CN1594297A - Process for synthesis of lonidamine - Google Patents
Process for synthesis of lonidamine Download PDFInfo
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- CN1594297A CN1594297A CN 200410041067 CN200410041067A CN1594297A CN 1594297 A CN1594297 A CN 1594297A CN 200410041067 CN200410041067 CN 200410041067 CN 200410041067 A CN200410041067 A CN 200410041067A CN 1594297 A CN1594297 A CN 1594297A
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- indazole
- lonidamine
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Abstract
The invention relates to a process for synthesizing 1-[(2,4-dichlorobenzene) methyl]-1H-indazole-3-carboxyl acid which consists of, using phenylhydrazine as starting raw material, producing beta-acetylphenylhydrazine through reaction with glacial acetic acid, reacting with hydrated chloral and hydroxylamine hydrochloride, obtaining N-acetamido-isonitro-acetanilide, preparing 1H-indazole-3-carboxylic acid under the condition of concentrated sulfuric acid, finally subjecting 1H-indazole-3-carboxylic acid with 2,4-dichlorin benzyl chloride.
Description
Technical field
The present invention relates to a kind of 1-[(2, the 4-dichlorophenyl) methyl]-1H-indazole-3-carboxylic acid is the synthetic method of lonidamine.
Background technology
Cancer is that current serious influences human health, threatens one of principal disease of human life; It constitutes world today's All Countries three big dead reasons with cardiovascular and cerebrovascular and mishap.Therefore, the World Health Organization and hygiene department of national governments classify capture cancer as a top priority as.Lonidamine (lonidamine) is the dichlorobenzene derivative of indazole acid, is used for the treatment of kinds of tumors, comprise, and colorectal carcinoma, lung cancer, mammary cancer, prostate cancer and kidney, chronic lymphocytic leukemia, and as the sensitizer of chemotherapy, thermotherapy, radiotherapy.At present, it is synthetic for existing one piece of patent and many pieces of bibliographical informations, and these literature methods final step basically all adopt following reaction scheme, i.e. 1H-indazole-3-carboxylic acid and 2,4-dichlorobenzyl chloride react lonidamine, reaction equation is as follows:
And the synthetic route of at present common 1H-indazole-3-carboxylic acid is to be starting raw material with the istain, hydrolysis under the NaOH existence condition, then with Sodium Nitrite react diazenium compound, again with tin protochloride react 1H-indazole-3-carboxylic acid, its reaction equation is as follows:
Above-mentioned route complex process, agents useful for same are relatively expensive, thereby cause the complex manufacturing of whole lonidamine, become.This is higher.
Summary of the invention
The technical problem to be solved in the present invention is exactly the problem that present lonidamine complex manufacturing, cost are asked.
For solving the problems of the technologies described above, the present invention adopts following simple relatively synthesis technique:
With the phenylhydrazine is starting raw material, generate β-pyrodin with the glacial acetic acid reaction, again with Chloral Hydrate, oxammonium hydrochloride react the different nitrous Acetanilide of N-kharophen, cyclization gets 1H-indazole-3-carboxylic acid under vitriol oil condition again, be about to most 1H-indazole-3-carboxylic acid and 2, the 4-dichlorobenzyl chloride react lonidamine, the reaction equation of whole technology is as follows:
Its concrete reactions steps is as follows:
1, β-pyrodin (I) is synthetic
Charging capacity (mol ratio):
| Phenylhydrazine | Glacial acetic acid |
| 1 part | 1-3 part |
In reaction flask, add the solution that phenylhydrazine and Glacial acetic acid and 200ml water are made into.Be warming up to backflow, stirred 1-10 hour, be cooled to 10-40 ℃ then.Separate out solid, filter, washing, drying gets off-white color crystal I 129 grams.Yield 78.2%
2, N-ethanoyl isonitroso Acetanilide (II) is synthetic
Charging capacity (mol ratio):
| ????I | Oxammonium hydrochloride | Chloral Hydrate |
| 1 part | 1-4 part | 1-3 part |
In reaction flask, add I, water 5000ml, concentration is 36% concentrated hydrochloric acid 100ml, oxammonium hydrochloride, anhydrous sodium sulphate 1000 grams, Chloral Hydrate.Be warming up to 60--120 ℃.Insulated and stirred 0.3-5 hour.Be rapidly heated to 80-150 ℃, stirred 0.5-50 minute, be cooled to 30--80 ℃ rapidly, the adding activated carbon decolorizing stirs, quick elimination oily matter, and the freezing yellow solid of separating out filters, washing, drying gets II 190.4.Yield 85%.mp：134-136℃
3, indazole-3-carboxylic acid (III) is synthetic
Charging capacity (mol ratio):
| ????II | The vitriol oil |
| 1 part | 1-50 part |
Adding concentration is 98% the vitriol oil in three-necked bottle, is warming up to 30-100 ℃, repeatedly adds II in reaction flask on a small quantity, adds and slowly is warming up to 60-150 ℃, stirs 5-50 minute, is cooled to room temperature.
Other gets beaker, adds 3000 gram trash ices, and above-mentioned reaction solution is slowly poured into wherein, stir fast simultaneously, treat that ice cube melts, and goes to it in three-necked bottle, stirring is warming up to backflow, reacts 1-8 hour, is chilled to room temperature then, separate out yellow solid, filter washing, drying, get III 118.8 grams, yield 77.6%.mp：263-269℃
4, lonidamine (IV) is synthetic
Charging capacity (mol ratio):
| ??III | Sodium hydroxide | 2, the 4-dichlorobenzyl chloride |
| 1 part | 1-5 part | 1-4 part |
In three-necked bottle, add entry 3000ml, sodium hydroxide, stirring makes molten entirely, adds III then, and heating makes molten entirely.Slowly splash into 2 at 80-130 ℃, the 4-dichlorobenzyl chloride drips off, keep 80-130 ℃ stirring reaction 2-6 hour, be cooled to room temperature, filter, wash, yellow solid, oven dry.The gained solid is added in the beaker, adds 1200ml water, stir down and drip dilute hydrochloric acid, regulate pH value to 2-5, be heated to 40-80 ℃, it is constant to 2-5 to regulate pH value, is cooled to room temperature, filters, be washed to neutrality, drying gets yellow solid lonidamine crude product IV 270.8g, yield 89.1%.
Make with extra care: add IV 135.4g in the flask, Glacial acetic acid 800ml, reflux makes molten entirely, and cooling adds the 4.5g gac, reflux 8-15min, filtered while hot, the filtrate cooling crystallization filters, and drying gets light yellow solid 110.5g, yield 84.5%; This solid is placed the 1L flask to add the 352ml Glacial acetic acid again, repeat above-mentioned steps, getting the off-white color solid is lonidamine finished product 91.7g, yield 83.0%.
Preparing by I in the process of II, prior art adopts carries out handling the method that obtains product again behind the vacuum concentration to reaction solution, we directly obtain product with activated carbon decolorizing, recrystallization to reaction solution without concentrating, reduced the required plant and instrument of vacuum, yield brings up to 85% by 79% of bibliographical information; Preparing in the process of III by II, need not directly to be chilled to room temperature and obtain the high product of content from reaction solution through the aftertreatment that Glacial acetic acid carries out recrystallization; Prepared by III in the lonidamine process, we search out best pH value with the dilute hydrochloric acid aftertreatment time, thereby make the crude product of gained need not to carry out aftertreatment can directly obtain meeting quality standard with the Glacial acetic acid purifying lonidamine with NaOH.Whole technology has obtained best optimization, thereby operation is simpler, the reaction safety and reliability, and the cycle is shorter, and yield is higher, and cost is lower, and does not have serious three-waste pollution, is convenient to suitability for industrialized production.
The present invention raw materials used as: phenylhydrazine, Glacial acetic acid, concentrated hydrochloric acid, the vitriol oil, sodium hydroxide, all available technical grade reagent such as ethanol, gac etc.React safe and reliable, products obtained therefrom simple to operate is through mass spectrum, nucleus magnetic resonance, and infrared spectra, ultimate analysis conclusive evidence structure is errorless.
| Mass spectrum (MS) | 321(M +) | ||
| Infrared spectra (IR) (KBr, cm -1) | νo-H，3150-2500；νC＝O，1682；νO-c，1247； νc-H3099，835，881，750；νc-N，1178；νC＝C，750 | ||
| Nucleus magnetic resonance ( 1H?NMR) ??(CD 3Cl，δ) | 13.20(s，1H，-COOH)；8.19，8.16(d，1H，-H4)；7.85， 7.83(d，1H，-H7)；7.69，7.68(d，1H，-H10)；7.54～7.49 (m，1H，-H6)；7.41～7.34(m，2H，-H12，H5)；7.00，6.97(d， 1H，-H13)；5.87(s，1H，-H8) | ||
| Ultimate analysis | Calculated value | Measured value | |
| ????C％ | ????56.10 | ????55.81 | |
| ????H％ | ????3.14 | ????3.31 | |
| ????N％ | ????8.72 | ????8.33 | |
The organic solvent Glacial acetic acid that experimentation is used, ethanol etc. are treated can recovery set usefulness, reduces cost; Waste residue, useless siccative can be through the incinerator burning disposal after storing classifiedly, and waste water solution to neutrality, enters unified processing the in the sewage lagoon through acid-base neutralisation, discharge after reaching emission standard, and environmental pollution reduces greatly.
Embodiment
1, β-pyrodin (I) is synthetic
In the three-necked bottle of 2L, add the solution that phenylhydrazine 265g (2.5mol) and 600ml (10.5mol) Glacial acetic acid and 350ml water are made into.Be warming up to backflow, stirred 3 hours, be cooled to room temperature then.Separate out solid, filter, washing, drying gets off-white color crystal I 290 grams.Yield 78.2%.mp：127.5-129.5℃
2, N-ethanoyl isonitroso Acetanilide (II) is synthetic
In the three-necked bottle of 3L, add I 76g (0.51mol), water 2300ml, concentrated hydrochloric acid 27ml, oxammonium hydrochloride 69 grams (0.9mol), anhydrous sodium sulphate 367 grams, Chloral Hydrate 157 grams (0.96mol).Be warming up to 80--95 ℃.Insulated and stirred 0.4 hour.Be rapidly heated to 110 ℃, stirred 4 minutes, be cooled to 55-65 ℃ rapidly, add gac 5 and restrain the stirring of decolouring, quick elimination oily matter, the freezing yellow solid of separating out filters, and washes, and drying gets II 95.4 and restrains.Yield 85.0%.mp：134-136℃
3, indazole-3-carboxylic acid (III) is synthetic
In the three-necked bottle of 1L, add vitriol oil 405ml (7.59mol).Be warming up to 55 ℃, in reaction flask, repeatedly add II 105 grams (0.48mol) on a small quantity, add and slowly be warming up to 95 ℃, stirred 15 minutes, be cooled to room temperature.
Other gets the beaker of 5L, adds 1000 gram trash ices, and above-mentioned reaction solution is slowly poured into wherein, stir fast simultaneously, treat that ice cube melts, and goes to it in 3L three-necked bottle, stirring is warming up to backflow, reacts 2.5 hours, is chilled to room temperature then, separate out yellow solid, filter washing, drying, get III 59.4 grams, yield 77.6%.mp：263-269℃
4, lonidamine is synthetic
In the 2L three-necked bottle, add entry 1000ml, sodium hydroxide 114.4 gram (2.8mol) stirrings make molten entirely, add III 76g (0.56mol) then, and heating makes molten entirely.Slowly splash into 2 at 110 ℃, 4-dichlorobenzyl chloride 120.4g (0.6mol) drips off, and keeps 110 ℃ of stirring reactions 4.5 hours, is cooled to room temperature, filters, washes, gets yellow solid, oven dry.The gained solid is added in the 2L beaker, adds 500ml water, stir down and drip dilute hydrochloric acid, regulate pH value to 2, be heated to 50-65 ℃, it is constant to regulate pH value to 2, is cooled to room temperature, filters, be washed to neutrality, drying gets yellow solid lonidamine crude product IV 135.4g, yield 89.1%.
Product is refining:
In the 1L flask, add IV 67.0g, Glacial acetic acid 300ml, reflux makes molten entirely, and cooling adds the 2.5g gac, reflux 8min, filtered while hot, the filtrate cooling crystallization filters, and drying gets light yellow solid 55.05g, yield 84.3%; This solid is placed the 0.5L flask to add the 140ml Glacial acetic acid again, repeat above-mentioned steps, getting the off-white color solid is lonidamine finished product 45.7g, yield 83.1%.
Claims (2)
1, a kind of synthetic method of lonidamine, it is characterized in that it is starting raw material with the phenylhydrazine, generate β-pyrodin with the glacial acetic acid reaction, again with Chloral Hydrate, oxammonium hydrochloride react the different nitrous Acetanilide of N-kharophen, cyclization gets 1H-indazole-3-carboxylic acid under vitriol oil condition again, at last with 1H-indazole-3-carboxylic acid and 2, the 4-dichlorobenzyl chloride react lonidamine.
2, the synthetic method of lonidamine as claimed in claim 1 is characterized in that comprising following concrete steps:
(1) β-pyrodin is synthetic
With phenylhydrazine and Glacial acetic acid in molar ratio 1: the ratio of 1-3 is mixed with the aqueous solution, is warming up to backflow, stirs 1-10 hour, is cooled to 10-40 ℃ then, separates out solid, after filtration, washing, drying obtains β-pyrodin off-white color crystal;
(2) N-ethanoyl isonitroso Acetanilide is synthetic
With β-pyrodin, oxammonium hydrochloride, Chloral Hydrate in molar ratio 1: the mixed of 1-4: 1-3, add entry, concentrated hydrochloric acid and anhydrous sodium sulphate again, be warming up to 60--120 ℃, be rapidly heated after insulated and stirred 0.3-5 hour to 80-150 ℃, stirred 0.5-50 minute, be cooled to 30--80 ℃ rapidly, adding activated carbon decolorizing stirs, quick elimination oily matter, the freezing solid of separating out, more after filtration, washing, drying gets N-ethanoyl isonitroso Acetanilide yellow solid, mp:134-136 ℃;
(3) indazole-3-carboxylic acid is synthetic
The vitriol oil is warming up to 30-100 ℃, again in the mol ratio 1-50 of the vitriol oil: 1 ratio repeatedly adds N-ethanoyl isonitroso Acetanilide on a small quantity, slowly is warming up to 60-150 ℃ after adding, and stirs 5-50 minute, is cooled to room temperature; Above-mentioned reaction solution is slowly poured in the container that trash ice is housed, stirred fast, treat that ice cube melts, it is gone in the three-necked bottle, stir and be warming up to backflow, reacted 1-8 hour, and be chilled to room temperature then, separate out solid, filter, washing, drying gets yellow indazole-3-carboxylic acid, mp:263-269 ℃;
(4) lonidamine is synthetic
Get the sodium hydroxide of indazole-3-carboxylic acid, make it water-soluble, add indazole-3-carboxylic acid then, the mol ratio of indazole-3-carboxylic acid and sodium hydroxide concentration is 1: 1-5 slowly splashes into 2, the 4-dichlorobenzyl chloride again under 80-130 ℃, indazole-3-carboxylic acid and 2, the mol ratio of 4-dichlorobenzyl chloride consumption is 1: 1-4; After dripping off, keep 80-130 ℃ stirring reaction 2-6 hour, be cooled to room temperature, filter, wash, yellow solid, oven dry; The gained solid is added in the beaker, adds water, stir down and drip dilute hydrochloric acid, regulate pH value to 2-5, be heated to 40-80 ℃, it is constant to 2-5 to regulate pH value, is cooled to room temperature, filters, and is washed to neutrality, and drying promptly gets yellow solid lonidamine crude product;
(5) refining
Adding lonidamine crude product and Glacial acetic acid in the flask, reflux makes molten entirely, and the cooling back adds gac, and reflux 8-15 minute, filtered while hot, the filtrate cooling crystallization filters, and drying gets light yellow solid; Place flask to add Glacial acetic acid this solid again, repeat above-mentioned steps, promptly getting the off-white color solid is the lonidamine finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410041067 CN1245388C (en) | 2004-06-23 | 2004-06-23 | Process for synthesis of lonidamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410041067 CN1245388C (en) | 2004-06-23 | 2004-06-23 | Process for synthesis of lonidamine |
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| Publication Number | Publication Date |
|---|---|
| CN1594297A true CN1594297A (en) | 2005-03-16 |
| CN1245388C CN1245388C (en) | 2006-03-15 |
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|---|---|---|---|
| CN 200410041067 Active CN1245388C (en) | 2004-06-23 | 2004-06-23 | Process for synthesis of lonidamine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1915978B (en) * | 2005-08-17 | 2011-04-20 | 杭州民生药业有限公司 | Crystal form of lonidamine, preparation method, and composition of containing the crystal form |
| WO2011086031A1 (en) | 2010-01-12 | 2011-07-21 | F. Hoffmann-La Roche Ag | Methods for the preparation of indazole-3-carboxyclic acid and n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN101759644B (en) * | 2005-08-17 | 2011-11-02 | 杭州民生药业有限公司 | Crystalline form III of Lonidamine and preparation method thereof and composition containing same |
| CN101735151B (en) * | 2005-08-17 | 2012-07-04 | 杭州民生药业有限公司 | Crystalline form I of lonidamine, preparation method thereof and composite containing the same |
| CN103159679A (en) * | 2013-04-17 | 2013-06-19 | 盐城格瑞茵化工有限公司 | Synthetic method of anti-tumor medicament lonidamine |
| CN103497156A (en) * | 2013-09-18 | 2014-01-08 | 苏州岚云医药科技有限公司 | 1-N-substitution method of fused ring pyrazole compounds |
-
2004
- 2004-06-23 CN CN 200410041067 patent/CN1245388C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1915978B (en) * | 2005-08-17 | 2011-04-20 | 杭州民生药业有限公司 | Crystal form of lonidamine, preparation method, and composition of containing the crystal form |
| CN101759644B (en) * | 2005-08-17 | 2011-11-02 | 杭州民生药业有限公司 | Crystalline form III of Lonidamine and preparation method thereof and composition containing same |
| CN101735151B (en) * | 2005-08-17 | 2012-07-04 | 杭州民生药业有限公司 | Crystalline form I of lonidamine, preparation method thereof and composite containing the same |
| WO2011086031A1 (en) | 2010-01-12 | 2011-07-21 | F. Hoffmann-La Roche Ag | Methods for the preparation of indazole-3-carboxyclic acid and n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN103159679A (en) * | 2013-04-17 | 2013-06-19 | 盐城格瑞茵化工有限公司 | Synthetic method of anti-tumor medicament lonidamine |
| CN103497156A (en) * | 2013-09-18 | 2014-01-08 | 苏州岚云医药科技有限公司 | 1-N-substitution method of fused ring pyrazole compounds |
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|---|---|
| CN1245388C (en) | 2006-03-15 |
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