CN103626772B - A kind of Temozolomide and the synthetic method of intermediate - Google Patents
A kind of Temozolomide and the synthetic method of intermediate Download PDFInfo
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- CN103626772B CN103626772B CN201210303798.8A CN201210303798A CN103626772B CN 103626772 B CN103626772 B CN 103626772B CN 201210303798 A CN201210303798 A CN 201210303798A CN 103626772 B CN103626772 B CN 103626772B
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention improves optimization to the synthetic method of Temozolomide and intermediate thereof, particularly it is newly introduced oxidation cyclization reagent to react in aqueous with lithium chloride, natrium nitrosum, improve the productivity of reaction, add the controllability of reaction, thus avoid the use bigger methyl isocyanate of toxicity.
Description
Technical field
The present invention relates to the high efficiency synthetic method of a kind of antineoplastic Temozolomide.
Background technology
Temozolomide, chemical entitled 3-methyl-8-amino carbonyl-imidazo [5,1-d]-1,2,3,5-4 (3H)-one, be
A kind of newtype drug that glioma is had good therapeutic effect；There is bioavilability high, orally available, it is easy to through blood-brain barrier,
Do not superpose toxicity with other drug ratio, there is wider Antitumor test.At present, Temozolomide is preferably to treat glioma
Cancer therapy drug with malignant mela noma.
The conventional synthesis process of Temozolomide be from 5-amino-1H-imidazoles-4-formamide or its hydrochloride be raw material with sub-
Sodium nitrate reacts, through diazotising carry out with methyl isocyanate (MIC) again reacting prepared Temozolomide (see J.Med.Chem.,
1984,27,196-201 and Chem.Commun., 1994,1687-1688).But owing to MIC toxicity is relatively big and reaction condition is difficult to
Control, be difficult to transport, bring certain difficulty to producing.WO2008038031 uses lithium chloride, natrium nitrosum cyclization, keeps away
Exempt from the use of toxic agent methyl isocyanate, but reaction yield is the highest.Present invention introduces new oxidation cyclization reagent and chlorine
Change lithium, natrium nitrosum reacts in aqueous, improves the productivity of reaction, adds the controllability of reaction, thus i.e. keep away
Exempt from use methyl isocyanate (MIC) and improve again yield and the purity of end-product, reach applicable large-scale industry metaplasia
The purpose produced.
Summary of the invention
It is an object of the invention to provide that a kind of environmental protection, yield be high, purification process is simply easy to industrial for not azoles
Amine synthetic method.
The preferred embodiment of the inventive method is illustrated in following scheme, and the common form of the program is described in it
After, scheme I:
In the first step of the method, 5-aminoimidazole-4-carbozamide and p-nitrophenyl chloro-formate, at 0 DEG C, add
Enter triethylamine, react for solvent with dichloromethane, obtain intermediate 2；In post-processing stages, dichloromethane and water is used to mix
Close liquid (dichloromethane: water=5:1) making beating mode of washing and carry out post-processing the yield that not only can ensure that reaction, also can get pure
Spend higher intermediate 2.
Scheme II:
This reaction is in the presence of organic aprotic solvents, at ambient temperature or less than such as environment temperature under environment temperature
Being 0 DEG C, preferred ambient temperature is less than 0 DEG C and reacts, and the reaction time is 18 hours.Described organic aprotic solvents is preferred
Dichloromethane is organic solvent.But other organic solvent includes THF, acetonitrile, ethyl acetate and n-hexane.
Scheme III:
In shown in scheme III, the second step of the method, under described reaction normal temperature inert organic solvents such as THF,
DMF, DMA and dichloromethane or wherein both mixed solvent are carried out.Preferably, use THF molten at described reaction 25 DEG C
Agent is carried out.It is demonstrated experimentally that alcohols can react with intermediate 2, thus affect reaction yield.At J.Org.Chem.1997,
Describe the synthetic method of this compound in 62,7288-7294., but do not mention the concrete post-processing approach of this reaction.This
In invention, the post-processing approach to this reaction has been described in detail.
The present invention use methylamine water solution replace J.Org.Chem.1997,62,7288-7294. as aminating agent
Described in the methylamine alcohol solution that uses as the aminating agent of this reaction, thus improve the receipts that this step is reacted largely
Rate.Using ether and acetone mixture (ether: acetone=3:2), making beating washing 1 hour, suction filtration, filter cake acetone washs, and dries in the air
Do to obtain product.The method is simple to operate, and gained intermediate product purity is high, has reached to prepare in bulk drug as internal control intermediate
Requirement.
Scheme IV:
The preparation of Temozolomide is shown in scheme IV, and the synthesis of Temozolomide has been passed through the diazotising of intermediate 3 or carried out
Corresponding amino group cyclization is formed.In this reactions steps, the oxidative cyclization reagent being newly introduced, be conducive to the ring structure of reaction to enter
OK, make ring-closure reaction more abundant, thus increase the productivity of reaction, preferably meet industrial prospect.
Oxidation cyclization reagent can be I2、ICl、ICl3And H5IO6.Preferably dioxide giving reagent is I2.In the method,
Inert organic solvents is carried out, inert organic solvents more options non-protonic solvent such as DMF, THF, dioxane, acetonitrile, two
Chloromethanes, toluene.Preferably, described organic solvent is dichloromethane.Carrying out under 0 DEG C of-25 DEG C of proper temperature of described reaction.
Preferably, temperature is at 0 DEG C.
The invention has the advantages that:
(1) in scheme III, the synthesis of intermediate 3 uses methylamine water solution as aminating agent, thus carries largely
The yield of high this step reaction.
(2) during scheme IV synthesis end-product Temozolomide, by the oxidation cyclization reagent being newly introduced, ring is shortened
Close the reaction time, substantially increase the productivity of ring-closure reaction, the marketable material low cost involved by the method, course of reaction is grasped
Making simple, stable reaction is easy to control.
(3) whole technique avoids the methyl isocyanate (MIC) using toxicity bigger, and this process route is simple, productivity
Height, post-processes and refined easy, and end-product purity is higher, reaches 99.822%, preferably meets industrial requirement.
Accompanying drawing explanation
Fig. 1 is patent route map；
Fig. 2 is Temozolomide intermediate nucleus magnetic hydrogen spectrum spectrogram；
Fig. 3 is Temozolomide HPLC spectrogram.
Detailed description of the invention
Following example are used for illustrating the present invention, but limit the present invention the most in any form.
The preparation of embodiment 1 Temozolomide
The preparation of step A intermediate 2
To equipped with in the 5L three neck round bottom flask of thermometer, be sequentially added into 5-aminoimidazole-4-carbozamide A (80g,
634.32mmol), dichloromethane (1920mL), triethylamine (176.82mL, 1268.63mmol)), 25 DEG C stir 10 minutes,
The temperature of reaction system is down to less than 0 DEG C, after 10 minutes, the 4-nitrobenzophenone chloromethane that dropping is dissolved in 1280mL dichloromethane
Acid esters (255.71g, 1268.36mmol), below 0 DEG C, after reacting 4 hours, temperature control, at 25 DEG C, reacts 18 hours.
Reactant liquor is used Buchner funnel suction filtration, and the filter cake 1000mL dichloromethane obtained and the making beating washing 1 of 200ml water mixed liquid are little
Time, suction filtration again, filter cake dichloromethane washs, and dries, obtain yellow solid product under normal temperature.Productivity: 92%, fusing point: 200 DEG C
Decompose.
1H NMR (400MHz, DMSO, δ ppm): 6.54 (brs, 2H), 6.98 (brs, 1H), 7.10 (brs, 1H), 7.75
(d, J=9.22Hz, 2H), 7.85 (s, 1H), 8.39 (d, J=9.22Hz, 2H)；
The preparation of step B intermediate 3
In 50ml round-bottomed flask, it is sequentially added into intermediate 2 (30g, 103.02mmol), solvents tetrahydrofurane 240ml, stirs
After mixing 10 minutes, adding the methylamine alcohol solution (12.6mL, 103.02mmol) of 33% slowly, temperature controls at 25 DEG C, reacts 5
Hour.Reactant liquor is used Buchner funnel suction filtration, the filter cake 300mL ether obtained and 200ml acetone mixture washing (ether:
Acetone=3:2), stirring to pulp 1 hour, suction filtration filter cake acetone washs, and dries to obtain light yellow product, productivity: 87%, fusing point:
170 DEG C (decomposition).
1HNMR (400MHz, DMSO, δ ppm): 8.46 (1H, q, NH), 7.62 (1H, s, CH), 6.83 (1H, bs, NH),
6.39(2H,brs,NH2),2.78(3H,d,CH3).
The preparation of step C Temozolomide
Take 1L three neck round bottom flask, be sequentially added into a chloride hydrate lithium (373.03g, 6175mmol), glacial acetic acid in order
, and water (290ml) (29mL).At normal temperatures, stirring 30 minutes.Addition intermediate 3 (29g, 158.32mmol), at normal temperatures,
After stirring 30 minutes, being placed in coolant circulation pump by reaction bulb, control temperature is below 0 DEG C, after cooling down 10 minutes, drips nitrous
The aqueous solution (14.5g is dissolved in 58ml water) of acid sodium, controls temperature within-10～5 DEG C, by reaction mixture 0～5
Within DEG C, after stirring one hour, add I2(4.00g, 15.8mmol), after reacting 2 hours the most at normal temperatures, by sulphur generation
The aqueous solution (29g is dissolved in 290ml water) of sodium sulphate, after stirring 20 minutes, terminates reaction.Extract with 5L dichloromethane every time,
Extract 8～10 times, and by after extract filtration, concentrated by rotary evaporation reclaims solution, is concentrated into solvent about 100ml, is carrying out suction filtration
After obtain pink colour Temozolomide finished product, fusing point: 212 DEG C (decomposition).
1HNMR(400MHz,DMSO),δ:8.80(s,1H),7.80(brs,1H),7.66(brs,1H),3.43(s,3H)；
Temozolomide finished product is refined by thick for Temozolomide product acetone soln at normal temperatures, carries out making beating washing, washes
Washing 2～3 times, suction filtration obtains product, productivity: 76%, through liquid phase analysis purity 99.82%.
Claims (5)
1. a synthetic method for Temozolomide, comprises the following steps:
A, the synthesis of 5-aminoimidazole-4-carbozamide-1H-formic acid p-nitrophenyl ester: 5-aminoimidazole-4-carbozamide with to nitro
Phenyl Chloroformate 99, at 0 DEG C, adds triethylamine, reacts for solvent with dichloromethane, obtain 5-aminooimidazole-4-first
Acid amides-1H-formic acid p-nitrophenyl ester, in post-processing stages, have employed dichloromethane and water mixed liquid that volume ratio is 5:1, beats
Plasm scouring mode；
B, the synthesis of 5-aminoimidazole-4-carbozamide-1-azodicarbonamide: add 5-aminoimidazole-4-carbozamide-1H-formic acid pair
Nitro phenyl ester, solvents tetrahydrofurane, after stirring 10 minutes, add methylamine water solution slowly, temperature controls at 25 DEG C, reacts 5
Hour, reactant liquor is used Buchner funnel suction filtration, the filter cake ether obtained and acetone mixture washing, making beating washing 1 hour, take out
Filter, filter cake acetone washs, and dries to obtain light yellow product；
C, the synthesis of Temozolomide: by lithium chloride glacial acetic acid and water, at normal temperatures, stir 30 minutes, and addition 5-aminooimidazole-
4-formamide-1-azodicarbonamide, at normal temperatures, after stirring 30 minutes, control temperature is below 0 DEG C, after cooling down 10 minutes, dropping
The aqueous solution of natrium nitrosum, controls temperature within-10～10 DEG C in titration, by reaction mixture within 0～5 DEG C, stirs
After mixing one hour, add I2, react complete the most at normal temperatures, add the aqueous solution of sodium thiosulfate, after stirring 20 minutes,
Terminating reaction, extract with dichloromethane, and will concentrate after extract filtration drying, suction filtration obtains the thick product of Temozolomide；
D, Temozolomide refined: with acetone soln at normal temperatures, carrying out being sufficiently stirred for washing, suction filtration obtains product.
Method the most according to claim 1, wherein the ratio of the ether described in step b and acetone is 3:2.
Method the most according to claim 1, wherein the addition I described in step c2, the reaction time is 2 hours at normal temperatures.
Method the most according to claim 1, wherein the addition I described in step c2: the mol ratio of LiCl is 3:1～8:1.
Method the most according to claim 1, within being wherein preferably controlled in-10～5 DEG C by temperature in titration in step c.
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102550770B1 (en) * | 2016-12-20 | 2023-06-30 | 크리스탈리아 프로듀토스 퀴미코스 파르마세우티코스 엘티디에이 | Manufacturing process of temozolomide and intermediates |
| 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 |
| CN113493417B (en) * | 2020-03-22 | 2024-03-15 | 鲁南制药集团股份有限公司 | Temozolomide intermediate compound VII |
| CN113493458B (en) * | 2020-03-22 | 2024-03-15 | 鲁南制药集团股份有限公司 | Preparation method of temozolomide |
| CN113493418B (en) * | 2020-03-22 | 2024-03-15 | 鲁南制药集团股份有限公司 | Temozolomide intermediate compound IV |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
| WO2008038031A1 (en) * | 2006-09-29 | 2008-04-03 | Cipla Limited | An improved process for the preparation of temozolomide and analogs |
| EP2151442A2 (en) * | 2008-08-07 | 2010-02-10 | Chemi SPA | Process for preparing temozolomide |
| WO2010140168A1 (en) * | 2009-06-03 | 2010-12-09 | Ind-Swift Laboratories Limited | Improved process for preparing temozolomide |
-
2012
- 2012-08-24 CN CN201210303798.8A patent/CN103626772B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
| WO2008038031A1 (en) * | 2006-09-29 | 2008-04-03 | Cipla Limited | An improved process for the preparation of temozolomide and analogs |
| EP2151442A2 (en) * | 2008-08-07 | 2010-02-10 | Chemi SPA | Process for preparing temozolomide |
| WO2010140168A1 (en) * | 2009-06-03 | 2010-12-09 | Ind-Swift Laboratories Limited | Improved process for preparing temozolomide |
Non-Patent Citations (1)
| Title |
|---|
| Antitumor Imidazotetrazines. 35. New Synthetic Routes to the Antitumor Drug Temozolomide;Yongfeng Wang et al.;《J.Org.Chem》;19971231;第62卷;第7288-7294页 * |
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