WO2009057133A2 - Procédé de synthèse d'acide 2-[2-[4-[(4-chlorophényl)phénylméthyl]-1-pipérazinyl]éthoxy-acétique - Google Patents

Procédé de synthèse d'acide 2-[2-[4-[(4-chlorophényl)phénylméthyl]-1-pipérazinyl]éthoxy-acétique Download PDF

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Publication number
WO2009057133A2
WO2009057133A2 PCT/IN2008/000419 IN2008000419W WO2009057133A2 WO 2009057133 A2 WO2009057133 A2 WO 2009057133A2 IN 2008000419 W IN2008000419 W IN 2008000419W WO 2009057133 A2 WO2009057133 A2 WO 2009057133A2
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formula
compound
phenyl
piperazinyl
ethoxy
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WO2009057133A3 (fr
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Santosh Ramesh Badgujar
Hemant Harishchandra Kamble
Vipin Sharma
Dharmeshkumar Arvindbhai Patel
Mubeen Ahmed Khan
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Glenmark Generics Ltd
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Glenmark Generics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a process for the preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid of formula (Ia) and pharmaceutically acceptable salts thereof,
  • the compound of formula (Ia) may exist in the levorotatory form, the dextrorotatory form or a mixture of the levorotatory and dextrorotatory forms or pharmaceutically acceptable salts thereof.
  • the present invention also relates to a novel compound of formula (Ha) and (Villa),
  • Rj H or Ci-C 4 alkyl
  • R 2 aryl or heteroaryl or Ri and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group
  • X is a suitable leaving group for example, chlorine, bromine, iodine, 4-methylphenyl-sulfonyloxy, methylsulfonyloxy group or 4- bromophenyl-sulfonyloxy group.
  • the dihydrochloride of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid also known as Cetirizine
  • Cetirizine is known as a medicament for the treatment of allergic syndromes, such as chronic and acute allergic rhinitis, allergic conjunctivies, pruritus, urticaria etc. Its pharmacological and medicinal properties have been described in the literature, C. De. Vos et. Al., Ann. Allergy 59, 278, 1987; L. Juhlin et. Al, J. Allergy Clin. Immunol., 80, 80,599 (1987).
  • the levorotatory isomer of cetirizine i..e Levocetirizine is also approved for allergic rhinitis and chronic idiopathic urticaria.
  • Patent No. 58,146 describes the synthesis of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid and its dihydrochloride.
  • Patent discloses the synthesis wherein the starting substance l-[(4-Chloro phenyl) phenyl methyl] piperazine is reacted with methyl (2-chloroethoxy) acetate to give methyl-2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetate in a yield 27.8%.
  • This methyl ester is then subjected to hydrolysis with an inorganic base (sodium or potassium hydroxide) to give the sodium or potassium salt, which is easily converted into the free acid, and then into cetirizine dihydrochloride
  • British Patent No. 2,225,321 describes a process for the preparation of the enantiomers of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid dihydrochloride.
  • This process is based on the use of levorotatory or dextrorotatory l-[(4- Chloro phenyl) phenyl methyl] piperazine which is obtained by the chemical resolution of racemic form, using conventional methods, in particular, by salt formation with a suitably selected optical isomer of tartaric acid.
  • the present invention provides a process for the preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid, a compound of formula (Ia), which is either in the levorotatory or dextrorotatory form or a mixture thereof.
  • the process comprises converting the compound of formula (Ha),
  • R 2 aryl or heteroaryl or R 1 and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • above defined compound of formula (Ha) is prepared by a process comprising condensing a compound of formula (Villa)
  • X is a suitable leaving group consisting of, chlorine, bromine, iodine, 4- methylphenyl-sulfonyloxy, methylsulfonyloxy group or 4-bromophenyl-sulfonyloxy group;
  • Ri H or C]-C 4 alkyl
  • R 2 aryl or heteroaryl or Rj and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • invention relates to the process of preparing a compound of formula (Villa) comprising halogenation or mesylation of a compound of formula (Vila),
  • Ri H or Ci-C 4 alkyl
  • R 2 aryl or heteroaryl or R] and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group, under suitable condition.
  • the process of preparing a compound of formula (Vila) by the condensation of an acetamide of formula (Va) (Va) with triethanol amine VI is provided.
  • the compound of formula (Va) can be prepared by the acylation of a requisite amine,
  • Rj H or C]-C 4 alkyl
  • R 2 aryl or heteroaryl or Rj and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • the present invention provides use of intermediate of formulae (Ha) and (Villa) in preparation of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid of formula (Ia) and pharmaceutically acceptable salts thereof.
  • the present invention provides a process for preparation of the levorotatory isomer, (R)- 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid, a compound of formula (I), depicted schematically in scheme I below;
  • R 2 aryl or heteroaryl or Ri and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • the compound of formula (Va) is prepared by any method known in the art which comprises acylation of a requisite amine (Ilia) by chloroacetylchloride, 000419
  • Ri H or C 1 -C 4 alkyl
  • R 2 aryl or heteroaryl or Ri and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • the present disclosure provides the preparation of 2-chloro-N-(l -phenyl ethyl) acetamide
  • the solvent used in said stage-A acylation reaction may be selected from water, non-polar hydrocarbon or chlorinated hydrocarbon solvent, aprotic solvent, aromatic solvent, ether solvent.
  • the aromatic solvent used in stage-A may be selected from benzene, toluene, xylene and the likes thereof, preferably toluene;
  • the chlorinated hydrocarbons used in stage-A may be selected from dichloromethane, dichloroethane, dibromoethane, preferably dichloromethane.
  • the base used in said stage-A may be selected from organic base or inorganic base.
  • the inorganic base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium carbonate; organic base may be tert.butyl dimethylamine, triethylamine, diisopropylethylamine, pyridine, morpholine, p-N,N-dimethyl amino pyridine and the likes thereof, preferably triethylamine.
  • the acylation reaction is advantageously carried out at a temperature range of about - 15 0 C to about +45 0 C, preferably about -5 0 C to about 35 0 C.
  • Ri H or C 1 -C 4 alkyl
  • R 2 aryl or heteroaryl or R 1 and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group.
  • the present invention further discloses that 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy- 1-N-benzyl acetamide (VIIb) may be prepared by condensation of 2-chloro-N-Benzyl acetamide (Vb) with triethanolamine (VI).
  • a solvent may be used in said stage-B selected from water, aprotic polar solvent or aromatic solvent.
  • the aprotic polar solvent may be selected from N,N-dimethyl formamide, N,N-dimethyl- acetamide, dimethylsulfoxide, N-methyl- 2-pyrrolidone and the likes thereof, preferably dimethylsulfoxide;
  • the aromatic solvent may be selected from benzene, toluene, xylene and the likes thereof, preferably toluene.
  • the base used in said stage-B may be selected from alkali hydrides, hydroxides, carbonates or bicarbonates.
  • the inorganic base may be selected from sodium hydride, lithium hydride, Butyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium hydroxide.
  • the mole equivalent ratio of triethanolamine (VI) to the acetamide (Va), may be 1 :1 1 :10, preferably 1 :4.5.
  • Advantageously triethanolamine can also act as a solvent, obviating the need of different solvent. The excess triethanol amine can be recovered by conventional method and recycled to increase the productivity.
  • the condensation reaction in stage-B may be carried out between about -15°C to about 130°C, preferably about 65°C to about 80 0 C.
  • the present disclosure further contemplates that the above obtained compound of formula (Vila) may be further converted to compound of formula (Villa) by halogenation or mesylation,
  • Ri H or Cj-C 4 alkyl
  • R 2 aryl or heteroaryl or R] and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group;
  • X is a suitable leaving group selected from the group consisting of chlorine, bromine, iodine, 4-methylphenyl-sulfonyloxy, methyl sulfonyloxy group or 4-bromophenyl- sulfonyloxy group.
  • X is a suitable leaving group selected from the group consisting of chlorine, bromine, iodine, 4-methylphenyl-sulfonyloxy, methylsulfonyloxy group or A- bromophenyl-sulfonyloxy group.
  • the solvent used in said stage-C may be selected from non-polar hydrocarbon, chlorinated hydrocarbon solvents, aprotic solvent, aromatic solvent, ether solvent.
  • the aromatic solvent may be selected from benzene, toluene, xylene and the likes thereof, preferably toluene;
  • the chlorinated hydrocarbons may be dichloromethane, dichloroethane, dibromoethane and the likes thereof, preferably dichloromethane.
  • the excess acid can be neutralized by using a base selected from organic base or inorganic base.
  • the inorganic base may be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium hydroxide or organic base may be triethylamine, diisopropylethylamine, pyridine, morpholine, p-N, N-dimethyl amino pyridine, preferably sodium hydroxide.
  • the halogenation reaction may be advantageously carried out at a temperature range of about -15°C to about +55 0 C, preferably about 5 0 C to about 30 0 C using halogenating agents like thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride and the likes thereof.
  • the mesylation reaction can be carried out using suitable agent like mesyl halide, tosyl halide at a temperature range of about -15°C to +50 0 C, preferably about 0°C to about
  • the present invention provides a novel intermediate of formula (Ha) and a process for the preparation of such novel intermediates wherein a compound of formula (Villa) is treated with compound of formula (IXa),
  • Ri H or Ci-C 4 alkyl
  • R 2 aryl or heteroaryl or Ri and R 2 together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl group ;
  • X is a suitable leaving group selected from the group consisting of chlorine, bromine, iodine, 4-methylphenyl-sulfonyloxy, methylsulfonyloxy group or 4-bromophenyl- sulfonyloxy group, under suitable condition.
  • the solvent used in said stage-D may be selected from aprotic polar solvents or hydrocarbon solvents for example, toluene, benzene, xylene, N, N-dimethyl formamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, preferably dimethylsulfoxide.
  • aprotic polar solvents or hydrocarbon solvents for example, toluene, benzene, xylene, N, N-dimethyl formamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, preferably dimethylsulfoxide.
  • the base used in stage-D may be selected from organic base or inorganic base.
  • the inorganic base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium carbonate;
  • the organic base may be selected from triethylamine, diisopropylethylamine, pyridine, morpholine, p-N, N-dimethyl amino pyridine, preferably diisopropylethyl amine.
  • the cyclization reaction may be advantageously carried out at a temperature range of 15°C to 145°C preferably about 120 0 C to about 13O 0 C.
  • the reaction may be carried out in a solvent like toluene, benzene, xylene, N,N-dimethyl formamide, N 5 N- dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone in presence of a base like pyridine, TEA, potassium carbonate at about 120°C to 13O 0 C.
  • a solvent like toluene, benzene, xylene, N,N-dimethyl formamide, N 5 N- dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone
  • a base like pyridine, TEA, potassium carbonate at about 120°C to 13O 0 C.
  • N, N- diisopropyl amine can serve as a solvent and a base to carry out the cyclisation, obviating the need to use another solvent.
  • the reaction may be carried out in a solvent like toluene, .benzene, xylene, N,N-dimethyl formamide, N,N- dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone in presence of a base like pyridine, TEA, potassium carbonate at about 120 0 C to 130 0 C.
  • a solvent like toluene, .benzene, xylene, N,N-dimethyl formamide, N,N- dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone
  • a base like pyridine, TEA, potassium carbonate at about 120 0 C to 130 0 C.
  • N, N- diisopropyl amine can serve as a solvent and a base to carry out the cyclisation, obviating the need to use another solvent.
  • These compounds of formula (Ha) can show diastereoisomerism.
  • the unwanted diastereomer can be removed by a simple leaching of the amide compound with suitable solvent or by solvent mixture to get substantially optically pure desired diastereomer which can be converted easily and with high yields into the substantially optically pure enantiomers of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid.
  • the hydrolysis of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]- 1-piperazinyl] ethoxy -1-(S)- [N-(I -phenyl ethyl)] acetamide (II) or (R)-2-[2-[4- [(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy -1-N-benzyl acetamide (lib) may be carried out by treatment with acid or base to obtain (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid (I).
  • the hydrolysis performed in said stage-E is either acid hydrolysis or alkaline hydrolysis, preferably acid hydrolysis.
  • acid used for the hydrolysis is selected from a group consisting of aq. hydrochloric acid, aq. hydrobromic acid, aq. sulfuric acid, preferably aq. sulfuric acid or aq. Hydrobromic acid.
  • the temperature for hydrolysis in said stage-E may be between about -20°C to about 13O 0 C, preferably about 80 0 C .to about 85 0 C.
  • the byproduct, amino compound like benzyl amine, 1 -phen ethyl amine, obtained by this hydrolysis step can be recovered by conventional methods and recycled to increase the productivity.
  • the compound of formula (Ia) can be converted to pharmaceutically acceptable salt thereof if desired, for example hydrochloride, hydrobromide, sodium, potassium salt and the likes thereof.
  • the hydrochloride salt of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid (I) may be prepared by purging or addition of organic solvent saturated with hydrochloric acid gas or by direct purging the hydrochloric acid gas in to the reaction mass. Depending on the amount of hydrochloric acid used monohydrochloride or dihydrochloride salt can be prepared.
  • the salt formation can be carried out in suitable solvent selected from ketone solvent or alcoholic solvent optionally containing water.
  • suitable solvent selected from ketone solvent or alcoholic solvent optionally containing water.
  • the ketone solvent may be selected from acetone, methylethylketone, methyl isobutyl ketone, methyl tert. butyl ketone, preferably acetone.
  • the alcoholic solvent may be selected from methanol, ethanol, isopropanol, t-butanol and the like.
  • the levorotatory and dextrorotatory enantiomers of 4-Chlorophenyl-phenyl methyl amine (IXa), used as starting materials are known compounds; they can be prepared by chemical resolution of racemic 4-Chlorophenyl-phenyl methyl amine by known methods using optically active resolving acid.
  • 4-Chlorophenyl-phenyl methyl amine can be resolved using process described by Clemo and Gardner in JMC, 1939, p-1958-1960 incorporated herein by reference.
  • the enantiomeric purity of levorotatory or dextrorotatory isomer of 2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy acetic acid (Ia) obtained by the above described process has optical purity of more than 99.5%.
  • Example-4 Preparation of 2-[N, N-Bis (2-chloro ethyl) amino] ethoxy-1-S- [N-(I- phenyl ethyl)] acetamide (VIII) 2-[N, N-Bis (2-hydroxy ethyl) amino] ethoxy-1 -S-[N-(I -phenyl ethyl)] acetamide oil
  • Example 2 10.0 g (0.03 mol) (Example-2) was dissolved in 100.0 ml dichloro methane and 0.5 ml N, N-dimethylformamide. Reaction mass was cooled to 0-5°C. Thionyl chloride 15.35 g
  • the toluene was completely distilled under vacuum.
  • the residue was stripped out using 200.0 ml of diisopropyl ether.
  • 500.0 ml of Diisopropyl ether was added to the residue and heated to reflux temperature and maintained the reflux for half an hour and cooled the mass to 25-30°C.
  • the white solid was filtred. Dry wt. 60.0 g-
  • Example-7 Preparation of (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl]-l- piperazinyl] ethoxy acetic acid (I) A mixture of 10.0 g (R)-2-[2-[4-[(4-chloro phenyl) phenyl methyl] -1-piperazinyl] ethoxy -l-S-[N-(l-phenyl ethyl)] acetamide (II) (Example-5), 30.0 ml of cone. Hydrobromic acid and 50.0 ml water was heated to 90°C -95 0 C for 24 hrs.
  • reaction mass was cooled to 25°C -30°C and the reaction mass was diluted by adding 50.0 ml water.
  • Product was extracted using 100.0 ml dichloro methane. Dichloromethane was distilled out to obtain oil (4.8 g).
  • Reaction mass was cooled to 25°C-30°C. Stir the reaction mass for 2 hour. Layer separated. To the organic layer 2000 ml of water was added and stirred mass for one hour.
  • reaction mass 10.0-11.0. Stirred reaction mass for one hour and layer separated. To the organic layer brine solution was added, reaction mass was stirred for one hour and layer separated.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'acide 2-[2-[4-[(4-chlorophényl)phénylméthyl]-1-pipérazinyl]éthoxy-acétique de formule (Ia) et de ses sels pharmaceutiquement acceptables, et de composés de formule (IIa) et (VIIIa), dans lesquelles R1 représente H ou un groupe alkyle en C1-C4 ; R2 représente un groupe aryle ou hétéroaryle ou R1 et R2 associés à l'atome de carbone auxquels ils sont attachés forment un groupe cycloalkyle en C3-C8 et X représente un groupe labile approprié, par exemple un atome de chlore, de brome, d'iode, un groupe 4-méthylphényl-sulfonyloxy, méthylsulfonyloxy ou 4-bromophényl-sulfonyloxy.
PCT/IN2008/000419 2007-07-24 2008-07-03 Procédé de synthèse d'acide 2-[2-[4-[(4-chlorophényl)phénylméthyl]-1-pipérazinyl]éthoxy-acétique Ceased WO2009057133A2 (fr)

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IN1428MU2007 2007-07-24
IN1428/MUM/2007 2007-07-24
IN1875/MUM/2007 2007-09-24
IN1875MU2007 2007-09-24

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101928223A (zh) * 2009-06-26 2010-12-29 华东理工大学 一种(r)-(-)-4-氯二苯甲胺的拆分方法
CN103044355A (zh) * 2011-10-13 2013-04-17 湖南九典制药有限公司 合成左西替利嗪的关键中间体及其制备方法
JP2021137000A (ja) * 2020-02-28 2021-09-16 国立大学法人東海国立大学機構 変異型ｇタンパク質共役型受容体
CN117209453A (zh) * 2023-08-24 2023-12-12 迪嘉药业集团股份有限公司 一种盐酸左西替利嗪中间体的制备及应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK154078C (da) * 1981-02-06 1989-05-22 Ucb Sa Analogifremgangsmaade til fremstilling af 2-(2-(4-(diphenyl-methyl)-1-piperazinyl)ethoxy)-acetamider eller syreadditionssalte heraf
CA2180993A1 (fr) * 1996-07-11 1998-01-12 Yong Tao Methodes pour la preparation de cetirizine
CN100584834C (zh) * 2007-08-02 2010-01-27 河北师范大学 左旋西替利嗪盐酸盐的一种合成方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101928223A (zh) * 2009-06-26 2010-12-29 华东理工大学 一种(r)-(-)-4-氯二苯甲胺的拆分方法
CN103044355A (zh) * 2011-10-13 2013-04-17 湖南九典制药有限公司 合成左西替利嗪的关键中间体及其制备方法
JP2021137000A (ja) * 2020-02-28 2021-09-16 国立大学法人東海国立大学機構 変異型ｇタンパク質共役型受容体
CN117209453A (zh) * 2023-08-24 2023-12-12 迪嘉药业集团股份有限公司 一种盐酸左西替利嗪中间体的制备及应用

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