WO2017154019A1 - Procédé amélioré pour la préparation de l,3-bis (2-chloroéthyl)-nitrosourée - Google Patents

Procédé amélioré pour la préparation de l,3-bis (2-chloroéthyl)-nitrosourée Download PDF

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Publication number
WO2017154019A1
WO2017154019A1 PCT/IN2017/000058 IN2017000058W WO2017154019A1 WO 2017154019 A1 WO2017154019 A1 WO 2017154019A1 IN 2017000058 W IN2017000058 W IN 2017000058W WO 2017154019 A1 WO2017154019 A1 WO 2017154019A1
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Prior art keywords
formula
compound
bis
chloroethyl
solvents
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PCT/IN2017/000058
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English (en)
Inventor
Srinivasan Thirumalai Rajan
Original Assignee
Msn Laboratories Private Limited
Eswaraiah, Sajja
PAVAN KUMAR REDDY, Bandla
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Application filed by Msn Laboratories Private Limited, Eswaraiah, Sajja, PAVAN KUMAR REDDY, Bandla filed Critical Msn Laboratories Private Limited
Publication of WO2017154019A1 publication Critical patent/WO2017154019A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
    • C07C275/68—N-nitroso ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/08—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to an improved process for the preparation of l,3-bis(2- chloroethyl)urea compound of formula-2 which is useful intermediate in the preparation of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formual-1 and is represented by the following structural formula:
  • l,3-bis(2-chloroethyl)-l -nitrosourea is known as Carmustine and is approved in USA under the brand names of BICNU for the treatment of chemotherapy of certain neoplastic diseases such as brain tumor, multiple myolema, Hodgkin's disease and non-Hodgkin's lymphomas & Gliadel for the treatment of newly-diagnosed high-grade-malignant glioma as an adjunct to surgery and radiation, recurrent glioblastoma multiforme as an adjunct to surgery.
  • BICNU neoplastic diseases
  • neoplastic diseases such as brain tumor, multiple myolema, Hodgkin's disease and non-Hodgkin's lymphomas & Gliadel for the treatment of newly-diagnosed high-grade-malignant glioma as an adjunct to surgery and radiation, recurrent glioblastoma multiforme as an adjunct to surgery.
  • US2288178 patent disclosed the process for the preparation of the compound of formula-2 from aziridine and phosgene. J. Med. Chem., 1979, 22 (10), pp 1193-1198 disclosed the process for the preparation of the compound of formula-2 using 2- chloroethanamine and 2-chloroisocyanoethane.
  • the first aspect of the present invention is to provide an improved process for the preparation of l,3-bis(2-chloroethyl)urea compound of formula-2.
  • the second aspect of the present invention is to provide an improved process for the preparation of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula- 1.
  • Figure 1 Illustrates the PXRD pattern of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula-1.
  • Figure 2 Illustrates the IR spectrum of 1, 3 -bis(2-chloroethyl)-l -nitrosourea compound of formula-1.
  • Figure 3 Illustrates the PXRD pattern of l,3-bis(2-chloroethyl)urea compound of formula-2. Advantages of the present invention:
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene and the like; "ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4- dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl tertiary butyl ether, 1,2-dimethoxy ethane and the like; "ester solvents”
  • pure refers to the compounds prepared according to the present invention having purity greater than 95%; preferably >97%; more preferably >99% and most preferably >99.5%.
  • suitable acid refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoro acetic acid [TFA], etc., and mixtures thereof.
  • the first aspect of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)urea compound of formula-2
  • the suitable solvent is selected from chloro solvents, 'hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, nitrile solvents, polar solvents and mixtures thereof.
  • the preferred embodiment of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)urea compound of formula-2
  • CDI is used in the molar ratio ranging between 0.3 to 0.6 moles with respect to the compound of formula-3a.
  • Another embodiment of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)urea compound of formula-2, comprising of :
  • step-e filtering the solid obtained in step-e), g) optionally slurring the compound obtained in step-f) in water,
  • the suitable alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; in step-a) the suitable temperature ranges from -25 to 25°C; in step-b) the suitable temperature ranges from 25°C to reflux temperature of the solvent used.
  • the second aspect of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula- 1
  • the suitable solvent is selected from chloro solvents, hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, nitrile solvents, polar solvents, acids and mixtures thereof;
  • metal nitrite is preferably sodium nitrite and acid is selected from inorganic acid and organic acid.
  • the preferred embodiment of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1, comprising of :
  • step-b) treating the compound of formula-2 obtained in step-b) with sodium nitrite in the mixture of hydrochloric acid and acetic acid to provide the compound of formula-1, d) dissolving the compound obtained in step-c) in dichloromethane,
  • Another preferred embodiment of the present invention provides an improved process for the preparation of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula-1 , comprising of :
  • An embodiment of the present invention provides an improved process for the purification of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula-1, comprising of : a) Dissolving the compound of formula-1 in chloro solvents at a suitable temperature, b) adding silicagel to the reaction mixture obtained in step-a),
  • step-d) distilling off the solvent from filtrate obtained in step-c), e) adding ether solvent to the compound obtained in step-d),
  • the suitable chloro solvent is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; the suitable temperature is ranges from -10 to 25°C;
  • the suitable ether solvent is selected from dimethoxymethane, tetrahydrofuran, 1,3- dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl tertiary butyl ether, 1,2-dimethoxy ethane and the like; preferably methyl tertiary butyl ether;
  • the hydrocarbon solvent is selected form n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene and the like; preferably n-heptane.
  • the preferred embodiment of the present invention provides an improved process for the purification of l,3-bis(2-chloroethyl)-l -nitrosourea compound of formula-1, comprising of :
  • An embodiment of the present invention provides crystalline l,3-bis(2-chloroethyl)-l- nitrosourea compound of formula- 1 characterized by its powder X-Ray diffraction pattern having peaks at 9.05, 18.64, 21.07, 22.92, 24.3, 25.06, 26.28, 27.8, 28.63, 29.59 and 32.97 ⁇ 0.2 degrees of 2-theta.
  • the said crystalline form is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1 and by its IR spectrum shown in figure-2.
  • a liquid chromatographic system is to be equipped with variable wave length UV-detector; Column: Waters Spherisorb ODS2, 150X4.6 mm, 5 ⁇ or equivalent; Wave length: 200 nm, Column temperature: 25°C; Injection volume: 10 ⁇ ,; Diluent: Chilled acetonitrile; Needle wash: Diluent; Elution: Isocratic; Mobile phase: Acetonitrile.
  • the present invention is schematically represented in the scheme- 1.
  • the present invention also provides an improved process for the preparation of the compound of formula- 1 and is schematically represented in schem-2.
  • R alky, aryl, aralkyl group
  • 2-chloroethanamine hydrochloride (429.19 gm) was added to the mixture of carbonyldiimidazole (200 gm) and tetrahydrofuran (1000 ml) at 25-30°C and stirred the reaction mixture for 5 minutes. Heated the reaction mixture to 65-70°C and stirred for 14 hours at the same temperature. Cooled the reaction mixture to 25-30°C and water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with isopropanol.
  • Example-2 Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (50 gm) was added to the mixture of dilute hydrochloric acid (16 ml) and acetic acid (205 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Sodium nitrite (46.6 gm) was added to the reaction mixture in lot-wise over the period of 3 hours at 0-5 °C and stirred the reaction mixture for 1 hour at the same temperature.
  • the reaction mixture was quenched into pre-cooled water at 0-5°C and stirred it for 30 minutes at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (100 ml) at 0-5°C.
  • the reaction mixture was added to pre-cooled n-heptane (250 ml) at 0-5°C and stirred for 1 1 ⁇ 2 hour at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.
  • Example-3 Preparation of l,3-bis(2-chloroethyl)urea compound of formuIa-2
  • Carbonyldiimidazole (8 kg) was slowly added to the pre-cooled mixture of 2- chloroethanamine hydrochloride (14.31 kg) and tetrahydrofuran (40 lit) at 0-5°C in lot-wise under nitrogen atmosphere and stirred the reaction mixture for 5 minutes. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 36 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the obtained compound at 25-30°C and stirred it for I hour at the same temperature. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water at 25-30°C, filtered and washed with water.
  • Example-4 Preparation of l,3-bis(2-ch!oroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (6 kg) was added to the mixture of dilute hydrochloric acid (1.9 lit) and acetic acid (24.5 lit) at 25-30°C.
  • Example-5 Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (150 gm) was added to the mixture of dilute hydrochloric acid (48 ml) and acetic acid (612 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (139.8 gm) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water.
  • PXPvD of the obtained compound is shown in figure-1 and IR shown in figure-2.

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation du composé 1,3-bis(2-chloroéthyl)-nitrosourée, qui est représenté par la formule structurale 1 suivante :
PCT/IN2017/000058 2016-03-11 2017-03-10 Procédé amélioré pour la préparation de l,3-bis (2-chloroéthyl)-nitrosourée WO2017154019A1 (fr)

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IN201641008562 2016-03-11
IN201641008562 2016-03-11

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4028410A (en) * 1974-11-13 1977-06-07 The United States Of America As Represented By The Secretary Of The Department Of Health, Education And Welfare Process of preparing 1,3-bis(2-chloroethyl)-1-nitrosourea
EP0056458A1 (fr) * 1981-01-19 1982-07-28 Tanabe Seiyaku Co., Ltd. Dérivés de nitrosourées, procédé pour leur préparation et compositions thérapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4028410A (en) * 1974-11-13 1977-06-07 The United States Of America As Represented By The Secretary Of The Department Of Health, Education And Welfare Process of preparing 1,3-bis(2-chloroethyl)-1-nitrosourea
EP0056458A1 (fr) * 1981-01-19 1982-07-28 Tanabe Seiyaku Co., Ltd. Dérivés de nitrosourées, procédé pour leur préparation et compositions thérapeutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KEISHA-GAY HYLTON: "Catalytic Carbonylation of Amines and Diamines as an alternative to Phosgene Derivatives: Application to Syntheses of the Core Structure of DMP 323 and DMP 450 and other functionalized Ureas", DISSERTATION, May 2004 (2004-05-01), XP055420067 *
MIRKO DIKSIC ET AL.: "Pharmacokinetics of Positron-labeled 1,3-Bis (2-chloroethyl) nitrosourea in Human Brain Tumors Using Positron Emission Tomography", CANCER RESEARCH, vol. 44, July 1984 (1984-07-01), pages 3120 - 3124, XP055420063 *
PEARSON, A. J. ET AL.: "Handbook of Reagents for Organic Synthesis", ACTIVATING AGENTS AND PROTECTING GROUPS, April 1999 (1999-04-01) *

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