WO2023102627A1 - Procédé de préparation de témozolomide - Google Patents

Procédé de préparation de témozolomide Download PDF

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WO2023102627A1
WO2023102627A1 PCT/BR2022/050478 BR2022050478W WO2023102627A1 WO 2023102627 A1 WO2023102627 A1 WO 2023102627A1 BR 2022050478 W BR2022050478 W BR 2022050478W WO 2023102627 A1 WO2023102627 A1 WO 2023102627A1
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temozolomide
nmci
aica
fact
process according
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PCT/BR2022/050478
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English (en)
Inventor
Ogari De Castro Pacheco
Vincenzo DE SIO
Murilo MASSONI
Marcelo SECATTO
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Cristália Produtos Químicos Farmacêuticos Ltda
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Application filed by Cristália Produtos Químicos Farmacêuticos Ltda filed Critical Cristália Produtos Químicos Farmacêuticos Ltda
Publication of WO2023102627A1 publication Critical patent/WO2023102627A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the chemical-pharmaceutical field and relates to an improved process for the preparation of temozolomide on a large industrial scale which involves the use of N-methyl carbamoylimidazole (NMCI) Form I in the preparation of the key intermediate 5-amino-Nl - imidazole-1 , 4 -dicarboxamide ( carbamoyl-AICA) .
  • NMCI N-methyl carbamoylimidazole
  • carbamoyl-AICA carbamoyl-AICA
  • NMCI Form I NMCI Form I and temozolomide are purified by crystallization, without the use of chromatographic column or continuous extraction.
  • Temozolomide chemically known as 8- carbamoyl -3 -methyl imidazole [5,l-d]-l,2,3,5- tetrazin-4 ( 3H) -one, is represented by the structural formula I,
  • Temozolomide is a drug that exhibits antitumor activity and was first described in patent US5260291 .
  • Carbamoyl-AICA can be prepared from AICA and 4- nitrophenyl chloroformate in dichloromethane (DCM) to provide 4 -nitrophenyl carbamate which is then treated with methylamine (MeNIh) , or directly by reaction with N-methylcarbamoyl chloride. Both processes are carried out in the presence of triethylamine (TEA or EtsN) as a catalyst base.
  • TEA triethylamine
  • EtsN triethylamine
  • tetramethylammonium hydroxide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate and hexadecyltrimethylammonium bromide did not improve the yield; and the use of other potential cyclization modulators, such as 15-crown-5, glyceraldehyde, succinimide,
  • other potential cyclization modulators such as 15-crown-5, glyceraldehyde, succinimide,
  • the document WO2008038031 describes the preparation of temozolomide through the nitrosative cyclization reaction of carbamoyl-AICA in the presence of an excess of metal halide (cyclization promoter for temozolomide) .
  • metal halide cyclization promoter for temozolomide
  • temozolomide is obtained in high proportion in relation to azahypoxanthine, however the proportion obtained of each one is not mentioned.
  • the nitrosative cyclization of carbamoyl- AICA is carried out in the presence of a metal halide, such as lithium chloride or bromide, an acid, and a source of nitrous acid.
  • the reaction is optimized by adding carbamoyl-AICA to the sodium nitrite solution achieving a yield of 43% to 65% (based on extraction method) .
  • the nitrosative cyclization reaction takes place in the presence of LiCl at room temperature (18 °C to 22 °C) for 5 hours, wherein the weight /volume ratio between carbamoyl-AICA and water is 1:24, providing temozolomide in 63% yield.
  • the complete process is represented below in Scheme 3.
  • Temozolomide obtained by the process in WO2008038031 is isolated by countercurrent extraction using continuous liquid-liquid extractor which requires large volumes of solvents such as dichloromethane.
  • solvents such as dichloromethane.
  • the use of large amounts of metal halide, a special equipment (extractor) and large volumes of dichloromethane makes the process generally expensive, uncompetitive and unfeasible from an industrial and environmental point of view.
  • NMCI can be purchased commercially or prepared by reacting N, N-carbonyldiimidazole (CDI) with methylamine hydrochloride (MeNIM.HCl) in a mixture of acetonitrile and dimethylformamide and purified via chromatographic column as described by Duspara et . al. J. Org. Chem. 2012, 77 (22) , 10362-10368.
  • CDI N, N-carbonyldiimidazole
  • MeNIM.HCl methylamine hydrochloride
  • NMCI reacts with AICA in acetonitrile or tetrahydrofuran (THE) to provide carbamoyl-AICA which is isolated by filtration.
  • Carbamoyl-AICA reacts with sodium nitrite, added to the reaction medium in solid form, in the presence of a tartaric acid solution, wherein the weight /volume ratio between carbamoyl-AICA and water is 1:15.
  • the mixture was heated to 60°C and filtered to provide temozolomide and azahypoxanthine in a ratio of 60:40. Temozolomide was purified via chromatographic column and then crystallized.
  • the NMCI carbamoylating agent has the advantage of being a non-hygroscopic, low-toxicity, non-explosive, easily stored and inexpensive crystalline solid.
  • its purification via chromatographic column makes its production on an industrial scale unfeasible.
  • the use of a chromatographic column for the isolation of temozolomide limits the use of this process on a large industrial scale, when the production of large quantities of product is required.
  • NMCI Example 17; compound 32
  • NMCI was purified by partitioning between dichloromethane and saturated aqueous ammonium chloride (NH4CI) and the layers were separated. The aqueous layer was extracted with dichloromethane, the organic layers were combined, dried, filtered and concentrated under reduced pressure to provide crystallized NMCI.
  • NH4CI saturated aqueous ammonium chloride
  • the purification step does not involve the use of a chromatographic column which limits the large industrial application, the process has a low yield, around 50% in the chemical transformation step with a long time of 72 hours (preliminary yield before purification ) .
  • the methylamine solution in tetrahydrofuran has restrictions on temperature and exposure to moisture in the air, requiring greater care with its handling and storage . This is because , when exposed to the air, tetrahydrofuran and methylamine absorb water from the environment . Methylamine is highly volatile at room temperature , which can also affect the reproducibility of the process due to the variation in the concentration of methylamine solubilized in the organic solvent .
  • the present invention relates to a process for the preparation of temozolomide comprising the following steps:
  • a process for the preparation of temozolomide comprising the following steps : (i) Reacting carbamoyl-AICA with an alkali or earth alkali metal nitrite in the presence of an acid in an aqueous medium, wherein the weight /volume ratio of carbamoyl-AICA and water is 1: (5-7) w/v, the temperature for diazotization reaction is -5°C to 5°C and the temperature for cyclization reaction is 30°C to 35°C, in order to provide a suspension comprising temozolomide and impurities in a ratio of 90:10, wherein azahypoxanthine it is the main impurity;
  • a process for the preparation of N-methyl carbamoyl imidazole (NMCI) Form I comprising the following steps: a) Reacting N, N-carbonyldiimidazole with methylamine hydrochloride in a mixture of acetonitrile and dimethylformamide to provide NMCI and the imidazole hydrochloride by-product; b) Distilling under vacuum the acetonitrile from the reaction medium; c) Adding ethyl acetate to the medium and filtering to remove the imidazole hydrochloride by-product and provide a solution containing crude NMCI; d) Acidifying the solution containing crude NMCI and discarding the aqueous phase; e) Concentrating the organic phase containing the NMCI by vacuum distillation of the ethyl acetate .
  • Figure 2 IR (ATR) for NMCI Form I.
  • Figure 4 DRX for purified temozolomide.
  • Figure 5 IR (ATR) for purified temozolomide
  • Figure 6 DSC for purified temozolomide
  • Figure 7 DRX for temozolomide Form III.
  • the present invention relates to an efficient and industrially advantageous process for the preparation of temozolomide, as depicted in Scheme 5.
  • AICA can be obtained from the reaction of AICA hydrochloride with an alkaline solution, such as a 20% aqueous sodium carbonate solution to provide AICA with high purity (99.9% by HPLC) .
  • AICA is reserved for the reaction step with N-methyl carbamoyl imidazole (NMCI) in the crystalline form designated Form I.
  • NMCI N-methyl carbamoyl imidazole
  • NMCI compound can be prepared as described in J. Org. Chem. 2012, 77 (22) , 10362-10368 from the reaction of N, N-carbonyldiimidazole (CDI) with methylamine hydrochloride in the presence of a solvent mixture consisting of acetonitrile and dimethylformamide.
  • CDI N, N-carbonyldiimidazole
  • NMCI is an important carbamoylation agent and its use in the preparation of the key carbamoyl-AICA intermediate for the synthesis of temozolomide was disclosed in document WO20 18112589 .
  • NMCI reacts with AICA for the preparation of carbamoyl-AICA without requiring the addition of a tertiary amine base, such as triethylamine (TEA or EtsN) or diisopropylethylamine (DIPEA) .
  • a tertiary amine base such as triethylamine (TEA or EtsN) or diisopropylethylamine (DIPEA) .
  • TEA or EtsN triethylamine
  • DIPEA diisopropylethylamine
  • the present invention reveals a production process that advocates classic unitary operations and widely used industrially such as extraction, distillation and crystalli zation . These operations are able of promoting a high efficiency of chemical transformation and, above all , of NMCI purification through the elimination of the imidazole hydrochloride by-product .
  • the NMCI Form I intermediate is obtained by a process comprising the steps : al ) Reacting N, N-carbonyldiimidazole with methylamine hydrochloride in a mixture of acetonitrile and dimethylformamide to provide NMCI and the imidazole hydrochloride by-product ; a2 ) Distilling under vacuum the acetonitrile from the reaction medium; a3 ) Adding ethyl acetate to the medium and filter to remove the imidazole hydrochloride by-product and provide a solution containing crude NMCI ; a4 ) Acidifying the solution containing crude NMCI and dis card the aqueous phase ; a5 ) Concentrating the organic phase containing the NMCI by vacuum distillation of the ethyl acetate ; a 6 ) Adding toluene to the organic phase and distilling under vacuum the azeotropic mixture of to
  • Toluene is added to the medium and the dimethylformamide which is still present in the reaction medium forms an azeotropic mixture with toluene, being eliminated by distillation. Toluene is added again to the medium for crystallizing NMCI Form I, obtained with 82% yield and 97.8% chromatographic purity (HPLC) .
  • the crystalline form obtained from NMCI designated Form I exhibits an X-ray powder diffraction (XRD) spectrum comprising characteristic peaks expressed in terms of 20° ⁇ 0.2 at 11.55, 13.77, 19.18, 20.11, 22.99, 26.27, 28.69, 29.58 and 32.66 ( Figure 1) ; infrared absorption spectrum comprises characteristic absorption peaks at 3199, 3143, 3109, 3037, 1712, 1554, 1514, 1479, 1421, 1363, 1330, 1288, 1251, 1203, 1192, 1153, 1109, 1068, 1045, 979, 908, 881, 837, 806 and 710 cm -1 ( Figure 2) ; and DSC (endothermic event) : 115°C - 123°C and 210°C - 234°C ( Figure 3) .
  • XRD X-ray powder diffraction
  • NMCI Form I and AICA for synthesis of carbamoyl-AICA is carried out in a polar aprotic organic solvent, preferably acetonitrile or tetrahydrofuran, more preferably acetonitrile.
  • a polar aprotic organic solvent preferably acetonitrile or tetrahydrofuran, more preferably acetonitrile.
  • the reaction takes place at a temperature between 55°C and 60°C for about 7 hours.
  • the reaction mixture is then cooled to 25°C and after one hour the carbamoyl-AICA crystals are isolated by filtration, without the need for further purification.
  • Carbamoyl-AICA is obtained on an industrial scale (in kilograms) with high yield and high purity (87% yield and 99.2% chromatographic purity) .
  • the convers ion reaction of carbamoyl-AICA to temozolomide is carried out in the presence of an alkali or earth alkali metal nitrite and an acid in an aqueous medium, which incorporates improvements over the prior art .
  • the al kali metal nitrite is sodium nitrite and the acid is tartaric acid .
  • the chemical reaction for the preparation of temozolomide involves intramolecular nitrosative cycli zation that pas ses through a diazonium salt intermediate , whose formation is due to the reaction between carbamoyl-AICA and sodium nitrite in an acidic environment in an aqueous medium .
  • the diazoti zed carbamoyl-AICA intermediate can cycli ze in two different ways :
  • the two cyclizations are likely to occur practically equally, leading to a temozolomide to azahypoxanthine ratio of approximately 50:50 [J. Org. Chem. 62, 7288-7294 (1997)] or with slightly enriched values of temozolomide, 60:40 as disclosed in WO2018112589 .
  • the reaction mixture is a suspension composed of temozolomide and azahypoxanthine between the solid and liquid phases. According to the state of the art, the best way to separate the two reaction products and obtain pure temozolomide is through a complete solubilization of the reaction mixture in water and, subsequently, the use of chromatographic columns or continuous extraction with organic solvents.
  • the process for preparing temozolomide comprises the reaction of carbamoyl-AICA with an alkali or earth alkali metal nitrite in the presence of an acid in an aqueous medium, wherein the weight /volume ratio of carbamoyl- AICA and water is 1: (5-7) w/v, the temperature for diazotization reaction is -5°C to 5°C, and the temperature for cyclization reaction is 30°C to 35°C.
  • the weight /volume ratio between carbamoyl-AICA and water is 1:5 w/v
  • the temperature for the diazotization reaction is maintained at 5°C for 4 hours
  • the temperature for the cyclization reaction is maintained at 30°C for 5 hours.
  • the more concentrated reaction medium promotes a much better ratio between temozolomide and impurities, respectively, in a ratio of about 90:10, wherein azahypoxanthine is the main impurity.
  • This result is attributed to the precipitation of temozolomide which is much less soluble than azahypoxanthine, particularly at higher concentrations.
  • Such condition generates a driving- force to obtain mainly the cyclization of the diazonium salt intermediate to temozolomide (Nucleophilic attack (1) of Scheme 6) .
  • intramolecular cyclization has a lower energy transition state with the secondary amide because it has a greater nucleophilic power when compared to the primary amide, in this respect, the higher the medium concentration, the easier will be to promote the intramolecular cyclization in the secondary amide nucleophile.
  • the suspension comprising temozolomide and impurities in a ratio of 90:10, wherein azahypoxanthine is the main impurity, is acidified with 30% to 35% hydrochloric acid up to pH 2-3 and the water in the medium is distilled off to give a concentrated suspension and then temozolomide is purified by crystallization.
  • the process of purifying temozolomide by crystallization comprises dissolving temozolomide in dimethylsulfoxide (DMSO) preheated to 60°C, filtering to remove the solid residue, and slowly adding ethyl acetate to the obtained filtrate and cooling to crystallization, filtering, washing the obtained crystals with ethyl acetate and drying to obtain purified temozolomide, wherein the w/v ratio between temozolomide (crude) and dimethylsulfoxide is 1:10, the w/v ratio between temozolomide (crude) and ethyl acetate is 1:4, the v/v ratio of dimethylsulfoxide and ethyl acetate is 1: (0.4-0.5) .
  • Purified temozolomide is obtained in 62% yield and 98.7% chromatographic purity (HPLC) .
  • the crystalline form of obtained purified temozolomide exhibits an X-ray powder diffraction (XRD) spectrum comprising characteristic peaks expressed in terms of 20° ⁇ 0.2 at 7.34, 8.61, 10.75, 12.78, 13.07, 13.98, 14.62, 16.01, 16.69, 17.72,
  • XRD X-ray powder diffraction
  • the process for preparing temozolomide further comprises the step of suspending purified temozolomide in acetone and water (3:1) , heating between 55°C and 60°C and cooling to provide temozolomide Form III that exhibits an X-ray powder diffraction (XRD) spectrum comprising characteristic peaks expressed in terms of 20° ⁇ 0.2 at 5.5, 10.9, 13.3, 14.2, 14.7, 16.3, 16.8, 18.0, 19.1, 19.6, 20.7, 21.5, 23.8, 25.2, 26.2, 26.5, 27.2, 27.8, 28.8, 29.8 and 30.3 (Figure 7) ; IR (ATR, cm- 1 ) : 3419, 3386, 3185, 3116, 1758, 1732, 1676, 1452, 1354, 1266 ( Figure 8) ; DSC: Exothermic event (Degradation) 204 °C - 213°C ( Figure 9) •
  • XRD X-ray powder diffraction
  • the process for preparing temozolomide comprises the following steps:
  • the conversion reaction of carbamoyl-AICA to temozolomide incorporates improvements over the prior art which surprisingly led to obtaining an enriched mixture of temozolomide.
  • the alkali metal nitrite is sodium nitrite added to the reaction medium in solid form
  • the acid is tartaric acid
  • the weight /volume ratio between carbamoyl-AICA and water is 1:5 w/v
  • the temperature for diazotization reaction is 5°C
  • the temperature for the cyclization reaction is 30°C.
  • the process for preparing temozolomide comprises reacting carbamoyl-AICA with sodium nitrite in the presence of tartaric acid in an aqueous medium, wherein the weight /volume ratio between carbamoyl-AICA and water is 1:5 w/ v, the temperature for the diazotization reaction is kept at 5°C for 4 hours and the temperature for the cyclization reaction is kept at 30 °C for 5 hours .
  • the more concentrated reaction medium favors a significantly better ratio between temozolomide and impurities, respectively, in a ratio of about 90:10, wherein azahypoxanthine is the main impurity.
  • the suspension comprising temozolomide and impurities in a ratio of 90:10, wherein azahypoxanthine is the main impurity is acidified with 30% to 35% hydrochloric acid up to pH 2-3 and the water of the medium is removed by distillation to give a concentrated suspension, and then temozolomide is purified by crystallization.
  • purification of temozolomide by crystallization comprises dissolving temozolomide in dimethylsulfoxide preheated to 60°C, filtering to remove solid residue, and slowly adding ethyl acetate to the obtained filtrate and cooling to crystallization, filtering, washing the obtained crystals with ethyl acetate and drying to obtain purified temozolomide, wherein the w/v ratio between temozolomide (crude) and dimethylsulfoxide is 1:10, the w/v ratio between temozolomide (crude) and ethyl acetate is 1:4 and the v/v ratio of dimethylsulfoxide and ethyl acetate is 1: (0.4-0.5) .
  • the process for preparing temozolomide further comprises the step of suspending purified temozolomide in acetone and water (3:1) , heating between 55°C and 60°C and cooling to provide temozolomide Form III that exhibits an X-ray powder diffraction (XRD) spectrum comprising characteristic peaks expressed in terms of 20 ⁇ 0.2 at 5.5, 10.9, 13.3, 14.2, 14.7, 16.3, 16.8, 18.0, 19.1, 19.6, 20.7, 21.5, 23.8, 25.2, 26.2, 26.5, 27.2, 27.8, 28.8, 29.8 and 30.3; IR (ATR, cm- 1 ) : 3419, 3386, 3185, 3116, 1758, 1732, 1676, 1452, 1354, 1266; DSC: Exothermic event
  • the process for preparing N-methyl carbamoyl imidazole (NMCI) Form I comprises the following steps: a) Reacting N, N-carbonyldiimidazole with methylamine hydrochloride in a mixture of acetonitrile and dimethylformamide to provide NMCI and the imidazole hydrochloride by-product; b) Destilling under vacuum the acetonitrile from the reaction medium; c) Adding ethyl acetate to the medium and filtering to remove the imidazole hydrochloride by-product and provide a solution containing crude NMCI; d) Acidifying the solution containing crude NMCI and discarding the aqueous phase; e) Concentrating the organic phase containing the NMCI by vacuum distillation of the ethyl acetate; f) Adding toluene to the organic phase and distilling under vacuum the azeotropic mixture of toluene and N,
  • the solution containing crude NMCI is acidified in step d) with a 10% citric acid aqueous solution.
  • Form I useful for the preparation of the key intermediate carbamoyl-AICA, with high yield and purity .
  • NMCI purification 385.0 L of ethyl acetate was added to the medium, kept under stirring for 30 minutes, and the crystallized imidazole hydrochloride was filtered and washed with ethyl acetate to obtain a solution containing crude NMCI with 90% purity.
  • the solution containing NMCI was treated with the addition of a 10% citric acid aqueous solution and, after separating the phases and discarding the aqueous solution, the organic solution containing the product was concentrated by vacuum distillation of all ethyl acetate. Then, 360.0 L of toluene was added to the organic phase and the azeotropic mixture of toluene and N,N- dimethylf ormamide was distilled under vacuum.
  • the crystalline form obtained from NMCI designated Form I exhibits an X-ray powder diffraction (XRD) spectrum comprising characteristic peaks expressed in terms of 20° ⁇ 0.2 at 11.55, 13.77, 19.18, 20.11, 22.99, 26.27, 28.69, 29.58 and 32.66 ( Figure 1) ; Infrared absorption spectrum comprises characteristic absorption peaks in 3199, 3143, 3109, 3037, 1712, 1554, 1514, 1479, 1421, 1363, 1330, 1288, 1251, 1203, 1192, 1153, 1109, 1068, 1045, 979, 908, 881, 837, 806 and 710 cm -1 ( Figure 2) ; and DSC (endothermic event) : 115°C - 123°C and 210°C - 234°C ( Figure 3) .
  • XRD X-ray powder diffraction
  • temozolomide purification 35.0 L of 30% to 35% hydrochloric acid were added to the suspension and, under vacuum at temperature between 50°C and 60°C, approximately 120 L of water of the system was distilled. Then, 300.0 L of dimethylsulfoxide preheated to 60 °C were added over the concentrated suspension and the medium was stirred for 10 minutes. The suspension was filtered and the solid residue was washed with 80.0 L of dimethylsulfoxide preheated to 60°C.
  • the crystalline form of the obtained purified temozolomide exhibits an X-ray powder diffraction spectrum (XRD) comprising characteristic peaks expressed in terms of 20° ⁇ 0.2 at 7.34, 8.61, 10.75, 12.78, 13.07, 13.98, 14.62, 16.01, 16.69, 17.72, 18.91, 19.37, 20.13, 20.68, 21.41, 22.84, 23.75, 24.38, 24.99, 25.56, 26.28, 28.07, 28.58, 29.43 and 30.97 ( Figure 4) ; IR (ATR, cm-1) : 3418; 3386; 3290; 3167; 3115; 1753; 1729; 1676; 1601; 1566; 1452; 1402; 1354; 1300; 1263; 1217; 1111; 1044; 1005; 946; 801; 735; 711; 634; 563; 510 ( Figure 5) ; DSC: Endothermic event 115°C - 123°C (Fusion)
  • Temozolomide Form III exhibits an X-ray powder diffraction spectrum (XRD) comprising characteristic peaks expressed in terms of 20 ⁇ 0.2 at 5.5, 10.9, 13.3, 14.2, 14.7, 16.3, 16.8, 18.0, 19.1, 19.6, 20.7, 21.5, 23.8, 25.2, 26.2, 26.5, 27.2, 27.8, 28.8, 29.8 and 30.3 ( Figure 7) ; IR (ATR, cm- 1 ) : 3419, 3386, 3185, 3116, 1758, 1732, 1676, 1452, 1354, 1266 ( Figure 8) ; DSC: Exothermic event (Degradation) 204 °C - 213°C ( Figure 9) •

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Abstract

La présente invention concerne un procédé de préparation de témozolomide à grande échelle industrielle qui utilise du N-méthyl carbamoyl imidazole (NMCI) de forme I dans la préparation de l'intermédiaire clé , à savoir le 5-amino-N1-imidazole-1,4-dicarboxamide (carbamoyl-AICA). De plus, la présente invention concerne un procédé de préparation de NMCI de forme I. Le NMCI de forme I et le témozolomide sont purifiés par cristallisation, sans recours à une colonne chromatographique ou une extraction continue.
PCT/BR2022/050478 2021-12-06 2022-12-05 Procédé de préparation de témozolomide WO2023102627A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008038031A1 (fr) * 2006-09-29 2008-04-03 Cipla Limited Procédé amélioré pour la préparation du témozolomide et d'analogues de celui-ci
US20100036121A1 (en) * 2008-08-07 2010-02-11 Chemi S.P.A. Process for preparing temozolomide
WO2010140168A1 (fr) * 2009-06-03 2010-12-09 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation de témozolomide
WO2015057585A1 (fr) * 2013-10-14 2015-04-23 Regents Of The University Of Minnesota Composés thérapeutiques
WO2018112589A1 (fr) * 2016-12-20 2018-06-28 Cristália Produtos Químicos Farmacêuticos Ltda Procédé de préparation de témozolomide et d'un intermédiaire
WO2018122724A1 (fr) * 2016-12-27 2018-07-05 Granules India Limited Procédé de preparation de témozolomide
WO2020194168A1 (fr) * 2019-03-25 2020-10-01 Shivalik Rasayan Limited Procédé de préparation de témozolomide de haute pureté

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008038031A1 (fr) * 2006-09-29 2008-04-03 Cipla Limited Procédé amélioré pour la préparation du témozolomide et d'analogues de celui-ci
US20100036121A1 (en) * 2008-08-07 2010-02-11 Chemi S.P.A. Process for preparing temozolomide
WO2010140168A1 (fr) * 2009-06-03 2010-12-09 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation de témozolomide
WO2015057585A1 (fr) * 2013-10-14 2015-04-23 Regents Of The University Of Minnesota Composés thérapeutiques
WO2018112589A1 (fr) * 2016-12-20 2018-06-28 Cristália Produtos Químicos Farmacêuticos Ltda Procédé de préparation de témozolomide et d'un intermédiaire
WO2018122724A1 (fr) * 2016-12-27 2018-07-05 Granules India Limited Procédé de preparation de témozolomide
WO2020194168A1 (fr) * 2019-03-25 2020-10-01 Shivalik Rasayan Limited Procédé de préparation de témozolomide de haute pureté

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