級アミン化合物の製造方法
JPH06340630A (ja) ２−クロロ−ピリジンメタノールの製造方法
JP2821700B2 (ja) ４―アミノ―ｃｉｓ―２―ブテン―１―オールの製造方法
TWI231811B (en) Process and intermediates for making 4-cyanosubstituted cyclohexanoic acids
CN119161302A (zh) 蛇足石杉碱衍生物、其制备方法及其在抗痛风药物中的应用
KR20120059148A (ko) 피타바스타틴의 제조를 위한 키랄 중간체의 제조방법
JP2023023928A (ja) レチノイドｘ受容体アゴニスト及びその中間体の製造方法
CZ196097A3 (cs) 4,4-(Disubstituované)cyklohexan-1-olové monomery a odvozené sloučeniny, farmaceutický prostředek a použití
JPH0529355B2 (fr)
WO2006108491A1 (fr) Procede ameliore de preparation de nitriles d'oxazole
JP2003252831A (ja) 含フッ素乳酸誘導体の製造方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060412

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL HR LT LV MK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20070403