WO2006006184A2 - Procede de production de loratadine et ses intermediaires - Google Patents

Procede de production de loratadine et ses intermediaires Download PDF

Info

Publication number
WO2006006184A2
WO2006006184A2 PCT/IN2005/000235 IN2005000235W WO2006006184A2 WO 2006006184 A2 WO2006006184 A2 WO 2006006184A2 IN 2005000235 W IN2005000235 W IN 2005000235W WO 2006006184 A2 WO2006006184 A2 WO 2006006184A2
Authority
WO
WIPO (PCT)
Prior art keywords
ketone
produce
acid
followed
ketonitrile
Prior art date
Application number
PCT/IN2005/000235
Other languages
English (en)
Other versions
WO2006006184A3 (fr
Inventor
Sanjay Suri
Tapan Kashyap
Krishan Singh Verma
Netar Singh
Original Assignee
Morepen Laboratories 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 Morepen Laboratories Limited filed Critical Morepen Laboratories Limited
Publication of WO2006006184A2 publication Critical patent/WO2006006184A2/fr
Publication of WO2006006184A3 publication Critical patent/WO2006006184A3/fr

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

  • the invention particularly relates to a process resulting into Loratadine with increased yield and higher purity. Further the process is simple to operate does not require any stringent conditions and special infrastructure. The process is reproducible, environment friendly and easy to scale up for industrial manufacture with improved quality of the title product.
  • HF in liquid from
  • BF3 in gas form
  • reaction may be carried out at a
  • the reaction may be effected in
  • the alcohol thus produced contains inherent impurities and thus the final product obtained requires further purification in order to get a desired quality.
  • '716 advocates ring closing employing super acid having a Hammett acidity function value of less than minus 12 to get a title compound.
  • This route will pose the similar problems associated with the process disclosed in '447 US patent 3,717,647 teaches condensing of nicotinic ester with phenylacetonitrile by sodium alkoxide in water miscible solvents such as ethanol at reflux temperature to produce ketonitrile.
  • ketonitrile is isolated and then converted to ketone by heating with strong mineral acid such as hydrobromic or hydrosulfuric acid at reflux temperature is further hydrolyzed, decarboxylated and then reduced by well-known method like Wolff-Kishner reaction.
  • the present invention aims at providing "A Process for Manufacturing
  • One of the objects of the present invention is to provide a process, which results in increased yield and higher purity.
  • Other object of the invention is to provide a process that is simple to operate, does not require any stringent conditions and special infrastructure.
  • Another object of the invention is to provide a process that eliminates using hazardous chemicals and stringent operating conditions.
  • Yet other object of the invention is to provide a process that is environment friendly, economical, easy to scale up for industrial manufacture with improved quality of the title product and also reproducible.
  • Loratadine and its Intermediates comprising: (a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods,
  • step (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile,
  • step (d) subjecting the ketone obtained in step (c) above to reduction followed by N- oxidation , cyanation, and hydrolysis by any known methods to produce picolinic acid,
  • step (h) subjecting the said olefin to N- carbethoxylation to produce Ioratadine wherein step (b) & (c) are carried out in one pot.
  • step (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile.
  • step (a) subjecting substituted benzyl halide to cyanation in a biphasic system using water immiscible solvents by any known methods, (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile, (c) hydrolyzing followed by decarboxylating the said ketonitrile to respective
  • step (b) condensing the phenyl acetonitrile thus obtained in step (a) with nicotinic ester in presence of alkali metal alkoxide and water immiscible organic solvent to produce ketonitrile,
  • step (d) subjecting the ketone obtained in step (c) above to reduction followed by N- oxidation , cyanation, and hydrolysis by any known methods to produce picolinic acid,
  • this invention also provides a process for manufacturing of loratadine comprising:
  • phase transfer catalyst used in cyanation of substituted benzylhalide in step (a) may be such as any conventionally used quaternary ammonium compound preferably tetrabutyl ammonium halide, Using appropriate substitution in the starting material i.e.
  • the water immiscible solvent used in the step (a) may be dichloromethane or toluene preferably toluene helps in saving water miseible solvents otherwise used in reported publications and in turn helps in increased yield.
  • the alkali metal alkoxide may preferably be, but not limited to, sodium methoxide.
  • the water immiscible organic solvent used insitu condensation of phenyl acetonitrile may be exemplified but not restricted to dimethyl fo ⁇ namide, dimethyl sulfoxide, tetrahydrofuran and toluene, preferably tetrahydrofuran and toluene advantageously replacing the water miseible solvents such as ethanol in condensation of nicotinic ester with phenylacetonitrile in the existing prior art.
  • the condensation is effected in ethanol at reflux temperature.
  • ketonitrile and impurities go in to the aqueous phase and the product is recovered from aqueous phase using organic solvent to remove impurities.
  • organic solvent to remove impurities.
  • the impurities goes directly to water immiscible organic solvent leaving ketonitrile in aqueous phase thereby helps in avoiding the yield losses and saving on water miseible solvents used in hitherto known processes.
  • the reaction also being effected in situ without isolating the phenylacetonitrile helps in increased yield.
  • phenyl acetonitrile may be used as crude after solvent recovery or as a distilled inte ⁇ nediate after high vacuum distillation.
  • Reaction product (enol nitrile in basic media as alkali metal salt) may be centrifuged or extracted in water from reaction mass, thus avoiding solvent extraction and/ or recovery or centrifugation for product isolation, making the process simple and easily scalable.
  • the water immiscible solvent can be recycled and reused thereby making the process environment friendly as against the ethanol, which puts load on environment through discharge in the effluent.
  • step (f) may be performed in presence of tetrahydrofuran (THF) as per known methods in the prior art.
  • the alcohol is purified prior to its dehydration using polar water miscible solvents exemplified by lower aliphatic alcohols with up to 3 carbon atoms, aliphatic ketones such as acetone methyl isobutyl ketone, methyl-tert-butyl ketone, methyl ethyl ketone, and acetonitrile, and crystallized with base.
  • polar water miscible solvents exemplified by lower aliphatic alcohols with up to 3 carbon atoms, aliphatic ketones such as acetone methyl isobutyl ketone, methyl-tert-butyl ketone, methyl ethyl ketone, and acetonitrile, and crystallized with base.
  • the purified carbinol/alcohol thus produced may then be dehydrated at a temperature
  • the cyano compound of formula VIII in step (i) of other alternative process may be generated by any known methods.
  • the source of boric acid used in cyclization may be such as boric acid or sodium borate or boric anhydride or mixture there of, Using sodium borate/sulfuric acid, boric anhydride/sulfuric acid, boric acid/sulfuric acid in
  • Loratadine is obtained following the route A Route A
  • Loratadine is obtained following the route B.
  • Example 1 Preparation of 3-Chlorobenzylcyanide (II)
  • 3-Chlorobenzyl chloride (10Og) is reacted with sodium cyanide (39 g) in a biphasic mixture of water (300 ml)- toluene (100 ml) in presence of tetrabutyl ammonium bromide under refluxing. Reaction mass is washed thoroughly with water to remove any sodium cyanide contents.
  • Toluene layer can be proceeded directly for the next step or the oily product after toluene recovery or high vacuum distilled product may be used for next step.
  • 3-chlorobenzyl cyanide 100 g either as oil or distilled oil or as toluene layer from examplel, is added slowly to a mixture of sodium methoxide (58 g) and ethyl nicotinate (110 g) in toluene at 65- 7O 0 C.
  • the reaction mixture is stirred at the same temperature for 2-4 hrs.
  • Reaction mass is cooled to room temperature and product is extracted in water. Aqueous solution of product is proceeded as such (in-situ) for the next step,
  • Aqueous solution of example 3 is cooled to 0-5 0 C and sulfuric acid (550 g) is slowly added at ⁇ 60 0 C. Reaction mass is heated to 120-125 0 C and stirring is continued for reaction completion. Reaction mass is quenched in water followed by basification and extraction in dichloromethane. Removal of solvent yielded the crude title compound which is proceeded as such for the next step.
  • reaction mass after quenching in water is basified to get crystallization. Mass is centrifuged, washed with water and wet cake is used as such for next stage.
  • 3-Chlorobezylcyanide (5.0 kg, 33 mole ) is added slowly to a mixture of sodium methoxide (2.9 kg , 54 mole) and ethyl nicotinate (6.25 kg, 41 mole) in tetrahydrofuran (7.5 It.) at 40-48°C.
  • the reaction mixture is stirred for 2 hrs at the same temperature .
  • the reaction mixture is cooled to 20-25 0 C and toluene (25It) is added slowly to get crystals of ⁇ - cyano- ⁇ - hydroxy- ⁇ -(3 ' pyridyl )-3- chlorostyrene as wet sodium salt.
  • This salt as such is subjected for hydrolysis with sulfuric acid (22 kg , 220 mole) and water (10 It.) at 120-122 0 C for 4hrs. Reaction mass is cooled to 80 to 9O 0 C and poured in chilled water (100 It.) followed by basification with caustic solution at pH 7.5 to 8.0 and extracted the product in methylene chloride. Removal of solvent yielded the crude, 3- pyridyl-3-chlorobezyl ketone (V).
  • Step 5 Preparation of 3- (3- Chlorophenethyl) pyridine -N -oxide (VII)
  • Compound from example 5 or 6 (31.18 kg, 150 mole ) is heated with acetic acid (25.44kg, 410 mole) and hydrogen peroxide (40%, 40.39kg, 1190 mole) at 65 to 75 0 C for 20 to 25 hrs.
  • the reaction mixture is basified with caustic solution (15%) to pH 8 to 9 to obtain title compound with a yield of 29.52 kg 81.9%) and purity of 97 % (HPLC).
  • Step 6 Preparation of 2-Cyano -3- (3- chlorophenethyl) pyridine (VIII)
  • Compound from example 7 (29.52 kg, 117 mole) is reacted with N,N-dimethyl carbamoyl (29.87 kg, 277 mole) in acetonitrile (59kg) at 35-40 0 C for 1-3 hrs followed by reaction with aqueous sodium cyanide (9. 45 kg , 190 mole in 59 It, water) at -5 to 0 0 C for 3-4 hrs.
  • aqueous sodium cyanide (9. 45 kg , 190 mole in 59 It, water) at -5 to 0 0 C for 3-4 hrs.
  • Caustic solution (5.9 kg, 0.147 mole in 89 It. water) is added to the reaction mixture and stirred for 2-3 hrs.
  • Step 7 Preparation of 3-(3-Chlorophenethyl) picolinic acid (IX) Compound from example 8 (20,84 kg, 86 mole) is heated with concentrated sulfuric acid (31.2 kg, 320 mole ) and water (17It) at 120-122 0 C for 10-12 hrs. Reaction mixture is cooled to 90 0 C and poured to cold water (166 It. ) followed by basification with sodium hydroxide solution (20%) to pH 3.2-3.5 to obtain title compound with an yield of 21.2 kg (94.4%) and purity of 99.12 % (HPLC).
  • IX 3-(3-Chlorophenethyl) picolinic acid
  • Step 8 Preparation of l l-[N-Methyl-4-piperidinyl]-8-chloro-6, l l-dihydro-5H-benzo [5,6]cyclohepta[l,2 - ⁇ pyridine
  • XI 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,l,374 mole ), dibromoethane (72.8 gm, 0.386 mole) and dry tetrahydrofuran (1.17L)at 20- 48°C is added slowly to a cooled (-70 to 8O 0 C) solution of 8-chloro-6, 1 1- dihydro-5H-benzo [5,6] cyclohepta [l,2-b]-l l- one, X (100gm,0.41 mole ) in dry THF (530m
  • the reaction mixture is stirred for 2-3 hrs at the same temperature.
  • the reaction mixture is quenched with 10% NH 4 Cl (600ml) and extracted twice with ethyl acetate (2x 400ml).
  • the organic phase is washed with water and dried over anhydrous sodium sulfate, filtered and solvent removed to get crude material (150 g),
  • the crude material obtained is purified by dissolving in methanol (560ml) and crystallized with caustic solution (140 ml) at refluxing temperature.
  • the material is filtered after cooling to 10-15 0 C and washed with water (560 ml) to obtain desired carbinol of formula XI in 73.6% yield with purity of 97.3% (ODB, HPLC) (b);
  • the experiment is conducted as described in example 10 except that methanol is replaced by ethanol to get purified carbinol of formula XI with an yield of 70.0% and purity of 96% (ODB.HPLC)
  • the experiment is conducted as described in example 10, except that methanol is replaced by isopropanol to get purified carbinol of Formula XI with an yield of 70% and purity of 95% (ODB, HPLC).
  • Triethylamine (2-10 g) is added and mass is stirred for 30 min followed by cooling to
  • Step 9 Preparation of 8-chloro-6, l l-dihydro-l l-(N-methyl-4-piperidinylidene)-5H- benzo[5,6]cyclohepta[l, 2-b]pyridine (XII)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé consistant: i) à soumettre un halide de benzyle substitué à une cyanuration dans un système biphase à l'aide de solvants non miscibles dans l'eau au moyen de procédés quelconques connus; ii) à condenser in situ le phényle acétonitrile ainsi obtenu à l'aide d'un ester nicotinique en présence d'un alkoxyde de métal alcalin et d'un solvant organique non miscible dans l'eau afin de produire un cétonitrile; iii) à hydrolyser puis à décarboxyler ledit cétonitrile in situ en cétone respective dans un environnement acide en-dessous de 60° C; iv) à soumettre la cétone ainsi obtenue à une réduction suivie d'une N-oxydation, d'une cyanuration et d'une hydrolyse au moyen de procédés quelconques connus afin de produire un acide picolinique; v) à cycliser l'acide picolinique en cétone tricyclique au moyen de procédés classiques; vi) à traiter la cétone tricyclique à l'aide d'un composé organométallique contenant Mg afin de produire un carbinol; viii) à purifier le carbinol à l'aide d'un agent de purification sélectionné à partir d'un solvant organique polaire miscible dans l'eau, puis à le déshydrater à l'aide d'un acide sulfurique à une température inférieure à 50° C afin d'obtenir un produit N-méthyle (oléfine) et à soumettre cette oléfine à une N-carbéthoxylation afin de produire une loratadine. Ladite loratadine peut également être préparée par traitement d'un composé cayano à l'aide du composé organométallique contenant Mg afin de produire une cétone au moyen des procédés connus de l'état de la technique suivi d'une cyclisation en présence d'un mélange d'acide sulfurique et d'une source d'acide borique afin d'obtenir un produit N-méthyle et de le convertir en loratadine par N-carbéthoxylation.
PCT/IN2005/000235 2004-07-08 2005-07-06 Procede de production de loratadine et ses intermediaires WO2006006184A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1271DE2004 2004-07-08
IN1271/DEL/2004 2004-07-08

Publications (2)

Publication Number Publication Date
WO2006006184A2 true WO2006006184A2 (fr) 2006-01-19
WO2006006184A3 WO2006006184A3 (fr) 2006-10-26

Family

ID=35457853

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000235 WO2006006184A2 (fr) 2004-07-08 2005-07-06 Procede de production de loratadine et ses intermediaires

Country Status (1)

Country Link
WO (1) WO2006006184A2 (fr)

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
CN112341433A (zh) * 2020-11-16 2021-02-09 成都大学 一种氯雷他定的制备方法
CN113135899A (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
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717647A (en) * 1971-04-09 1973-02-20 Schering Corp Alpha-nicotinoyl phenylacetonitriles
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717647A (en) * 1971-04-09 1973-02-20 Schering Corp Alpha-nicotinoyl phenylacetonitriles
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

Non-Patent Citations (1)

* 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[5,6Ücycloh epta-[1,2-bÜpyridin-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 *

Cited By (6)

* 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
CN112341433A (zh) * 2020-11-16 2021-02-09 成都大学 一种氯雷他定的制备方法
CN113135899A (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
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

Also Published As

Publication number Publication date
WO2006006184A3 (fr) 2006-10-26

Similar Documents

Publication Publication Date Title
JPS6134426B2 (fr)
HU219911B (hu) Pirazolo-piridin-származékok, alkalmazásuk és ezeket tartalmazó gyógyászati készítmények
CN111630049B (zh) 用于制备2-(5-甲氧基异色满-1-基)-4,5-二氢-1h-咪唑及其硫酸氢盐的方法
WO2006006184A2 (fr) Procede de production de loratadine et ses intermediaires
JPH0567136B2 (fr)
WO2006114676A2 (fr) Processus de preparation de la rupatadine
OA10694A (en) Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine.
EP1136470B1 (fr) Procede de preparation de derive piperazine
WO2015124764A1 (fr) Procédé de synthèse de dabigatran étexilate mésylate, intermédiaires de ce procédé et nouveau polymorphe de dabigatran étexilate
ITMI991486A1 (it) Processo per la sintesi di citalopram
JP3930736B2 (ja) ピリジンメタノール化合物の製造方法
WO2009139002A2 (fr) Procédé perfectionné de fabrication de solifénacine et de ses sels pharmaceutiquement acceptables
US20090131664A1 (en) Method for Producing 4(3H)-Quinazolinone Derivative
AU2002360117B2 (en) Aralkyl-tetrahydro-pyridines, their preparation and pharmaceutical compositions containing same
CN104557671B (zh) 一种非索非那定及中间体的合成方法
US6538138B1 (en) Process and a novel intermediate for the preparation of Flecainide
Pedrosa et al. Synthesis of enantiopure mono-and disubstituted tetrahydroisoquinolines by 6-exo radical cyclizations
KR20090028682A (ko) 1-할로-2,7-나프티리디닐 유도체를 제조하는 방법
Couturier et al. Efficient synthesis of the κ-opioid receptor agonist CJ-15,161: four stereospecific inversions at a single aziridinium stereogenic center
CA2465686C (fr) Procede de preparation d'ethylester d'acide 4-(8-chloro-5,6-dihydro-11h-benzo-(5,6)-cyclohepta-(1,2b)-pyridin-11-ylidene)-1-piperidinecarboxylique (loratadine)
CN102827152A (zh) 噻加宾的制备方法及其前体化合物
JPH0892242A (ja) 新規製造中間体及びピリジン誘導体の製造方法
HU217445B (hu) Eljárás 2-{4-[4-(4-klór-1-pirazolil)-butil]-1-piperazinil}-pirimidin előállítására
US20080182987A1 (en) Method For Producing 2-(4-Methyl-2-Phenylpiperazine-1-Yl)-3-Cyanopiridine
US4843163A (en) Certain 3-(2-phenethyl)-1-carbamoyloxypyridinium halide intermediates

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase