WO2005019225A1 - Procede de production d'un compose presentant un antagonisme par rapport au recepteur nk1 et production d'un intermediaire de celui-ci - Google Patents

Procede de production d'un compose presentant un antagonisme par rapport au recepteur nk1 et production d'un intermediaire de celui-ci Download PDF

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Publication number
WO2005019225A1
WO2005019225A1 PCT/JP2004/011965 JP2004011965W WO2005019225A1 WO 2005019225 A1 WO2005019225 A1 WO 2005019225A1 JP 2004011965 W JP2004011965 W JP 2004011965W WO 2005019225 A1 WO2005019225 A1 WO 2005019225A1
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WIPO (PCT)
Prior art keywords
internal temperature
methylphenyl
hour
water
methylthio
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PCT/JP2004/011965
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English (en)
Japanese (ja)
Inventor
Ichiro Araya
Shintaro Kanazawa
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
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Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to JP2005513299A priority Critical patent/JPWO2005019225A1/ja
Publication of WO2005019225A1 publication Critical patent/WO2005019225A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides 2- (4-acetylbiperazine-1-yl) -6- [3,5, which has an excellent antagonism to tachykinin receptor, in particular, a NK1 receptor antagonism.
  • the compound I is a condensed bicyclic pyrimidine derivative having an excellent antagonistic action to tachykinin receptors, particularly an NK1 receptor antagonistic action, and is useful for various pathological conditions involving tachykinin receptors (frequent urination, urinary incontinence). It is known that it is useful for medical use such as treatment of vomiting, inflammation, allergy, respiratory tract disease, pain, central nervous system disease, etc. (compound of Example 16 in Patent Document 1).
  • the method for producing compound I is also specifically described in International Publication Pamphlet of Patent Document 1.
  • the production method disclosed in Patent Document 1 is difficult to implement on an industrial scale, and it is necessary to further improve the operability, purification efficiency, yield, etc. of production, and to find a production method suitable for actual production. was there.
  • Patent document 1 W ⁇ 03 / 062245 pamphlet
  • the invention's effect The starting compound of the present invention, 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro
  • -5-Pyrimidinecarboxylic acid or a hydrate thereof is a novel compound without specific disclosure, and its usefulness was not known.
  • this 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5_pyrimidinecarboxylic acid as a production intermediate, the yield with less impurities is improved, The present inventors have found that subsequent purification is also easy, and provide an industrial production method of Compound I.
  • novel raw material compound of the present invention 4_ (2-methylphenyl) -2-methylthio_6_oxo-1,6-dihydro-5_pyrimidinecarboxylic acid (7) or a hydrate thereof is as follows. Obtained.
  • a chlorinating agent preferably an organic solvent such as phosphorus oxychloride or ethyl acetate
  • 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidine phenolic acid (7) is added to 4- (2-methylphenyl) -2-methylthio-6-oxo-1,6-dihydro-5-pyrimidine phenolic acid (7).
  • Add thionyl chloride in the medium in the presence of N, N-dimethylformamide stir with heating (70 ° C-90 ° C, 11-13 hours). When no organic solvent is used. Cool, put into ice water, filter, and use.
  • reaction solution is washed with water, an acid and an aqueous alkali solution, dried over anhydrous sodium sulfate, and the solvent is distilled off to give N_ [3,5-bis (trifluoromethyl) phenylmethyl] -N- (3-hydrogen).
  • Xypropyl) -4-chloro-6- (2-methylphenyl) -2-methylthio_5_pyrimidinecarboxamide is obtained.
  • This oily substance or crystals are dissolved in an organic solvent such as dimethylsulfoxide, dimethylformamide, toluene, or the like, in a base such as 1,8-diazabicyclo [5,4,0] indene-7-ene (DBU) or potassium t-butoxide.
  • a reaction temperature 50-80 ° C and a reaction time of 1-3 hours, 6- [3,5-bis (trifluoromethyl) phenylmethyl] -4- (2-methylphenyl) -2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [ l, 5] oxazocin-5-one (8) is obtained.
  • oxidizing agent such as magnesium monoperoxyphthalate hexahydrate (MMPP), metaclo-perbenzoic acid (m_CPBA), and hydrogen peroxide (in the presence of a catalyst such as tungsten).
  • MMPP magnesium monoperoxyphthalate hexahydrate
  • m_CPBA metaclo-perbenzoic acid
  • hydrogen peroxide in the presence of a catalyst such as tungsten.
  • the precipitated crystals are collected by filtration, and 5%
  • the wet crude crystals (4.10 kg) obtained in 9.32 L of 2-propanol were dried, heated and dissolved (completely dissolved at 73 ° C), and 2.34 L of water was dried. After water cooling to an internal temperature of 30 ° C, and then cooling with ice water to an internal temperature of 10 ° C, the mixture was stirred at an internal temperature of 8 to 10 ° C for 0.5 hour. The precipitated crystals were collected by filtration and cooled with ice water 80%
  • the wet crystal (1.85 kg) was blow-dried at 60 ° C. for 17 hours to obtain 1.44 kg (yield 90%) of pale brown powder (6).
  • the precipitated crystals were collected by filtration, washed with 5.74 L of water, and dried under aeration for 0.5 hour.
  • the wet crude crystals (1.91 kg) obtained in 10.0 L of 2-propanol were added, and the suspension was heated to reflux for 1 hour.
  • the mixture was water-cooled to 30 ° C, then ice-cooled, and stirred at an internal temperature of 6-10 ° C for 1 hour.
  • the crystals were collected by filtration, washed with 2.87 L of 2-propanol, and dried by aeration for 0.5 hour.
  • the wet crystals (1.61 kg) were blast-dried at 60 ° C. for 8 hours to obtain 1.26 kg (97% yield) of a pale brown-white powder (7).
  • the wet crude crystals were added to 12.6 L of 2_propanol and dissolved by heating to 60 ° C, and then 2.52 L of water was added and air-cooled (crystallized at an internal temperature of 52 ° C). After water cooling at a temperature of 50 ° C, the mixture was stirred at an internal temperature of 19 to 25 ° C for 1 hour. The precipitated crystals are collected by filtration and 50%
  • the precipitated crystals were collected by filtration, washed with 3.06 L of a mixed solution of n-hexane / ethyl acetate (4: 1), and dried by blowing at 60 ° C. for 17 hours to obtain 0.91 kg of a white solid. 2.72 L of acetone was added to this solid, which was heated and dissolved, filtered, and the filter was washed with 0.91 L of acetone. The filtrate and washing solution are combined, heated to an internal temperature of 40 ° C, heated with 3.20 L of water, and stirred at 35-40 ° C for 0.5 hour (crystal crystallization). Further, after adding 4.04 L of water, the mixture was cooled with water and stirred at an internal temperature of 23 to 25 ° C for 1 hour. The precipitated crystals are collected by filtration and 20%
  • the mixture was stirred at room temperature for 0.5 hour and left overnight.
  • the mixture was adjusted to pH 12.0 by adding 675 mL of a 4 mol / L aqueous sodium hydroxide solution at an internal temperature of 23 to 28 ° C, cooled to an internal temperature of 16 ° C, crystallized by adding seeds, and purified. 726 mL of water was added, and the mixture was stirred at an internal temperature of 410 ° C. for 1 hour. The precipitated crystals are collected by filtration, and 5%
  • the mixture was washed with 726 mL of a 2-propanol aqueous solution, and dried under aeration for 1 hour to obtain 338 g of wet crystals.
  • 605 mL of 2-propanol and 1.82 L of purified water are suspended in the wet crystals, and 160 mL of concentrated hydrochloric acid is added thereto with stirring to dissolve. Adjusted to 1.2.
  • the mixture was adjusted to pH 12.0 by adding 550 mL of a 4 mol / L aqueous sodium hydroxide solution at an internal temperature of 20 to 26 ° C, cooled, seeded at an internal temperature of 16 ° C, and stirred at an internal temperature of 10 to 16 ° C. .
  • the mixture was stirred at an internal temperature of 6-10 ° C for 1 hour, and the precipitated crystals were collected by filtration, washed with 726 mL of a 5% aqueous 2-propanol solution, and dried under aeration for 1 hour to obtain 334 g of wet crystals. .
  • the wet crystals were suspended in 605 mL of 2_propanol and 1.82 L of purified water, and dissolved by adding 85 mL of concentrated hydrochloric acid with stirring.
  • Adjusted to 1.2 The mixture was adjusted to pH 12.0 by adding 300 mL of a 4 mol / L aqueous sodium hydroxide solution at an internal temperature of 20 to 24 ° C, cooled, stirred at an internal temperature of 12 to 24 ° C, crystallized and cooled. The mixture was stirred at an internal temperature of 6-10 ° C for 1 hour. The precipitated crystals are collected by filtration, and 5%
  • the precipitated crystals were collected by filtration, washed with 669 mL of purified water, and dried under aeration for 0.5 hour to obtain 296 g of wet crystals.
  • the wet crystals are dissolved in 558 mL of ethanol while hot (dissolved at an internal temperature of 45 ° C), 558 mL of purified water is added at an internal temperature of 50 to 55 ° C, and then cooled (crystallization started at 49 ° C). The mixture was stirred at a temperature of 6-10 ° C for 1 hour.
  • the precipitated crystals are collected by filtration and 30%
  • the wet crystals are dissolved in 1.34 L of 2_propanol by heating, purified at an internal temperature of 55 60 ° C. After 1.34 L of water is cooled, the mixture is cooled (crystallization starts at 55 ° C) and the internal temperature is 8-10 ° C. For 0.5 hour. The precipitated crystals are collected by filtration and 30%
  • the precipitated crystals were collected by filtration, washed with 740 mL of purified water, and dried under aeration for 0.5 hour to obtain 331 g of wet crystals.
  • the wet crystals were calo-dissolved in 2.46 L of 2-propanol (completely dissolved at 57 ° C) and purified water at an internal temperature of 55-60 ° C. 1.23
  • the precipitated crystals were collected by filtration, washed with 20 mL of purified water, and dried under aeration for 0.5 hour to obtain 10.4 g of wet crystals.
  • the wet crystals were blown and dried at 60 ° C. for 15 hours to obtain 5.12 g of crude crystals.
  • the crude crystals were dissolved in 25 mU of acetone, 2 mL of purified water was added at an internal temperature of 45 ° C to 50 ° C (it became cloudy), and the mixture was stirred at an internal temperature of 45 ° C for 1.5 hours, and further 13.0 mL of purified water was added. added.
  • the mixture was stirred at an internal temperature of 4550 ° C for 0.5 hour, and stirred at an internal temperature of 25 ° C or less for 1 hour.
  • the precipitated crystals were collected by filtration, washed with 25% OmL of a 20% aqueous acetone solution, dried by aeration for 0.5 hour, then dried by blowing at 60 ° C. for 16 hours to obtain 4.65 g of white crystals.
  • the crystals were dissolved in 20.0 mL of acetone, filtered, and washed with 5.0 mL of acetone.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un procédé de production de 2-(4-acétylpipérazin-1-yl)-6-[3,5-bis(trifluorométhyl)phénylméthyl]-4-(2-méthylphényl)-6,7,8,9-tétrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (composé 1), pour une production industrielle d'un composé présentant un excellent antagonisme contre le récepteur de la tachykinine, en particulier un antagonisme au récepteur NK1. Ce procédé est caractérisé en ce qu'il consiste à faire réagir un agent de chloration sur de l'acide 4-(2-méthylphényl)-2-méthylthio-6-oxo-1,6-dihydro-5-pyrimidinecarboxylique (7), servant d'intermédiaire; à faire réagir ce produit avec du 3-[3,5-bis-trifluorométhyl)benzilamino]-1-propanol; à faire réagir une base sur le produit pour produire une cyclisation; à effectuer une oxydation de ceci; et à faire réagir l'oxyde avec de la N-acétylpipérazine.
PCT/JP2004/011965 2003-08-21 2004-08-20 Procede de production d'un compose presentant un antagonisme par rapport au recepteur nk1 et production d'un intermediaire de celui-ci WO2005019225A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005513299A JPWO2005019225A1 (ja) 2003-08-21 2004-08-20 Ｎｋ１受容体拮抗作用を有する化合物の製造方法及びその製造中間体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003297870 2003-08-21
JP2003-297870 2003-08-21

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WO2005019225A1 true WO2005019225A1 (fr) 2005-03-03

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WO (1) WO2005019225A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
WO2019162519A1 (fr) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Antagonistes nk-1 destinés à être utilisés dans le traitement de la douleur oculaire
WO2021180885A1 (fr) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Traitement d'une déficience en cellules souches

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09263585A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤
WO2001007027A2 (fr) * 1999-07-22 2001-02-01 Vertex Pharmaceuticals Incorporated Inhibiteurs d'helicase virale
JP2002541259A (ja) * 1999-04-08 2002-12-03 アクゾ・ノベル・エヌ・ベー 黄体化ホルモン作動薬として有用な二環式へテロ芳香族化合物
WO2003062245A1 (fr) * 2002-01-18 2003-07-31 Kyorin Pharmaceutical Co., Ltd. Derives de pyrimidine fusionnes bicycliques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09263585A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤
JP2002541259A (ja) * 1999-04-08 2002-12-03 アクゾ・ノベル・エヌ・ベー 黄体化ホルモン作動薬として有用な二環式へテロ芳香族化合物
WO2001007027A2 (fr) * 1999-07-22 2001-02-01 Vertex Pharmaceuticals Incorporated Inhibiteurs d'helicase virale
WO2003062245A1 (fr) * 2002-01-18 2003-07-31 Kyorin Pharmaceutical Co., Ltd. Derives de pyrimidine fusionnes bicycliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAMPER B C ET AL: "Solid phase synthesis of dihydropyrimidinones and pyrimidinone carboxylic acids from malonic acid resin", TETRAHEDRON LETTERS, vol. 40, no. 27, 2 July 1999 (1999-07-02), pages 4973 - 7976, XP004169373 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
WO2019162519A1 (fr) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Antagonistes nk-1 destinés à être utilisés dans le traitement de la douleur oculaire
EP4371613A2 (fr) 2018-02-26 2024-05-22 Ospedale San Raffaele S.r.l. Composés destinés à être utilisés dans le traitement de la douleur oculaire
WO2021180885A1 (fr) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Traitement d'une déficience en cellules souches

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