CN114805360A - Preparation method of temozolomide - Google Patents
Preparation method of temozolomide Download PDFInfo
- Publication number
- CN114805360A CN114805360A CN202210016130.9A CN202210016130A CN114805360A CN 114805360 A CN114805360 A CN 114805360A CN 202210016130 A CN202210016130 A CN 202210016130A CN 114805360 A CN114805360 A CN 114805360A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- temozolomide
- intermediate compound
- preparation
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 229960004964 temozolomide Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 27
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 24
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 9
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 6
- 229940045803 cuprous chloride Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- GRRYSIXDUIAUGY-UHFFFAOYSA-N n-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000005457 ice water Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 201000007983 brain glioma Diseases 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- IKZLMSPFYNDYIL-UHFFFAOYSA-N (5E)-5-diazoimidazole-4-carboxamide Chemical compound NC(=O)C1=NC=NC1=[N+]=[N-] IKZLMSPFYNDYIL-UHFFFAOYSA-N 0.000 description 1
- -1 3-trimethylsilylmethyl imidazole tetrazine Chemical compound 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001490 effect on brain Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of temozolomide. The preparation method of temozolomide takes the compound II and methylamino formyl chloride as raw materials, the raw materials are cheap and easy to obtain, the whole synthesis step is simple and convenient to operate, the reaction condition is mild, the use of a virulent reagent methyl isocyanate is avoided, the safety in the production process is relatively improved, the method is economical and environment-friendly, the product yield and the purity are high, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of temozolomide.
Background
Temozolomide (Temozolomide), chemical name 8-carbamoyl-3-methylimidazole [5,1-d]-1,2,3, 5-tetrazin-4 (3H) -one of formula: c 6 H 6 N 6 O 2 (ii) a Molecular weight: 194.15, respectively; CAS accession number: 85622-93-1, the structural formula is as follows:
temozolomide was first developed by easton university, uk, and later acquired in the german pioneer pauy pharmaceutical, and was marketed in the united states in 1999. Pharmacological research proves that temozolomide is a novel medicine with better curative effect on brain glioma; has high bioavailability, can be orally taken, is easy to permeate blood brain barrier, has no superimposed toxicity compared with other medicines, and has wider anti-tumor spectrum. Currently, temozolomide is a better anticancer drug for treating brain glioma and malignant melanoma, and the capsule of temozolomide is approved in Europe and America to be used for treating malignant glioma.
The conventional synthesis method of temozolomide is to react 5-amino-1H-imidazole-4-formamide or hydrochloride thereof serving as a raw material with sodium nitrite, diazotize the reaction product and react with methyl isocyanate to prepare temozolomide (Journal of the Chemical Society, Perkin Transactions 1, 1998, 10: l669-1775), and the synthesis route is as follows. The method has high atom utilization rate, so that the temozolomide product with high purity and high yield is obtained, but methyl isocyanate with high toxicity is tried in the synthesis process, the operation risk is high, and the temozolomide product is not easy to produce and synthesize.
The second type of process is the methyl isocyanate substitution: one is temozolomide synthesized by deprotonation of 3-carboxy temozolomide in a yield of 26% (Journal of the Chemical Society, Chemistry Commum, 19914, 14: 1687-; the other method is to react 3-trimethylsilylmethyl imidazole tetrazine with tetrabutyl ammonium fluoride in a mixed solvent of acetonitrile and acetic acid to obtain temozolomide with the yield of 78% (Biochemistry, 1994, 33 (31): 9045-9051). Although these two methods avoid the direct use of methyl isocyanate, the yield is not high because the substitute is not very stable.
The third method is a method for synthesizing methylcarbamoyl chloride (Journal of the Organic Chemistry, 1997, 62: 7288-. 5-amino-1- (N-methylcarbamoyl) imidazole-4-formamide is synthesized from 5-aminoimidazole-4-formamide, and then temozolomide is obtained through diazotization. The method uses moderate-toxicity methylaminocarbonyl chloride to replace virulent methyl isocyanate, and the 5-amino-1- (N-methylcarbamoyl) imidazole-4-formamide has a plurality of diazotization reaction sites, so that an isomer byproduct is generated in the step, and the reaction yield needs to be improved.
The fourth method is a novel method which does not use 5-diazoimidazole-4-carboxamide and methyl isocyanate (Journal of the Chemical Society, Perkin Transactions 1, 2002, 16: 1877-. The method has high yield, but the synthesis route is long and too complex, so the method is not suitable for industrial production.
The fifth method is a new method of carbonyl diimidazole participating in the reaction (WO 2018/112589): and starting carbonyl diimidazole, performing imidazole ring exchange twice, and diazotizing to close a ring to obtain temozolomide. The method has low reagent toxicity and easy operation, but the intermediate N-methyl-1-H-imidazole formamide needs silica gel column purification and has complex operation. Meanwhile, the intermediate compound to be diazotized has double reaction sites, and two products are obtained by ring closure, so that the yield of the step is reduced.
In conclusion, the existing temozolomide preparation method has the problems of long synthesis route, low yield, low purity, high technical requirement, serious environmental pollution, unstable intermediate and high production cost. Therefore, the problem to be solved at present is to explore a process route for temozolomide, which is simple and convenient to operate, high in yield and more suitable for industrial production.
Disclosure of Invention
The invention provides a novel preparation method of temozolomide, aiming at solving the problems of long temozolomide synthesis route, complex operation, low yield, low purity and the like in the prior art. The method has the advantages of short reaction route, simple and convenient operation, milder reaction, high product purity and yield, and suitability for industrial production.
The invention is realized by the following technical scheme:
a preparation method of temozolomide comprises the following synthetic route:
a preparation method of temozolomide specifically comprises the following steps:
1) adding the compound II into the organic solvent A, stirring for dissolving, adding alkali and the compound III at controlled temperature, continuing to react at controlled temperature, and obtaining an intermediate compound IV after the reaction is finished;
2) sequentially adding the intermediate compound IV, cuprous salt and trimethylsilyl cyanide into an organic solvent B, and stirring at a controlled temperature to react to obtain an intermediate compound V;
3) and adding the intermediate compound V into an acid solution, controlling the temperature, hydrolyzing, and finishing the reaction to obtain a compound I.
Preferably, the base in step 1) is selected from one or a combination of diethylisopropylamine, pyridine and triethylamine, wherein diethylisopropylamine is particularly preferred.
Preferably, the organic solvent A in the step 1) is selected from one of toluene, DMF, DMSO or a combination thereof.
Preferably, the feeding molar ratio of the compound II, the base and the compound III in the step 1) is 1: 1.0-4.0: 1.0 to 2.2, wherein a ratio of 1: 3.0: 2.0.
preferably, the base, the compound III and the reaction temperature in step 1) are all-5 ℃ to 5 ℃, wherein 0 ℃ is particularly preferred.
Preferably, the compound III in the step 1) is added in a manner that the compound III is dissolved in the organic solvent A and then dropped into the reaction system.
In a preferred scheme, after the reaction in step 1) is finished, post-treatment operation is required, specifically: after the reaction is finished, concentrating to remove an organic phase, adding ice water, cooling in an ice bath, stirring, filtering under reduced pressure, washing a filter cake with the ice water and acetone in sequence, and drying to obtain an intermediate compound IV.
Preferably, the cuprous salt in the step 2) is selected from one or a combination of cuprous iodide, cuprous chloride and cuprous bromide, wherein cuprous chloride is particularly preferred.
Preferably, the feeding molar ratio of the intermediate compound IV, the inorganic cuprous salt and the trimethylsilyl cyanide in the step 2) is 1: 0.05-0.1: 1.0 to 2.0, wherein 1: 0.5: 1.2.
preferably, the organic solvent B in the step 2) is selected from one of DMSO, N-dimethylformamide, N-methylpyrrolidone or a combination thereof, wherein DMSO is particularly preferred.
Preferably, the reaction temperature in step 2) is 80 ℃ to 90 ℃.
In a preferred scheme, after the reaction in step 2) is finished, post-treatment operation is required, which specifically comprises the following steps: and after the reaction is finished, adding a saturated sodium thiosulfate solution for quenching, filtering, adding water, then adding ethyl acetate for extraction, drying by anhydrous magnesium sulfate, and carrying out rotary evaporation to obtain an intermediate compound V.
Preferably, the feeding mass-to-volume ratio of the intermediate compound V to the acid solution in the step 3) is 1: 20-50 g/mL.
Preferably, the acid solution in step 3) is selected from concentrated hydrochloric acid or a mixed acid solution of concentrated hydrochloric acid and glacial acetic acid, wherein a mixed acid solution of concentrated hydrochloric acid and glacial acetic acid is particularly preferred.
Further preferably, the feeding volume ratio of the concentrated hydrochloric acid to the glacial acetic acid is 1: 0.2 to 1.0, wherein a ratio of 1: 0.5.
preferably, the hydrolysis temperature in step 3) is 70 ℃ to 75 ℃.
In a preferred scheme, after the reaction in step 3) is finished, post-treatment operation is required, specifically: and cooling and stirring after the reaction is finished, carrying out suction filtration, adding a filter cake into DMSO, pulping, carrying out suction filtration, washing the filter cake with glacial ethanol, and drying to obtain a compound I.
Compared with the prior art, the invention provides a novel preparation method of temozolomide, which takes a compound II and methylaminoformyl chloride as raw materials, is cheap and easy to obtain, has simple and convenient operation of the whole synthesis step and mild reaction conditions, avoids the use of a virulent reagent methyl isocyanate, relatively improves the safety in the production process, is economic and environment-friendly, has high product yield and purity, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are all within the scope of the present invention as claimed.
The structure of the compound obtained by the invention is confirmed:
structural characterization of compound IV:
high resolution mass spectrum of compound IV: ESI-HRMS: M/z 152.0496[ M + H ]] + ； 1 H-NMR(400MHz,CDCl 3 ):δ8.15(s,1H),7.03(s,2H),2.75(s,3H)； 13 C-NMR(400MHz,CDCl 3 )δ145.8,139.6,136.7,125.9,37.7.
Structural characterization of compound V:
high resolution mass spectrum of compound V: ESI-HRMS, M/z 199.0453[ M + Na ]] + ； 1 H-NMR(400MHz,CDCl 3 ):δ8.14(s,1H),2.74(s,3H)； 13 C-NMR(400MHz,CDCl 3 ):δ145.7,139.7,115.6,136.7,71.4,37.8.
Preparation of intermediate Compound IV
Example 1
Adding a compound II (14.11g, 0.15mol) into 270mL of toluene, stirring for dissolving, cooling to 0 ℃, slowly dripping diisopropylethylamine (58.16g, 0.45mol) into a reaction system, dissolving a compound III (28.05g, 0.30mol) into 50mL of toluene after 15min, slowly dripping into the reaction system, continuing temperature-controlled reaction, monitoring the completion of the reaction, concentrating to remove the toluene, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with the ice water and acetone in sequence, and drying to obtain 21.42g of an intermediate compound IV, wherein the yield is 94.5%, and the HPLC purity is 99.93%.
Example 2
Adding a compound II (14.11g, 0.15mol) into 270mL of DMF, stirring for dissolving, cooling to 5 ℃, slowly dropwise adding triethylamine (15.18g, 0.15mol) into the reaction system, after 15min, dissolving a compound III (30.86g, 0.33mol) into 50mL of DMF, slowly dropwise adding into the reaction system, continuing temperature-controlled reaction, monitoring the reaction to be complete, concentrating to remove DMF, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with ice water and acetone in sequence, and drying to obtain 20.67g of an intermediate compound IV, wherein the yield is 91.2%, and the HPLC purity is 99.87%.
Example 3
Adding a compound II (14.11g, 0.15mol) into 270mL of toluene, stirring for dissolving, cooling to-5 ℃, slowly dropwise adding pyridine (47.46g, 0.60mol) into a reaction system, after 15min, dissolving a compound III (14.03g, 0.15mol) into 50mL of toluene and slowly dropwise adding into the reaction system, continuing temperature-controlled reaction, monitoring the completion of the reaction, concentrating for removing the toluene, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with the ice water and acetone in sequence, and drying to obtain 20.56g of an intermediate compound IV, wherein the yield is 90.7%, and the HPLC purity is 99.76%.
Example 4
Adding a compound II (14.11g, 0.15mol) into 270mL of toluene, stirring for dissolving, cooling to 0 ℃, slowly dripping triethylamine (30.36g, 0.30mol) into a reaction system, dissolving a compound III (21.51g, 0.23mol) into 50mL of toluene after 15min, slowly dripping into the reaction system, continuing temperature-controlled reaction, monitoring the completion of the reaction, concentrating for removing the toluene, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with ice water and acetone in sequence, and drying to obtain 20.86g of an intermediate compound IV, wherein the yield is 92.0% and the HPLC purity is 99.90%.
Example 5
Adding the compound II (14.11g, 0.15mol) into 270mL of toluene, stirring for dissolving, cooling to 10 ℃, slowly dripping diisopropylethylamine (58.16g, 0.45mol) into the reaction system, dissolving the compound III (28.05g, 0.30mol) into 50mL of toluene after 15min, slowly dripping into the reaction system, continuing temperature-controlled reaction, monitoring the completion of the reaction, concentrating for removing the toluene, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with ice water and acetone in sequence, and drying to obtain 19.84g of intermediate compound IV, wherein the yield is 87.5%, and the HPLC purity is 95.69%.
Example 6
Adding compound II (14.11g, 0.15mol) into 270mL DMF, stirring for dissolving, cooling to 0 ℃, slowly dripping diisopropylethylamine (96.94g, 0.75mol) into the reaction system, dissolving compound III (42.08g, 0.45mol) into 50mL DMF after 15min, slowly dripping into the reaction system, continuing temperature-controlled reaction, monitoring the reaction is complete, concentrating to remove DMF, adding 250mL ice water, stirring, filtering under reduced pressure, washing a filter cake with ice water and acetone in sequence, and drying to obtain 20.24g of intermediate compound IV, wherein the yield is 89.3%, and the HPLC purity is 93.74%.
Example 7
Adding a compound II (14.11g, 0.15mol) into 270mL of toluene, stirring for dissolving, cooling to 0 ℃, slowly dripping diisopropylethylamine (38.78g, 0.30mol) into a reaction system, dissolving a compound III (28.05g, 0.30mol) into 50mL of toluene after 15min, slowly dripping into the reaction system, continuing temperature-controlled reaction, monitoring the reaction to be complete, concentrating to remove the toluene, adding 250mL of ice water, stirring, filtering under reduced pressure, washing a filter cake with the ice water and acetone in sequence, and drying to obtain 21.10g of an intermediate compound IV, wherein the yield is 93.1%, and the HPLC purity is 99.91%.
Preparation of intermediate compound V
Example 8
The intermediate compound IV (15.11g, 0.10mol), cuprous chloride (0.99g, 0.01mol) and trimethylsilyl chloride (11.90g, 0.12mol) were sequentially added to 200mL of DMSO, the reaction was stirred at 85 ℃ and was monitored for completion, and after the completion of the reaction, a saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL of water was added, and then ethyl acetate (100 mL. times.3) was added for extraction, dried over anhydrous magnesium sulfate and rotary evaporated to give 15.91g of intermediate compound V, yield 90.3% and HPLC purity 99.92%.
Example 9
The intermediate compound IV (15.11g, 0.10mol), cuprous iodide (0.95g, 0.005mol) and trimethylsilyl cyanide (19.84g, 0.20mol) were sequentially added to 200mL of N, N-dimethylformamide, the reaction was stirred at 80 ℃ and monitored for completion, and after completion of the reaction, saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL of water was added, and then ethyl acetate (100 mL. times.3) was added for extraction, and anhydrous magnesium sulfate was dried and rotary evaporated to give 15.15g of intermediate compound V, yield 86.0% and HPLC purity 99.74%.
Example 10
The intermediate compound IV (15.11g, 0.10mol), cuprous bromide (2.87g, 0.02mol) and trimethylsilyl cyanide (9.92g, 0.10mol) were sequentially added to 200mL of N-methylpyrrolidone, the reaction was stirred at 90 ℃ and monitored to be complete, and after the completion of the reaction, a saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL of water was added, and then ethyl acetate (100 mL. times.3) was added for extraction, and anhydrous magnesium sulfate was dried and rotary evaporated to obtain 15.34g of intermediate compound V, the yield was 87.1%, and the HPLC purity was 99.80%.
Example 11
The intermediate compound IV (15.11g, 0.10mol), cuprous iodide (1.90g, 0.01mol) and trimethylsilyl cyanide (11.90g, 0.12mol) were sequentially added to 200mL of DMSO, the reaction was stirred at 90 ℃ and was monitored for completion, and after completion of the reaction, a saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL of water was added, followed by extraction with ethyl acetate (100 mL. times.3), dried over anhydrous magnesium sulfate and rotary evaporated to give 15.61g of intermediate compound V, yield 88.6%, and HPLC purity 99.85%.
Example 12
The intermediate compound IV (15.11g, 0.10mol), cuprous chloride (0.40g, 0.004mol) and trimethylsilyl cyanide (14.88g, 0.15mol) were sequentially added to 200mL of DMSO, the reaction was stirred at 85 ℃ and was monitored for completion, and after the completion of the reaction, a saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL of water was added, and then ethyl acetate (100 mL. times.3) was added for extraction, dried over anhydrous magnesium sulfate and rotary evaporated to give 14.67g of intermediate compound V, yield 83.3% and HPLC purity 99.67%.
Example 13
The intermediate compound IV (15.11g, 0.10mol), cuprous chloride (0.99g, 0.01mol) and trimethylsilyl chloride (11.90g, 0.12mol) were sequentially added to 200mL THF, the reaction was stirred at 65 ℃ and monitored for completion, then a saturated sodium thiosulfate solution was added to quench, the reaction was filtered, 50mL water was added, then ethyl acetate (100 mL. times.3) was added for extraction, anhydrous magnesium sulfate was dried and rotary evaporated to give 14.18g of intermediate compound V, yield 80.5% and HPLC purity 99.42%.
Preparation of temozolomide
Example 14
Adding the intermediate compound V (17.61g, 0.10mol) into a mixed solution of concentrated hydrochloric acid (400mL) and glacial acetic acid (200mL), controlling the temperature to react at 70-75 ℃, after the reaction is monitored to be complete, cooling the reaction solution to-5 ℃, performing suction filtration, adding a filter cake into DMSO (100mL), pulping, performing suction filtration, washing the filter cake with glacial ethanol (25mL multiplied by 2), and drying to obtain 19.08g of white pale powder solid temozolomide, wherein the yield is 98.3%, and the purity is 99.95%.
Example 15
Adding the intermediate compound V (17.61g, 0.10mol) into concentrated hydrochloric acid (400mL), controlling the temperature at 70-75 ℃ for reaction, monitoring the reaction to be complete, cooling the reaction liquid to-5 ℃, performing suction filtration, adding a filter cake into DMSO (100mL), pulping, performing suction filtration, washing the filter cake with glacial ethanol (25mL multiplied by 2), and drying to obtain 18.37g of white pale powder solid temozolomide, wherein the yield is 94.6% and the purity is 99.91%.
Example 16
Adding the intermediate compound V (17.61g, 0.10mol) into a mixed solution of concentrated hydrochloric acid (400mL) and glacial acetic acid (80mL), controlling the temperature to react at 70-75 ℃, after the reaction is monitored to be complete, cooling the reaction solution to-5 ℃, performing suction filtration, adding a filter cake into DMSO (100mL), pulping, performing suction filtration, washing the filter cake with glacial ethanol (25mL multiplied by 2), and drying to obtain 18.66g of white partial powder solid temozolomide, wherein the yield is 96.1% and the purity is 99.89%.
Example 17
Adding the intermediate compound V (17.61g, 0.10mol) into a mixed solution of concentrated hydrochloric acid (400mL) and glacial acetic acid (400mL), controlling the temperature to react at 70-75 ℃, after the reaction is monitored to be complete, cooling the reaction solution to-5 ℃, performing suction filtration, adding a filter cake into DMSO (100mL), pulping, performing suction filtration, washing the filter cake with glacial ethanol (25mL multiplied by 2), and drying to obtain 18.83g of white partial powder solid temozolomide, wherein the yield is 97.0%, and the purity is 99.54%.
Claims (10)
1. A preparation method of temozolomide is characterized by comprising the following steps:
2. the preparation method of temozolomide according to claim 1, which comprises the following specific preparation steps:
1) adding the compound II into the organic solvent A, stirring for dissolving, adding alkali and the compound III at controlled temperature, continuing to react at controlled temperature, and obtaining an intermediate compound IV after the reaction is finished;
2) sequentially adding the intermediate compound IV, cuprous salt and trimethylsilyl cyanide into an organic solvent B, and stirring at a controlled temperature to react to obtain an intermediate compound V;
3) and adding the intermediate compound V into an acid solution, controlling the temperature, hydrolyzing, and finishing the reaction to obtain a compound I.
3. The method of claim 2, wherein the base in step 1) is selected from one or a combination of diethylisopropylamine, pyridine and triethylamine.
4. The method of claim 2, wherein the base, compound III and reaction temperature in step 1) are all-5 ℃ to 5 ℃.
5. The preparation method according to claim 2, wherein the compound II, the base and the compound III are fed in the step 1) in a molar ratio of 1: 1.0-4.0: 1.0 to 2.2.
6. The method according to claim 2, wherein the organic solvent A in step 1) is selected from one of toluene, DMF, DMSO, or a combination thereof.
7. The method of claim 2, wherein the cuprous salt in step 2) is selected from cuprous iodide, cuprous chloride, cuprous bromide, and combinations thereof.
8. The method according to claim 2, wherein the reaction temperature in the step 2) is 80 ℃ to 90 ℃.
9. The method according to claim 2, wherein the organic solvent B in step 2) is one selected from DMSO, N-dimethylformamide, N-methylpyrrolidone, and a combination thereof.
10. The method according to claim 2, wherein the hydrolysis temperature in the step 3) is 70 ℃ to 75 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021100655766 | 2021-01-18 | ||
| CN202110065576 | 2021-01-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114805360A true CN114805360A (en) | 2022-07-29 |
Family
ID=82527282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210016130.9A Pending CN114805360A (en) | 2021-01-18 | 2022-01-07 | Preparation method of temozolomide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114805360A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659789A (en) * | 2011-04-27 | 2012-09-12 | 四川科瑞德凯华制药有限公司 | Method preparing temozolomide in one-pot mode and refining method of temozolomide |
| CN109467534A (en) * | 2017-09-07 | 2019-03-15 | 湖北半天制药有限公司 | A kind of synthetic method of Temozolomide intermediate |
| CN111233871A (en) * | 2020-03-17 | 2020-06-05 | 江苏美迪克化学品有限公司 | Preparation method of temozolomide |
| US20200190088A1 (en) * | 2016-12-20 | 2020-06-18 | Cristália Produtos Químicos Farmacêuticos Ltda | Process for preparing temozolomide and an intermediary |
-
2022
- 2022-01-07 CN CN202210016130.9A patent/CN114805360A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659789A (en) * | 2011-04-27 | 2012-09-12 | 四川科瑞德凯华制药有限公司 | Method preparing temozolomide in one-pot mode and refining method of temozolomide |
| US20200190088A1 (en) * | 2016-12-20 | 2020-06-18 | Cristália Produtos Químicos Farmacêuticos Ltda | Process for preparing temozolomide and an intermediary |
| CN109467534A (en) * | 2017-09-07 | 2019-03-15 | 湖北半天制药有限公司 | A kind of synthetic method of Temozolomide intermediate |
| CN111233871A (en) * | 2020-03-17 | 2020-06-05 | 江苏美迪克化学品有限公司 | Preparation method of temozolomide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101463013B (en) | Preparation of erlotinid hydrochloride | |
| CN107235923B (en) | Preparation method of 3-aryl quinoxalinone derivatives | |
| CN106588897A (en) | New preparation method of Pranlukast | |
| CN113121430B (en) | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone | |
| CN105198718A (en) | Preparation method for buparvaquone | |
| CN109575017A (en) | A kind of preparation method of Olprinone HCl compound | |
| CN109776407B (en) | Preparation method of 2-methyl-4-hydroxymethyl quinoline and derivatives thereof | |
| CN114057642B (en) | Synthetic method of mickey ammonium chloride intermediate | |
| CN114805360A (en) | Preparation method of temozolomide | |
| CN116023359A (en) | Synthesis method of aminothiophene compound and aminothiophene compound | |
| CN108558974B (en) | Preparation and application of sugar-derived nickel pyridine triazole catalyst | |
| CN1931857A (en) | Prepn process of 5-losartan carboxylate | |
| CN111848527A (en) | 4-chloro-2- (2-fluoro-4-methoxyphenyl) -6-methoxyquinazoline and synthetic method thereof | |
| CN106631872A (en) | Synthesis method of florfenicol analogue intermediate | |
| CN107216361A (en) | The preparation method of rope Citropten | |
| CN107216360B (en) | A method of preparing rope Citropten | |
| CN103833660A (en) | Preparation method of lamotrigine and intermediate thereof | |
| CN113493458B (en) | Preparation method of temozolomide | |
| CN114605320B (en) | Synthesis method of 5-nitro-6-methylnicotinic acid ethyl ester | |
| CN114621109B (en) | Synthesis method of apatamide and intermediate thereof | |
| CN111499607B (en) | Preparation method of hexabasic aryl lactone or hexabasic aryl lactam compound | |
| CN114716340B (en) | Preparation method of iopromide intermediate | |
| CN111747874B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN111747873B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN110746336B (en) | Green preparation method of N-methyl-2-cyano-3-arylpyrrole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |