CN100453543C - A temodar synthesis method - Google Patents
A temodar synthesis method Download PDFInfo
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- CN100453543C CN100453543C CNB2004100202334A CN200410020233A CN100453543C CN 100453543 C CN100453543 C CN 100453543C CN B2004100202334 A CNB2004100202334 A CN B2004100202334A CN 200410020233 A CN200410020233 A CN 200410020233A CN 100453543 C CN100453543 C CN 100453543C
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- temozolomide
- toluene
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- 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 32
- 238000001308 synthesis method Methods 0.000 title 1
- 229940061353 temodar Drugs 0.000 title 1
- 229960004964 temozolomide Drugs 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 claims description 28
- 238000005406 washing Methods 0.000 claims description 28
- 238000000967 suction filtration Methods 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 22
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000012954 diazonium Substances 0.000 claims description 18
- 150000001989 diazonium salts Chemical class 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 239000012452 mother liquor Substances 0.000 claims description 15
- GRRYSIXDUIAUGY-UHFFFAOYSA-N n-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 claims description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000007670 refining Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 230000006698 induction Effects 0.000 claims description 7
- 238000003860 storage Methods 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 230000007547 defect Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 31
- 239000000843 powder Substances 0.000 description 16
- -1 imidazoles monohydrate Chemical class 0.000 description 15
- 238000005303 weighing Methods 0.000 description 14
- 238000010521 absorption reaction Methods 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 8
- 238000007363 ring formation reaction Methods 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 241000972773 Aulopiformes Species 0.000 description 5
- 235000019515 salmon Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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Abstract
The present invention discloses a method for synthesizing temozolomide, which optimizes parameters of the prior art and overcomes defects of the prior art simultaneously.
Description
Technical field
The present invention relates to chemical field, be specifically related to the new synthetic method of a kind of Temozolomide synthetic method.
Background technology
Temozolomide (Temozolomide) is a kind of alkanisation formulation cancer therapy drug, by Britain Can research ventures company initiative, and the exploitation of Schering-Plough company, get permission listing through the FDA approval in the U.S. in August, 1999, the multinational listing in Europe simultaneously.Has broad-spectrum anti-tumor activity [L.H.Tsang, et al.Cancer Chemother Pharmacol.27 (1991): 342-346], especially to neurospongioma (cancer of the brain) and melanoma (skin carcinoma).The capsule of Temozolomide is used for the treatment of glioblastoma in America and Europe's approval.
At present; the synthetic method of the Temozolomide of domestic report is a lot; but key step all is to be raw material with 4-amino-5-formamyl imidazoles monohydrate; with Sodium Nitrite under acidic conditions, low temperature carries out diazotization reaction, generates diazonium salt; diazonium salt and methyl isocyanate carry out ring-closure reaction under anhydrous condition; obtain crude product, vacuum-drying obtains exquisite product.
But there are the following problems in production practice for above-mentioned reported method.
● the range of choice of reacting each process parameter is wide.As Sodium Nitrite in reaction and AIC.H
2O, i.e. 4-amino-5-formamyl imidazoles monohydrate etc., the reaction amount ranges is wide, is difficult to hold in the actual production operation, thereby makes the yield instability of product.
● diazenium compound, adopt intensification exsiccant method very easily to set off an explosion in the exquisite process, be unfavorable for suitability for industrialized production.In view of the problems referred to above that exist, the inventor provides a kind of new Temozolomide synthetic method.
Summary of the invention
The object of the invention is to provide a kind of synthetic method of Temozolomide.
Temozolomide synthetic method step of the present invention is as follows:
1. diazonium salt (MIC) is synthetic: add NaNO in the 3L there-necked flask
2With the water stirring and dissolving; Ice bath is cooled to 0 ℃; Preparation 2N hydrochloric acid soln.Taking by weighing 4-amino-5-formamyl imidazoles (AIC) is dissolved in the above-mentioned 2N hydrochloric acid for preparing; The 2N hydrochloric acid solution of the AIC of gained is added dropwise to above-mentioned NaNO
2The aqueous solution in, under the certain temperature, drip off, filter, ethanol is washed, and dries, and obtains light yellow solid.
2. methyl isocyanate is synthetic: get a certain amount of Methylaminoformyl chloride in the 500mL four-hole bottle, add the toluene stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets methyl isocyanate (MIC).
3. the preparation of Temozolomide: add methyl isocyanate (DIC) in 500ml single port bottle, add dimethyl sulfoxide (DMSO) (DMSO), induction stirring under the water-bath, dripped MIC, and the black out reaction adds ethanol under the room temperature ,-15～-19 ℃ of stir abouts 3 hours.The suction filtration washing with alcohol is drained, and gets product.
4. Temozolomide is refining: add Temozolomide and DMSO in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles, mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence, suction filtration, the solid washing with alcohol is drained; Mother liquor kept in cold storage spend the night, analyse essence, suction filtration is used washing with alcohol, drains.
In aforesaid method, Sodium Nitrite (NaNO in the step 1
2) with the ratio of water be 1: 18～22 (g/ml), optimum proportion is 1: 20 (g/ml), because the problem of the undercompounding that operation causes should be dissolved Sodium Nitrite and portion water earlier when adding water, surplus water mixes with sodium nitrite solution after cleaning bottleneck again in order to prevent; Temperature of reaction is 0～5 ℃; Concerning building-up reactions of the present invention, because its side reaction is very fast, therefore how well controlling reaction time is just extremely important, the reaction times of diazonium salt of the present invention is 35-45 minute, the best is 40 minutes, compares with 2.5 hours of prior art, has not only saved the reaction times, simultaneously suppress the generation of side reaction well, thereby can guarantee the productive rate of diazonium salt well; The exquisite step of diazonium salt has now adopted vacuum-drying by method, because the diazonium salt instability that generates is easy to blast under the dry hot conditions, industrial production is difficult to control, and the present invention adopts the washing with alcohol method, and 3 times, each 300ml.By the improvement of above-mentioned steps, make productive rate from before 80%, improve present about 90%; By adjusting NaNO
2Reduced consumption of raw materials with the AIC feed ratio, and the easier control of feasible reaction; Meanwhile attempted the new dried condition of making an uproar, drying effect is significantly improved, and helps industrialized production more.
In the step 2, the Methylaminoformyl chloride of adding and the ratio of toluene are 100: 70-90 (g/ml), optimum proportion are 100: 80 (g/ml); Triethylamine: toluene is 150: 90～110 (ml/ml), and optimum proportion is 150: 100 (ml/ml); Existing process using method is directly mixed Methylaminoformyl chloride with triethylamine, emit a large amount of heat energy, industrial production is wayward, the inventive method is controlled at reaction in the toluene solvant carries out, and makes reaction carry out steadily, and controllability is strong, adopted smart slide method of a step simultaneously, simplified the operation of producing, and the existing technology of productivity ratio has improved 20%, has reached about 70%.
In the step 3, the ethanol that the black out reaction adds is 14: 1 with the ratio of DIC, and the reaction times is 20 hours.Prior art adopts the method that adds ice block cooling in reaction, but because the fusing point very high (about about 18 ℃) of DSMO itself, so after adding ice cube, DMSO self is frozen into piece easily, makes to filter difficulty more.By comparison, the present invention has adopted adding alcoholic acid method, its advantage is as follows: 1) because the favorable solubility of ethanol in DMSO, make the depression of the freezing point much of solution, thereby can be under lower temperature crystallization, reduce owing to the solubility with temperature of product reduces, so productive rate is greatly improved, and operation helps industrial applications more; 2) owing to product decomposes in water easily, and more stable in ethanol, all can be more favourable to the quality and the productive rate of product; 3) product is far smaller than solubleness in water in alcoholic acid solubleness, so product is more abundant separates out; 4), make the residual very little of DMSO, and ethanol makes the quality of product be greatly improved than the easier drying of water because the good mutual solubility of ethanol and DMSO.In addition, the proportioning of having carried out charging capacity changes experiment, from mol ratio (DIC/MIC) 1～2, finds that still reaction in 1: 2 is for good, and productive rate and product quality are better.
In the step 4, use the DMSO recrystallization, the method for 2 times of washing with alcohol obtains the pure white solid.If add the solid of separating out from ethanol and DMSO mother liquor, productive rate has improved the productive rate of product widely more than 90%.
Embodiment
The present invention is further illustrated below in conjunction with Comparative Examples and embodiment, and following this embodiment only is used to the present invention is described and to the present invention without limits.
The existing method of Comparative Examples prepares Temozolomide
1. diazonium salt is synthetic: in the triangular flask that agitator, dropping funnel are housed; add 37.92g (0.55mol) Sodium Nitrite; 400ml distilled water; stir dissolving Sodium Nitrite down; solution is cooled to 0～5 ℃; drip 39g4-amino-5-formamyl imidazoles monohydrate, i.e. AIC.H from dropping funnel
2O is dissolved in the 360ml2.5N hydrochloric acid, dropwises half an hour approximately, and temperature of reaction is controlled between 0～5 ℃, keeps 2 hours.Stop to stir, suction filtration gets filter cake, and filter cake washes with water, and drying gets the 26g finished product, and yield is 75.3%.
2. methyl isocyanate is synthetic: in the triangular flask that prolong, agitator, dropping funnel are housed, add 100g (1.07mol) methylamino formyl chloride, drip triethylamine 120ml under the cooling and stirring, finish, heating, and change condensing works into rectifier unit, the cut that rectifying is 37～45 ℃ in this rectifying, is collected 39～40 ℃ cut, get 25ml, yield is 41.6%.
3. ring-closure reaction: in the triangular flask that agitator, dropping funnel are housed, add 4-formamyl-5-diazo imidazoles 1.4g (diazonium salt), 15mlDMSO; be cooled to 5-10 ℃; stir adding 1.4g methyl isocyanate down, added in about 15 minutes, reaction is 5 hours under the room temperature.Add the 20g trash ice, after treating all to melt, suction filtration, frozen water are washed and are dripped twice, and the products obtained therefrom decompression is dry down, 1.7g, yield is 87%.
4. Temozolomide is refining: add the Temozolomide crude product 20g of step 3 gained in the round-bottomed flask of 250ml, 100mlDSMO is warming up to 90 ℃, is stirred to whole dissolvings, cooling, and suction filtration, filter cake get solid 15.2g, yield 76% 40 ℃ of following vacuum-dryings.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Embodiment 1
1. diazonium salt is synthetic: add 75gNaNO in the 3L there-necked flask
2With 1000ml water stirring and dissolving, and wash bottleneck with 500ml.Ice bath is cooled to 0 ℃, and the dense HCl and the 95ml water that take by weighing 192ml (36.5%) are made into the 2N hydrochloric acid soln.Take by weighing 144.1g 4-amino-5-formamyl imidazoles monohydrate (AIC) and be dissolved in 2N hydrochloric acid.The 2N hydrochloric acid solution of the AIC of gained is added dropwise to NaNO
2The aqueous solution in, temperature is about 0～2 ℃.Dripped off in about 40 minutes.Dropwise, filter, washing with alcohol, 3 times, each 300ml drains.Light yellow solid vacuum drying with obtaining, spends the night by 50 ℃.Obtain light yellow solid 124g, productive rate 90.5%.
2. methyl isocyanate is synthetic: take by weighing the 100g Methylaminoformyl chloride in the 500mL four-hole bottle, add toluene 80mL stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene (150mL triethylamine/100mL toluene) solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets 40.7g, productive rate 66.69%.
3. ring-closure reaction: charge to 13.7g methyl isocyanate (DIC) in the 500ml single port bottle, add 148mlDMSO, induction stirring.Under the water-bath, drip 11.4g (12ml) MIC.The black out reaction is 20 hours under the room temperature.Add 196ml ethanol to system ,-15～-19 ℃ of stir abouts three hours.The suction filtration washing with alcohol, 4 times, each 50ml drains.Weigh: 17.68g; Productive rate: 91.05%.
4. Temozolomide is refining: add Temozolomide (Temo) and the 64mlDMSO that obtains in the 12.65g step 3 in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles.Mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence.Suction filtration, solid is drained with 2 * 64ml washing with alcohol.Weigh: 10.92g; Productive rate: 86.32%; Proterties: white powder.Mother liquor kept in cold storage under-15～-19 ℃ spend the night, analyse essence.Suction filtration, washing with alcohol 2 times, each 64ml drains.Weigh: 1.31g; Productive rate: 10.35%; Proterties: light salmon powder.Add up to productive rate: 96.67%.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Embodiment 2
1. diazonium salt is synthetic: add 75gNaNO in the 3L there-necked flask
2With 1000ml water stirring and dissolving, and wash bottleneck with 350ml.Ice bath is cooled to 0 ℃, and the dense HCl and the 95ml water that take by weighing 192ml (36.5%) are made into the 2N hydrochloric acid soln.Take by weighing 144.1g 4-amino-5-formamyl imidazoles monohydrate (AIC) and be dissolved in 2N hydrochloric acid.The 2N hydrochloric acid solution of the AIC of gained is added dropwise to NaNO
2The aqueous solution in, temperature is about 0～2 ℃.Dripped off in about 35 minutes.Dropwise, filter, washing with alcohol, 3 times, each 300ml drains.Light yellow solid vacuum drying with obtaining, spends the night by 50 ℃.Obtain light yellow solid 124g, productive rate 88.5%.
2. methyl isocyanate is synthetic: take by weighing the 100g Methylaminoformyl chloride in the 500mL four-hole bottle, add toluene 80mL stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene (150mL triethylamine/100mL toluene) solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets 40.7g, productive rate 66.88%.
3. ring-closure reaction: charge to 13.7g methyl isocyanate (DIC) in the 500ml single port bottle, add 148mlDMSO, induction stirring.Under the water-bath, drip 11.4g (12ml) MIC.The black out reaction is 20 hours under the room temperature.Add 196ml ethanol to system ,-15～-19 ℃ of stir abouts three hours.The suction filtration washing with alcohol, 4 times, each 50ml drains.Weigh: 17.68g; Productive rate: 91.11%.
4. Temozolomide is refining: add Temozolomide (Temo) and the 64mlDMSO that obtains in the 12.65g step 3 in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles.Mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence.Suction filtration, solid is drained with 2 * 64ml washing with alcohol.Weigh: 10.92g; Productive rate: 86.32%; Proterties: white powder.Mother liquor kept in cold storage under-15～-19 ℃ spend the night, analyse essence.Suction filtration, washing with alcohol 2 times, each 64ml drains.Weigh: 1.31g; Productive rate: 10.35%; Proterties: light salmon powder.Add up to productive rate: 96.38%.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Embodiment 3
1. diazonium salt is synthetic: add 75gNaNO in the 3L there-necked flask
2With 1000ml water stirring and dissolving, and wash bottleneck with 500ml.Ice bath is cooled to 0 ℃, gets the hydrochloric acid soln of 2N concentration.Take by weighing 144.1g 4-amino-5-formamyl imidazoles monohydrate (AIC) and be dissolved in 2N hydrochloric acid.The 2N hydrochloric acid solution of the AIC of gained is added dropwise to NaNO
2The aqueous solution in, temperature is about 0～2 ℃.Dripped off in about 30 minutes.Dropwise, filter, washing with alcohol, 3 times, each 300ml drains.Light yellow solid vacuum drying with obtaining, spends the night by 50 ℃.Obtain light yellow solid 124g, productive rate 89.7%.
2. methyl isocyanate is synthetic: take by weighing the 100g Methylaminoformyl chloride in the 500mL four-hole bottle, add toluene 70mL stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene (150mL triethylamine/90mL toluene) solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets 40.7g, productive rate 68%.
3. ring-closure reaction: charge to 13.7g methyl isocyanate (DIC) in the 500ml single port bottle, add 148mlDMSO, induction stirring.Under the water-bath, drip 11.4g (12ml) MIC.The black out reaction is 20 hours under the room temperature.Add 196ml ethanol to system ,-15～-19 ℃ of stir abouts three hours.The suction filtration washing with alcohol, 4 times, each 50ml drains.Weigh: 17.68g; Productive rate: 88%.
4. Temozolomide is refining: add Temozolomide (Temo) and the 64mlDMSO that obtains in the 12.65g step 3 in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles.Mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence.Suction filtration, solid is drained with 2 * 64ml washing with alcohol.Weigh: 10.92g; Productive rate: 86.32%; Proterties: white powder.Mother liquor kept in cold storage under-15～-19 ℃ spend the night, analyse essence.Suction filtration, washing with alcohol 2 times, each 64ml drains.Weigh: 1.31g; Productive rate: 10.35%; Proterties: light salmon powder.Add up to productive rate: 88%.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Embodiment 4
1. diazonium salt is synthetic: add 75gNaNO in the 3L there-necked flask
2With 1000ml water stirring and dissolving, and wash bottleneck with 650ml.Ice bath is cooled to 0 ℃, and the dense HCl and the 95ml water that take by weighing 192ml (36.5%) are made into the 2N hydrochloric acid soln.Take by weighing 144.1g 4-amino-5-formamyl imidazoles monohydrate (AIC) and be dissolved in 2N hydrochloric acid.The 2N hydrochloric acid solution of the AIC of gained is added dropwise to NaNO
2The aqueous solution in, temperature is about 0～2 ℃.Dripped off in about 45 minutes.Dropwise, filter, washing with alcohol, 3 times, each 300ml drains.Light yellow solid vacuum drying with obtaining, spends the night by 50 ℃.Obtain light yellow solid 124g, productive rate 87.5%.
2. methyl isocyanate is synthetic: take by weighing the 100g Methylaminoformyl chloride in the 500mL four-hole bottle, add toluene 80mL stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene (150mL triethylamine/100mL toluene) solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets 40.7g, productive rate 67.63%.
3. ring-closure reaction: charge to 13.7g methyl isocyanate (DIC) in the 500ml single port bottle, add 148mlDMSO, induction stirring.Under the water-bath, drip 11.4g (12ml) MIC.The black out reaction is 20 hours under the room temperature.Add 196ml ethanol to system ,-15～-19 ℃ of stir abouts three hours.The suction filtration washing with alcohol, 4 times, each 50ml drains.Weigh: 17.68g; Productive rate: 90.36%.
4. Temozolomide is refining: add Temozolomide (Temo) and the 64mlDMSO that obtains in the 12.65g step 3 in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles.Mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence.Suction filtration, solid is drained with 2 * 64ml washing with alcohol.Weigh: 10.92g; Productive rate: 85.36%; Proterties: white powder.Mother liquor kept in cold storage under-15～-19 ℃ spend the night, analyse essence.Suction filtration, washing with alcohol 2 times, each 64ml drains.Weigh: 1.31g; Productive rate: 10.35%; Proterties: light salmon powder.Add up to productive rate: 97.66%.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Embodiment 5
1. diazonium salt is synthetic: add 75gNaNO in the 3L there-necked flask
2With 1000ml water stirring and dissolving, and wash bottleneck with 500ml.Ice bath is cooled to 0 ℃, gets the hydrochloric acid soln of 2N concentration.Take by weighing 144.1g 4-amino-5-formamyl imidazoles monohydrate (AIC) and be dissolved in 2N hydrochloric acid.The 2N hydrochloric acid solution of the AIC of gained is added dropwise to NaNO
2The aqueous solution in, temperature is about 0～2 ℃.Dripped off in about 30 minutes.Dropwise, filter, washing with alcohol, 3 times, each 300ml drains.Light yellow solid vacuum drying with obtaining, spends the night by 50 ℃.Obtain light yellow solid 124g, productive rate 89.7%.
2. methyl isocyanate is synthetic: take by weighing the 100g Methylaminoformyl chloride in the 500mL four-hole bottle, add toluene 90ml stirring and dissolving, cool to 5 ℃, begin to drip triethylamine/toluene (150mL triethylamine/110mL toluene) solution, dripped off in about 2 hours, reacting balance carries out.39-40 ℃ cut is collected in the direct rectifying that begins then to heat up, and gets 40.9g, productive rate 68%.
3. ring-closure reaction: charge to 13.7g methyl isocyanate (DIC) in the 500ml single port bottle, add 148mlDMSO, induction stirring.Under the water-bath, drip 11.4g (12ml) MIC.The black out reaction is 20 hours under the room temperature.Add 196ml ethanol to system ,-15～-19 ℃ of stir abouts three hours.The suction filtration washing with alcohol, 4 times, each 50ml drains.Weigh: 17.68g; Productive rate: 88%.
4. Temozolomide is refining: add Temozolomide (Temo) and the 64mlDMSO that obtains in the 12.65g step 3 in the 250ml there-necked flask, stir evenly.Heating in water bath to 90 ℃, treat basic dissolving after, filtered while hot is removed insolubles.Mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, analysed essence.Suction filtration, solid is drained with 2 * 64ml washing with alcohol.Weigh: 10.92g; Productive rate: 86.32%; Proterties: white powder.Mother liquor kept in cold storage under-15～-19 ℃ spend the night, analyse essence.Suction filtration, washing with alcohol 2 times, each 64ml drains.Weigh: 1.31g; Productive rate: 10.35%; Proterties: light salmon powder.Add up to productive rate: 88%.
Product description: this product is an off-white powder, and UV scanning is presented at 254.9 has maximum absorption with the wavelength place of 330.0nm, with the wavelength place of 279.9nm minimal absorption is arranged 240.0, and the dry product assay is with C
6H
6N
6O
2Count 99.1%, up to specification.
Claims (8)
1. the preparation method of a Temozolomide comprises the following steps:
A. diazonium salt is synthetic: Sodium Nitrite and water stirring and dissolving, ratio are 1: 18～22 (g/ml); The ice bath cooling is got 4-amino-5-formamyl imidazoles and is dissolved in the 2N hydrochloric acid; The 2N hydrochloric acid solution of the 4-amino-5-formamyl imidazoles of gained is added dropwise in the aqueous solution of above-mentioned Sodium Nitrite, under the certain temperature, filters, ethanol is washed, and dries, and obtains light yellow solid;
B. methyl isocyanate is synthetic: get a certain amount of Methylaminoformyl chloride and be dissolved in the toluene, and stirring and dissolving, cooling begins to drip triethylamine/toluene solution, drips off in 2 hours, and 39-40 ℃ cut is collected in the direct rectifying that heats up, and gets methyl isocyanate;
C. the preparation of Temozolomide: with methyl isocyanate, add in the dimethyl sulfoxide (DMSO), induction stirring under the water-bath, drips diazonium salt, and the black out reaction adds ethanol under the room temperature, and-15～-19 ℃ of stirrings, the suction filtration washing with alcohol is drained, and gets product;
D. Temozolomide is refining: Temozolomide is dissolved in the dimethyl sulfoxide (DMSO), stirs evenly, and heating in water bath, after waiting to dissolve, filtered while hot is removed insolubles, and mother liquor stirred 1 hour, naturally cooled to 18～10 ℃, crystallization, suction filtration, the solid washing with alcohol is drained; Mother liquor kept in cold storage spends the night, crystallization, suction filtration is used washing with alcohol, drain, the Temozolomide highly finished product.
2. the described method of claim 1, wherein the ratio of Sodium Nitrite described in the step a and water is 1: 20 (g/ml).
3. the described method of claim 1, wherein the reaction times of the diazonium salt described in the step a is 35-45 minute.
4. the described method of claim 3, the reaction times of wherein said diazonium salt is 40 minutes.
5. the described method of claim 1, wherein the ratio of Methylaminoformyl chloride described in the step b and toluene is 100: 70-90 (g/ml).
6. the described method of claim 5, the Methylaminoformyl chloride wherein and the ratio of toluene are 100: 80 (g/ml).
7. the described method of claim 1, wherein the ratio of triethylamine described in the step b and toluene is 150: 90～110 (ml/ml).
8. the described method of claim 7, the triethylamine wherein and the ratio of toluene are 150: 100 (ml/ml).
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| CN102070639B (en) * | 2010-12-21 | 2012-10-10 | 中南大学 | Method for synthesizing temozolomide |
| CN102659789B (en) * | 2011-04-27 | 2014-10-15 | 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 |
| CN102329319B (en) * | 2011-07-19 | 2014-01-15 | 江苏奥赛康药业股份有限公司 | Novel crystal form for temozolomide, method for preparing temozolomide and medicinal composition of temozolomide |
| RU2669777C2 (en) * | 2013-10-29 | 2018-10-16 | Цзянсу Тасли Дии Фармасьютикал Ко., Лтд. | Crystalline forms of temozolomide and method for preparing same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260291A (en) * | 1981-08-24 | 1993-11-09 | Cancer Research Campaign Technology Limited | Tetrazine derivatives |
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260291A (en) * | 1981-08-24 | 1993-11-09 | Cancer Research Campaign Technology Limited | Tetrazine derivatives |
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
Non-Patent Citations (4)
| Title |
|---|
| Antitumor Imidazotetrazines. 35. New Synthetic Routes to theAntitumor Drug Temozolomide. Wang, Yongfeng et al.Journal of Organic Chemistry,Vol.62 No.21. 1997 |
| Antitumor Imidazotetrazines. 35. New Synthetic Routes to theAntitumor Drug Temozolomide. Wang, Yongfeng et al.Journal of Organic Chemistry,Vol.62 No.21. 1997 * |
| Synthetic studies of8-carbamoylimidazo-[5,1-D]-1,2,3,5-tetrazin-4(3H)-one: a keyderivative of antitumor drug temozolomide. Wang, Yongfeng et al.Bioorg. Med. Chem. Lett,Vol.6 No.2. 1996 |
| Synthetic studies of8-carbamoylimidazo-[5,1-D]-1,2,3,5-tetrazin-4(3H)-one: a keyderivative of antitumor drug temozolomide. Wang, Yongfeng et al.Bioorg. Med. Chem. Lett,Vol.6 No.2. 1996 * |
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