WO2000062782A1 - Nouvelle synthese et cristallisation de composes contenant de la piperazine - Google Patents

Nouvelle synthese et cristallisation de composes contenant de la piperazine Download PDF

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Publication number
WO2000062782A1
WO2000062782A1 PCT/US2000/010357 US0010357W WO0062782A1 WO 2000062782 A1 WO2000062782 A1 WO 2000062782A1 US 0010357 W US0010357 W US 0010357W WO 0062782 A1 WO0062782 A1 WO 0062782A1
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WO
WIPO (PCT)
Prior art keywords
mirtazapine
phenyl
methyl
piperazine
cyanopyridyl
Prior art date
Application number
PCT/US2000/010357
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English (en)
Inventor
Claude Singer
Anita Liberman
Nina Finkelstein
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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 Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to AU43577/00A priority Critical patent/AU781221B2/en
Priority to IL14602300A priority patent/IL146023A0/xx
Priority to EP00923457A priority patent/EP1178805A4/fr
Priority to KR1020017013267A priority patent/KR20020019902A/ko
Priority to JP2000611918A priority patent/JP2004500324A/ja
Priority to CA002368815A priority patent/CA2368815A1/fr
Priority to SK1467-2001A priority patent/SK14672001A3/sk
Publication of WO2000062782A1 publication Critical patent/WO2000062782A1/fr
Priority to HR20010747A priority patent/HRP20010747A2/hr
Priority to HK02105027.4A priority patent/HK1044116A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to synthetic organic chemistry, particularly, to synthesis of piperazine ring-containing compounds, such as mirtazapine, and to the crystallization of mirtazapine from different solvents and solvent systems.
  • Mirtazapine has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin reuptake inhibitors, tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds. Mirtazapine may be made by methods described in U.S. Patent No. 4,062,848.
  • the mirtazapine intermediate l-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by a three step process starting with a 2,3-substituted pyridine derivative. Therefore, as shown in Scheme 1, when starting with 2-amino-3-cyano-pyridine, the process of the '848 patent requires four synthetic steps to make mirtazapine. It is desirable to have a process for making mirtazapine that requires fewer steps, and therefore requires less reagent, solvent and time.
  • the mirtazapine intermediate l-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by the hydrolysis of the nitrile l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine under highly basic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile, at high temperature and for long reaction times of 24 hours.
  • KOH potassium hydroxide
  • mirtazapine comprising the steps of: reacting a compound of the formula
  • mirtazapine wherein R 1 is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R 2 is amine; and R 3 is selected from the group consisting of chloro, fluoro, bromo and iodo.
  • a preferred embodiment of the present invention is directed to a method for the preparation of mirtazapine, comprising the steps of reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-l-phenyl-2,2'-iminodiethyl chloride to form l-(3- hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the l-(3- hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
  • mirtazapine intermediate l-(3- carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolysis of the nitrile 1- (3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new more favorable reaction conditions.
  • the new reaction conditions of the present invention include a low mole to mole ratio of potassium hydroxide to nitrile and shorter reaction times.
  • the present invention relates to a improved process for making 1 -(3- carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing l-(3-cyanopyridyl-2)-4- methyl-2-phenyl-piperazine comprising the step of reacting l-(3-cyanopyridyl-2)-4-methyl-2- phenyl-piperazine with a base wherein the base is present in a ratio of up to about 12 moles of the base per one mole of l-(3-cyanopyridyl-2)-4-methyl-2 -phenyl-piperazine.
  • (3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of base to about one mole of l-(3-cyanopyridyl-2)-4-methyl-2 -phenyl-piperazine.
  • the base is potassium hydroxide or sodium hydroxide.
  • the mixture of the l-(3- cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130° C.
  • the hydrolysis of l-(3- cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
  • the present invention also relates to improved processes for making mirtazapine from crude mirtazapine comprising the steps of (a) heating a mixture of crude mirtazapine and solvent; and (b) isolating mirtazapine.
  • water is added to the heated mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.
  • preferred solvents are methanol, ethanol, isopropanol, acetone, toluene, and hexane and mixtures thereof.
  • preferred solvents are toluene, hexane, and methylene chloride.
  • the present invention relates to a novel process for preparing piperazine ring- containing compounds, such as mirtazapine, as described in Scheme 2 below.
  • the process of the present invention is advantageous over prior art processes due to, inter alia, the higher yield, smaller number of steps in relation to the alternative methods, and minimized raw material costs.
  • the present invention relates to the process of making mirtazapine from compounds of the formulae II, III and IV.
  • the compound of formula II in Scheme 2 above wherein R 1 denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and R 2 denotes amine, preferably -NH 2 , is reacted with the compound of formula III in Scheme 2 above, wherein R 3 denotes chloro, fluoro, bromo or iodo, to form the compound of formula IV wherein R 1 is defined as above.
  • the compound of formula II is dissolved in a solvent such as methylene chloride.
  • the compound of formula III is added to the solvent mixture and the resulting mixture is heated.
  • the reaction mixture is heated to the reflux temperature of the solvent.
  • the mixture is heated to form the compound of formula IV.
  • Mirtazapine is then prepared by ring closure of the compound of formula IV. Ring closure of the compound of formula IV may be performed using a ring-closing reagent. Suitable ring closing reagents are dehydrating or dehydrohalogenating agents.
  • Dehydrating or dehydrohalogenating agents that may be added to the reaction mixture for this purpose include acids, such as sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
  • acids such as sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and
  • Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid most preferred.
  • a particularly preferred dehydrohalogenating agent is aluminum chloride.
  • the compounds of the formulae II, III and IV are compounds of the formulae II', III' and IV respectively as shown in Scheme 3 below.
  • 2-amino-3 -hydroxymethyl pyridine is reacted with N-methyl-l-phenyl-2,2'-iminodi ethyl chloride to form l-(3- hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine.
  • 2-amino- 3 -hydroxymethyl pyridine is added to a solvent.
  • suitable solvents include 1,2- dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
  • N-Methyl-l-phenyl-2,2'-imidodiethyl-chloride (III') is added to the solvent mixture and the resulting mixture is heated.
  • the reaction mixture is heated to the reflux temperature of the solvent.
  • the mixture is heated until l-(3- hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed and the reaction is complete.
  • a suitable time is about six to about 24 hours.
  • the l-(3-hydroxymethylpyridyl-2)- 4-methyl-2-phenyl-piperazine is then converted to mirtazapine by ring closure.
  • dehydrating agents include acids, such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide.
  • acids such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide.
  • PPA polyphosphoric acid
  • phosphorus oxychloride phosphorus trioxide
  • pentoxide phosphorus pentoxide
  • Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.
  • the present invention also provides new processes for making the mirtazapine intermediate l-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrile l-(3- cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrile is (I) hydrolyzed by base using a new low mole to mole ratio of base to the nitrile l-(3-cyanopyridyl-2)-4-methyl-2- phenyl-piperazine and (ii) hydrolyzed using short reaction times.
  • the present invention provides improved methods for making the mirtazapine intermediate l-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine
  • the nitrile 1- (3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in a mixture of water and organic solvent.
  • Preferred organic solvents include polar aprotic solvents and alcohols. Polar aprotic organic solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide and the like are preferred.
  • Preferred alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like.
  • a suitable amount of base such as potassium hydroxide or sodium hydroxide, is added to the reaction mixture.
  • An amount of base such as potassium hydroxide or sodium hydroxide, of up to about 12 moles of base per mole of nitrile (for example 12:1 KOH:nitrile) is preferred.
  • KOH:nitrile to about 12 moles of potassium hydroxide per mole of nitrile (12:1 KOH:nitrile) are preferred.
  • the mixture of the nitrile l-(3-cyanopyridyl-2)-4- methyl-2 -phenyl-piperazine, solvent and base is heated to at least about 130°C. Reaction temperatures of about 130°C to about 150° are preferred. In an embodiment of the present invention, the reaction may be conducted under pressure to facilitate the attainment of high temperatures. A pressure of at least about 3 atmospheres is preferred. Pressures of at least about 3 atmospheres to about 4 atmospheres are more preferred. The reaction mixture is heated until the reaction is complete. The completion of the reaction may be monitored by
  • the amount of time needed for the completion of the hydrolysis of the nitrile varies with the temperature of the reaction. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally requires longer reaction times. While not limiting the reaction time of the present invention, preferred reaction times of the present invention may be from abo ⁇ t 2 hours to about 8 hours.
  • the pH of the reaction mixture is lowered, preferably to a pH of about 6 to about 7. Preferably the pH is lowered with hydrochloric acid.
  • the mirtazapine intermediate, 1 -(3- cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
  • the reaction mixture of the nitrile l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassium hydroxide is heated while using a minimum amount of water, such as about 0.25-1 mL of water per gram of KOH, and small amounts of an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, such as about 0.1 to 0.5 grams of aprotic solvent per gram of nitrile, under very concentrated conditions or almost neat conditions at atmospheric pressure.
  • a minimum amount of water such as about 0.25-1 mL of water per gram of KOH
  • an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide
  • the mirtazapine intermediate, l-(3-cyanopyridyl-2)-4-methyl-2- phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
  • the new processes of the present invention for making the mirtazapine intermediate l-(3-carboxypyridyl-2)-4-methyl-2 -phenyl-piperazine from the nitrile l-(3- cyanopyridyl-2)-4-methyl-2-phenyl-piperazine significantly reduce the quantity of potassium hydroxide used, from 25 moles of potassium hydroxide per mole of the nitrile as in the '848 patent, to about 12 moles or less of potassium hydroxide to one mole of the nitrile.
  • the present invention also provides new methods for making pure mirtazapine by purifying crude mirtazapine by recrystallization. Upon the ring closure of l-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine, the crude product, mirtazapine, is purified by recrystallization.
  • solvents such as toluene or methylene chloride and solvent systems such as alcohol-water can be used in the recrystallization of crude mirtazapine.
  • crude mirtazapine is suspended in a suitable solvent.
  • Preferred solvents include methanol, ethanol, isopropanol, and acetone and mixtures thereof, or mixtures of one or more of those solvents with water. Additional preferred solvents also include toluene, hexane, and methylene chloride.
  • Solvent mixtures of water and ethanol are more preferred. Solvent mixtures of ratios of about 1 : 1 to about 1 :4 ethanol : water are preferred.
  • the suspension of crude mirtazapine and solvent is heated to a suitable temperature.
  • suitable temperatures include, for example, the reflux temperature of the solvent system being used in any particular embodiment of the present invention.
  • a temperature of about 110°C is suitable.
  • Purified mirtazapine precipitates upon cooling of the reaction mixture. Filtration and drying of the resulting precipitate yields purified, recrystallized mirtazapine.
  • crude mirtazapine is suspended in a solvent such as ethanol, and the mixture is heated to reflux. Water is then added dropwise and the solution is cooled to facilitate precipitation of mirtazapine. The precipitate is purified by filtration, washing and drying to yield purified mirtazapine.
  • the crystallized mirtazapine may be a water adduct thereby containing up to 3 % water by weight (3% w/w).
  • the solvents and solvent systems of the present invention are suitable for large scale reactions, and are more suitable for large scale reactions than ether or petrol ether 40-60. Additionally, the crystallization yield can be substantially improved when using the solvent system of the present invention.
  • Mirtazapine and mirtazapine intermediates each contain an asymmetric carbon atom, as a result of which separate optical isomers may be prepared in addition to a racemic mixtures.
  • Processes of the present invention include these optical isomers just as the racemic mixtures are included in the invention.
  • mirtazapine produced by the process of the present invention may be prepared as pharmaceutical compositions that are particularly useful for the treatment of depression.
  • Such compositions comprise a therapeutically effective amount of mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
  • reaction mixture is added to 25 g of ice under mixing and basified with a
  • Potassium hydroxide 150 g of KOH flakes, 85%
  • 75 mL of water and 6.5 g of DMSO are added to l-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and the reaction mixture is heated to 145-150° C and mixed for 8 hours.
  • the inorganic phase containing water and potassium hydroxide (KOH) is separated and the organic phase, containing mainly a product oil, is cooled.
  • Fresh water and toluene are added and the two phases are separated.
  • the inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of l-(3-carboxypyridyl-2-)-4-methyl-
  • Table 1 sets forth a summary of additional experiments generally following procedures described above wherein the Yield % is the percent yield of mirtazapine crystals from crude mirtazapine and the Purity % is the percent purity as compared to a mirtazapine standard.

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Abstract

L'invention concerne des procédés de préparation de composés contenant de la pipérazine, notamment de la mirtazapine. Selon l'invention, l'intermédiaire de mirtazapine 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine est fabriqué par l'hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec une base, laquelle est présente selon un rapport pouvant atteindre environ 12 moles de la base par mole de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine. L'intermédiaire de mirtapazine de 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine peut être fabriqué par hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec de l'hydroxyde de potassium, à une température d'au moins environ 130 °C. Le procédé de l'invention consiste également à faire réagir du 2-amino-3-hydroxyméthyl pyridine avec du chlorure de N-méthyl-1-phényl-2, 2'-iminodiéthyle, de sorte que de la 1-(3-hydroxyméthylpyridyl-2)-4-méthyl-2-phényl pipérazine soit formée, et à ajouter de l'acide sulfurique à la 1-(3-hydroxyméthylpyridyl-2)-phényl-4-méthylpipérazine, de sorte que de la mirtazapine soit formée. L'invention porte également sur des nouveaux procédés de cristallisation de la mirtazapine, permettant la production de mirtazapine brute.
PCT/US2000/010357 1999-04-19 2000-04-18 Nouvelle synthese et cristallisation de composes contenant de la piperazine WO2000062782A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU43577/00A AU781221B2 (en) 1999-04-19 2000-04-18 Novel synthesis and crystallization of piperazine ring-containing compounds
IL14602300A IL146023A0 (en) 1999-04-19 2000-04-18 Novel synthesis and crystallization of piperazine ring-containing compounds
EP00923457A EP1178805A4 (fr) 1999-04-19 2000-04-18 Nouvelle synthese et cristallisation de composes contenant de la piperazine
KR1020017013267A KR20020019902A (ko) 1999-04-19 2000-04-18 피페라진 고리 함유 화합물의 신규한 합성법 및 결정화법
JP2000611918A JP2004500324A (ja) 1999-04-19 2000-04-18 ピペラジン環含有化合物の新規の合成及び結晶化
CA002368815A CA2368815A1 (fr) 1999-04-19 2000-04-18 Nouvelle synthese et cristallisation de composes contenant de la piperazine
SK1467-2001A SK14672001A3 (sk) 1999-04-19 2000-04-18 Spôsob syntézy a kryštalizácie zlúčenín obsahujúcich piperazínový kruh
HR20010747A HRP20010747A2 (en) 1999-04-19 2001-10-15 Novel synthesis and crystallization of piperazine ring-containing compounds
HK02105027.4A HK1044116A1 (zh) 1999-04-19 2002-07-05 含哌嗪環化合物的新型合成和結晶方法

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US13004799P 1999-04-19 1999-04-19
US60/130,047 1999-04-19

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WO2000062782A1 true WO2000062782A1 (fr) 2000-10-26

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JP (1) JP2004500324A (fr)
KR (1) KR20020019902A (fr)
CN (4) CN1679586A (fr)
CA (1) CA2368815A1 (fr)
CZ (1) CZ20013658A3 (fr)
HK (1) HK1044116A1 (fr)
HR (1) HRP20010747A2 (fr)
HU (1) HUP0200839A3 (fr)
IL (1) IL146023A0 (fr)
PL (1) PL366289A1 (fr)
RU (1) RU2001128229A (fr)
SK (1) SK14672001A3 (fr)
TR (1) TR200103028T2 (fr)
WO (1) WO2000062782A1 (fr)
YU (1) YU74101A (fr)
ZA (1) ZA200108220B (fr)

Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO2001042240A1 (fr) * 1999-12-13 2001-06-14 Sumika Fine Chemicals Co., Ltd. Procede de preparation d'un compose pyridinemethanol
EP1209159A2 (fr) * 2000-11-27 2002-05-29 SUMIKA FINE CHEMICALS Co., Ltd. Cristaux de mirtazapine anhydride et leur procédé d' obtention
EP1225174A1 (fr) * 1999-11-24 2002-07-24 SUMIKA FINE CHEMICALS Co., Ltd. Cristaux de mirtazapine anhydres et leur procede de fabrication
WO2005005410A1 (fr) * 2003-07-10 2005-01-20 Akzo Nobel N.V. Procede de preparation de mirtazapine enantiomeriquement pure
WO2006008302A2 (fr) * 2004-07-22 2006-01-26 Medichem, S.A. Procede ameliore de fabrication de mirtazapine
WO2008125578A2 (fr) 2007-04-11 2008-10-23 N.V. Organon Procédés de préparation d'un énantiomère d'une benzazépine tétracyclique
US7994314B2 (en) 2007-04-11 2011-08-09 N.V. Organon Method for the preparation of an enantiomerically pure benzazepine
AU2008227637B2 (en) * 2007-03-22 2012-02-16 Sumitomo Chemical Company, Limited Process for production of mirtazapine

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JP4848704B2 (ja) * 2004-08-24 2011-12-28 住友化学株式会社 ２−（４−メチル−２−フェニルピペラジン−１−イル）−３−シアノピリジンの製造方法
KR101485418B1 (ko) * 2013-05-29 2015-01-26 주식회사 메디켐코리아 고순도 미르타자핀의 제조방법
JP6571497B2 (ja) * 2015-11-13 2019-09-04 株式会社トクヤマ ミルタザピンの製造方法
JP2017088564A (ja) * 2015-11-13 2017-05-25 株式会社トクヤマ ミルタザピンの製造方法
CN108191873B (zh) * 2018-01-08 2021-09-24 山东省食品药品检验研究院 一种盐酸米安色林的纯化方法

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Title
KASPERSEN ET AL.: "The synthesis of ORG 3770 labelled with 3H, 13C and 14C", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS,, vol. 27, no. 9, September 1989 (1989-09-01), pages 1055 - 1068, XP002929854 *

Cited By (23)

* Cited by examiner, † Cited by third party
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EP1225174A1 (fr) * 1999-11-24 2002-07-24 SUMIKA FINE CHEMICALS Co., Ltd. Cristaux de mirtazapine anhydres et leur procede de fabrication
EP1225174A4 (fr) * 1999-11-24 2002-10-23 Sumika Fine Chemicals Co Ltd Cristaux de mirtazapine anhydres et leur procede de fabrication
US7297790B2 (en) 1999-11-24 2007-11-20 Sumitomo Chemical Company, Limited Anhydrous mirtazapine crystals and process for preparing the same
WO2001042240A1 (fr) * 1999-12-13 2001-06-14 Sumika Fine Chemicals Co., Ltd. Procede de preparation d'un compose pyridinemethanol
US6437120B1 (en) * 1999-12-13 2002-08-20 Sumika Fine Chemicals Co., Ltd. Process for preparing pyridinemethanol compounds
AU771484B2 (en) * 1999-12-13 2004-03-25 Sumitomo Chemical Company, Limited Process for the preparation of a pyridinemethanol compound
EP1209159A2 (fr) * 2000-11-27 2002-05-29 SUMIKA FINE CHEMICALS Co., Ltd. Cristaux de mirtazapine anhydride et leur procédé d' obtention
EP1209159A3 (fr) * 2000-11-27 2003-03-05 SUMIKA FINE CHEMICALS Co., Ltd. Cristaux de mirtazapine anhydride et leur procédé d' obtention
US6660730B2 (en) * 2000-11-27 2003-12-09 Sumika Fine Chemicals Co., Ltd. Anhydrous mirtazapine and process for preparing the same
AU781974B2 (en) * 2000-11-27 2005-06-23 Sumitomo Chemical Company, Limited Anhydrous mirtazapine and process for preparing the same
WO2005005410A1 (fr) * 2003-07-10 2005-01-20 Akzo Nobel N.V. Procede de preparation de mirtazapine enantiomeriquement pure
US8058436B2 (en) 2003-07-10 2011-11-15 N.V. Organon Method for the preparation of enantiomerically pure mirtazapine
JP4668184B2 (ja) * 2003-07-10 2011-04-13 ナームローゼ・フエンノートチヤツプ・オルガノン エナンチオマー的に純粋なミルタザピンの調製方法
LT5382B (lt) 2003-07-10 2006-11-27 Akzo Nobel N. V. ENANTIOMERISKAI GRYNO MIRTAZAPINO GAVIMO BuDAS
JP2009513537A (ja) * 2003-07-10 2009-04-02 ナームローゼ・フエンノートチヤツプ・オルガノン エナンチオマー的に純粋なミルタザピンの調製方法
AU2004255874B2 (en) * 2003-07-10 2010-10-28 Merck Sharp & Dohme B.V. A method for the preparation of enantiomerically pure mirtazapine
WO2006008302A2 (fr) * 2004-07-22 2006-01-26 Medichem, S.A. Procede ameliore de fabrication de mirtazapine
WO2006008302A3 (fr) * 2004-07-22 2006-04-13 Medichem Sa Procede ameliore de fabrication de mirtazapine
ES2246161A1 (es) * 2004-07-22 2006-02-01 Medichem, S.A. Proceso mejorado para la fabricacion de mirtazapina.
AU2008227637B2 (en) * 2007-03-22 2012-02-16 Sumitomo Chemical Company, Limited Process for production of mirtazapine
US8173804B2 (en) 2007-03-22 2012-05-08 Sumitomo Chemical Company, Limited Process for production of mirtazapine
WO2008125578A2 (fr) 2007-04-11 2008-10-23 N.V. Organon Procédés de préparation d'un énantiomère d'une benzazépine tétracyclique
US7994314B2 (en) 2007-04-11 2011-08-09 N.V. Organon Method for the preparation of an enantiomerically pure benzazepine

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IL146023A0 (en) 2002-07-25
KR20020019902A (ko) 2002-03-13
CN1680365A (zh) 2005-10-12
JP2004500324A (ja) 2004-01-08
HUP0200839A2 (en) 2002-08-28
TR200103028T2 (tr) 2002-01-21
HK1044116A1 (zh) 2002-10-11
CA2368815A1 (fr) 2000-10-26
CN1679586A (zh) 2005-10-12
CZ20013658A3 (cs) 2002-08-14
ZA200108220B (en) 2006-02-26
HRP20010747A2 (en) 2002-12-31
RU2001128229A (ru) 2003-07-10
CN1680374A (zh) 2005-10-12
CN1356903A (zh) 2002-07-03
YU74101A (sh) 2004-09-03
PL366289A1 (en) 2005-01-24
SK14672001A3 (sk) 2002-11-06
HUP0200839A3 (en) 2003-05-28

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