CN103373963B - Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride - Google Patents
Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride Download PDFInfo
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- CN103373963B CN103373963B CN201210131002.5A CN201210131002A CN103373963B CN 103373963 B CN103373963 B CN 103373963B CN 201210131002 A CN201210131002 A CN 201210131002A CN 103373963 B CN103373963 B CN 103373963B
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- ZHUNJVCQJTVITO-UHFFFAOYSA-N Cc1c(ccc(N=C)c2)c2n[n]1C Chemical compound Cc1c(ccc(N=C)c2)c2n[n]1C ZHUNJVCQJTVITO-UHFFFAOYSA-N 0.000 description 2
- JTKWSKSSIYFOAA-UHFFFAOYSA-N Cc1c(ccc(NC)c2)c2n[n]1C Chemical compound Cc1c(ccc(NC)c2)c2n[n]1C JTKWSKSSIYFOAA-UHFFFAOYSA-N 0.000 description 2
- 0 C*C(C)=C(C=CC(NC)=C1)C1=N Chemical compound C*C(C)=C(C=CC(NC)=C1)C1=N 0.000 description 1
- DVGMRZQSSNNTFY-UHFFFAOYSA-N Cc1c(ccc(N(C)c2nc(Cl)ncc2)c2)c2n[n]1C Chemical compound Cc1c(ccc(N(C)c2nc(Cl)ncc2)c2)c2n[n]1C DVGMRZQSSNNTFY-UHFFFAOYSA-N 0.000 description 1
- PVNVSSNARYHLRF-UHFFFAOYSA-N Cc1c(ccc(N)c2)c2n[n]1C Chemical compound Cc1c(ccc(N)c2)c2n[n]1C PVNVSSNARYHLRF-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N Clc1ccnc(Cl)n1 Chemical compound Clc1ccnc(Cl)n1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an intermediate compound of pazopanib hydrochloride and a preparation method of the intermediate compound of the pazopanib hydrochloride. The preparation method in which intermediates III and IIIa are used can be used for preparing a key intermediate (2,3-dimethyl-N-(2-chloropyrimidine-4-base)-N-methyl-2H-indazole-6-amine) of pazopanib hydrochloride. According to the preparation method, raw materials are low in price and easy to obtain, and the preparation method is convenient to operate, high in product yield and suitable for industrial large-scale production.
Description
Technical field
The present invention's intermediate being specifically related to pazopanib hydrochloride and preparation method thereof.
Background technology
Pazopanib hydrochloride, namely chemistry 5-by name [[4-[(2,3-dimethyl-2H-indazole-6-base) methylamino] pyrimidine-2-base] is amino]-2-Methyl benzenesulfonyl amine hydrochlorate, is s-generation Mutiple Targets tyrosinase inhibitor.Researched and developed by GlaxoSmithKline company of Britain, obtain U.S. FDA approval listing in October, 2009, be clinically used for the treatment of advanced renal cell cancer.2,3-dimethyl N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine is the key intermediate of preparation pazopanib hydrochloride, itself and the condensation of 2-methyl-5-aminobenzene sulfonamide, salify pazopanib hydrochloride.
Patent WO02059110, WO03106416, WO2007064752, WO2009062658 describe and are prepared such as formula the compound shown in I by formula II, and the method can illustrate with route below:
In second step reaction, method disclosed in document and patent is with methyl iodide as N methylating reagent, and in a large amount of production, methyl iodide has certain danger and lower operability, but also employs expensive cesium carbonate.
Summary of the invention
Technical problem to be solved by this invention there is provided a kind of with diverse intermediate for the preparation of pazopanib hydrochloride of prior art and preparation method thereof.The preparation method that intermediate III of the present invention and IIIa participate in can be used for the key intermediate 2 preparing pazopanib hydrochloride, 3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine, and the method raw material is cheap and easy to get, easy to operate, product yield is high, is suitable for industrialization scale operation.
The invention provides intermediate compound III or the IIIa of pazopanib hydrochloride,
Present invention also offers the preparation method of the intermediate compound III of above-mentioned pazopanib hydrochloride, it comprises the following step:
Step (1): in protic solvent, under alkali-metal effect, carries out condensation reaction as follows by Compound II per and paraformaldehyde;
Step (2): the material obtain step (1) and reductive agent carry out reduction reaction;
In step (1), preferably, after basic metal is dissolved in protic solvent entirely, add Compound II per, then add paraformaldehyde and carry out condensation reaction.
In step (1), described protic solvent is preferably one or more in methyl alcohol, ethanol, Virahol and butanols, and better is methyl alcohol and/or ethanol.The volume mass of protic solvent and Compound II per is 5 ~ 50ml/g than preferably.Described basic metal is preferably one or more in sodium, potassium and magnesium.The mol ratio of basic metal and Compound II per is preferably 1: 1 ~ 20: 1, and better is 1: 1 ~ 6: 1.Described paraformaldehyde can paraformaldehyde protic solvent suspension liquid form participate in reaction, described in the definition ditto of this protic solvent, but in use, concrete kind can be different from the concrete kind of aforesaid protic solvent.The mol ratio of paraformaldehyde and Compound II per is preferably 1: 1 ~ 10: 1, and better is 1: 1 ~ 4: 1.The temperature of described condensation reaction is preferably 0 ~ 100 DEG C, and better is 20 ~ 50 DEG C.Time of described condensation reaction can till detection reaction completes, and being generally 0 ~ 10h, is preferably 3 ~ 8h.
In step (2), described reductive agent is preferably one or more in sodium borohydride, tetrahydrochysene lithium aluminium, ammonium formiate, formic acid and hydrogen, and better is sodium borohydride and/or tetrahydrochysene lithium aluminium.Described reductive agent and the mol ratio of Compound II per are preferably 0.1: 1 ~ 10: 1, and better is 1: 1 ~ 4: 1.The temperature of reduction reaction is preferably 0 ~ 100 DEG C, and better is 50 ~ 100 DEG C.Time of described reduction reaction can detection reaction completely till, being generally 0 ~ 10h, is preferably 1 ~ 5h.
In the present invention, described intermediate compound III, by the intermediate (2 of following method preparation such as formula the pazopanib hydrochloride shown in I, 3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine): in organic solvent, under the effect of alkali, by compound III and 2,4-dichloro pyrimidine carries out nucleophilic substitution reaction,, wherein, temperature of reaction is 0 ~ 160 DEG C;
Wherein, the method for described nucleophilic substitution reaction and condition all can this area this type of reaction ordinary method and condition, the present invention is following method and condition particularly preferably:
Described organic solvent is preferably methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, chloroform, DMF (N, dinethylformamide), one or more in DMSO (methyl-sulphoxide) and acetonitrile, the mixed solvent of better is ethanol and tetrahydrofuran (THF), or the mixed solvent of methyl alcohol and tetrahydrofuran (THF).The consumption of organic solvent is not particularly limited, and its volume mass with compound III is 5 ~ 50ml/g than preferably.
Described alkali is preferably one or more in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, pyridine, potassium tert.-butoxide, potassium tert.-butoxide and sodium hydrogen, and better is sodium bicarbonate and/or saleratus.Described alkali be preferably 0.1: 1 ~ 10: 1 with the mol ratio of compound III, better is 1: 1 ~ 4: 1.
2,4-described dichloro pyrimidines and the mol ratio of compound III are preferably 1: 1 ~ 10: 1, and better is 1: 1 ~ 6: 1.
Described temperature of reaction is preferably 50 ~ 100 DEG C.Reaction times of described formula III and 2,4-dichloro pyrimidine can detection reaction completely till, can be 1 ~ 30h, that better is 2 ~ 20h.
In the present invention, with compound III and IIIa for intermediate, the reaction scheme of preparation Compound I is preferably as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is:
(1) compound as shown in formula III and IIIa of the present invention is Late Cambrian and the intermediate of the antitumour drug pazopanib hydrochloride of synthesis.
(2) preparation 2 of intermediate compound III of the present invention and IIIa participation, the method of 3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine can avoid methyl iodide or the larger methyl-sulfate of toxicity, and the methylating reagent of some other high price, improve security and the operability of technique.
(3) what intermediate compound III of the present invention and IIIa participated in can be used for the key intermediate 2 preparing pazopanib hydrochloride, in the method for 3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine, raw material is cheap and easy to get, easy to operate, product yield is high, be suitable for industrial scale operation, the synthesis for pazopanib hydrochloride provides a new approach.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
The preparation of reference example Compound II per
2-ethyl-5-N-methyl-p-nitroaniline (2)
2-ethylaniline (24.2g, 0.2mol) adds in the vitriol oil (100ml).Be cooled to less than 0 DEG C, slowly drip nitrosonitric acid (18.6g, 0.3mol), drip complete stirring at room temperature 30min.Reaction solution pours in frozen water (1000ml), and the sodium hydroxide solution slowly adding 50% adjusts about pH to 8.Filter, filter cake sherwood oil recrystallization, obtains yellow needles solid 2 (26.6g, 80.1%), mp60-61 DEG C of (document
[6]: yield 60%, 61-62 DEG C).
1HNMR(400MHz，CDCl
3)δ：1.28(t，3H)，2.56(q，2H)，7.17(d，J＝8.0Hz，1H)，7.49(d，J＝2.0Hz，1H)，7.57(dd，J＝8.0、2.0Hz，1H)。MS(m/z)：189(M+Na)。
3-methyl-6-nitro-2H-indazole (3)
Under room temperature, Glacial acetic acid (100ml) solution of nitrite tert-butyl (25ml, 0.15mol) is dropped in glacial acetic acid (500ml) solution of 2 (25g, 0.15mol).Drip Bi Jixu stirring reaction 1h.After reaction terminates, reaction solution is concentrated into dry, gained solid is dissolved in ethyl acetate (250ml), saturated sodium bicarbonate aqueous solution (125ml × 3), saturated aqueous common salt (50ml) is used to wash successively, remove solvent under reduced pressure, obtain yellow solid 3 (25.5g, 95.7%).
Mp182.3-182.6 DEG C of (document
[4]: yield 98%, 180.9-181.4 DEG C).
1HNMR(400MHz，CDCl
3)δ：2.64(s，3H)，7.78(d，J＝8.8Hz，1H)，8.01(dd，J＝8.8、1.6Hz，1H)，8.38(d，J＝1.6Hz，1H)，10.22(s，1H)。MS(m/z)：176(M-H)。
2,3-dimethyl-6-nitro-2H-indazole (4)
3 (17.7g, 0.1mol) are suspended in 200ml toluene, at room temperature drip methyl-sulfate (16.4g, 0.13mol).Drip to finish and be heated to back flow reaction 4h.After reaction solution is cooled to room temperature, drips saturated sodium bicarbonate aqueous solution and adjust about pH to 8.Filter, filter cake toluene (10ml × 2) washing, dry yellow solid 4 (15.3g, 80.1%).
Mp182-183 DEG C of (document
[4]: 183.6-185.4 DEG C).
1HNMR(400MHz，CDCl
3)δ：2.67(s，3H)，4.17(s，3H)，7.63(d，J＝9.2Hz，1H)，7.83(dd，J＝9.2、2.0Hz，1H)，8.61(d，J＝2.0Hz，1H)。MS(m/z)：192(M+H)。
2,3-dimethyl-2H-indazole-6-amine (5)
4 (15.3,0.08mol) be suspended in 150ml methyl alcohol, add the Pd/C (1.53g) of 10%, logical hydrogen under atmospheric agitation, in 50 DEG C of reactions 2 hours, filters, filter residue methyl alcohol (10ml × 2) is washed, filtrate is concentrated into dry, obtains light tan solid (12.3g, 95.5%).Mp148-150 DEG C (document: 149-150 DEG C).
1HNMR(400MHz，CDCl
3)δ：2.49(s，3H)，3.72(br s，2H)，3.97(s，3H)，6.52(dd，J＝8.8、2.0Hz，1H)，7.71(d，J＝2.0Hz，1H)，7.33(d，J＝8.8Hz，1H)。MS(m/z)：184(M+Na)
Embodiment 1N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (3.6g, 0.156mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.5g, 82.8%), HPLC:99%.
mp 147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 2N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (7.2g, 0.313mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.6g, 84.6%), HPLC:99%.
mp 147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 3N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (6.1g, 0.156mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.4g, 81.0%), HPLC:99%.
mp 147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 4N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (12.2g, 0.313mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.5g, 82.8%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 5N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (3.6g, 0.156mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.4g, 81.0%), HPLC:99%.
mp 147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 6N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (7.2g, 0.313mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.4g, 81.0%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 7N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (6.1g, 0.156mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.2g, 77.3%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 8N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (7.2g, 0.313mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in methyl alcohol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds sodium borohydride (3.6g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.4g, 81.0%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 9N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (3.6g, 0.156mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds tetrahydrochysene lithium aluminium (3.5g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.2g, 77.3%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 10N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Sodium (3.6g, 0.156mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds tetrahydrochysene lithium aluminium (3.5g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.1g, 75.4%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 11N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (6.1g, 0.156mol) add in methyl alcohol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds tetrahydrochysene lithium aluminium (3.5g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.2g, 77.3%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 12N, 2,3-trimethylammonium-2H-indazole-6-amine (formula III)
Potassium (6.1g, 0.156mol) add in ethanol (50ml) in batches, reflux be stirred to entirely molten after add formula II (5g, 0.031mol), after continuing to stir 10min, pour into while hot in ethanol (50ml) suspension of paraformaldehyde (2.8g, 0.093mol).Stirring at room temperature, after 6 hours, adds tetrahydrochysene lithium aluminium (3.5g, 0.093mol) in batches, is heated to backflow 3 hours.Reaction is complete is cooled to room temperature, reaction solution is concentrated into dry, add ethyl acetate (50ml) and water (30ml), after being separated organic layer, aqueous layer with ethyl acetate (20ml × 2) extracts, and merges organic layer, ethyl acetate (35ml) recrystallization is used after removing solvent under reduced pressure, obtain off-white color solid (4.1g, 75.4%), HPLC:99%.
mp147-159℃。
1HNMR(400MHz，CDCl
3)δ：2.51(s，3H)，2.89(s，3H)，3.75(s，1H)，3.99(s，3H)，6.47(dd，J＝8.8、2.0Hz，1H)，6.55(d，J＝2.2Hz，1H)，7.31(d，J＝8.8Hz，1H)。MS(m/z)：176(M+H)。
Embodiment 132,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium bicarbonate (7.2g, 0.086mol) add in the mixed solution of THF (20ml) and dehydrated alcohol (80ml).Add 2,4-dichloro pyrimidine (12.8g, 0.086mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.7g, 81.6%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 142,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium bicarbonate (9.8g, 0.117mol) add in the mixed solution of THF (20ml) and dehydrated alcohol (80ml).Add 2,4-dichloro pyrimidine (25.6g, 0.172mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.7g, 81.6%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 152,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium bicarbonate (7.2g, 0.086mol) add in the mixed solution of THF (20ml) and anhydrous methanol (80ml).Add 2,4-dichloro pyrimidine (12.8g, 0.086mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.3g, 76.7%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 162,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium bicarbonate (9.8g, 0.117mol) add in the mixed solution of THF (20ml) and anhydrous methanol (80ml).Add 2,4-dichloro pyrimidine (25.6g, 0.172mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.3g, 76.7%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 172,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium carbonate (9.1g, 0.086mol) add in the mixed solution of THF (20ml) and dehydrated alcohol (80ml).Add 2,4-dichloro pyrimidine (12.8g, 0.086mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.6g, 80.4%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 182,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium carbonate (12.4g, 0.117mol) add in the mixed solution of THF (20ml) and anhydrous methanol (80ml).Add 2,4-dichloro pyrimidine (25.6g, 0.172mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.6g, 80.4%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 192,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium bicarbonate (7.2g, 0.086mol) add in the mixed solution of THF (20ml) and anhydrous methanol (80ml).Add 2,4-dichloro pyrimidine (12.8g, 0.086mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.2g, 75.5%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Embodiment 202,3-dimethyl-N-(2-chloropyrimide-4-base)-N-methyl-2H-indazole-6-amine (formula I)
Formula III (5g, 0.029mol) and sodium carbonate (12.4g, 0.117mol) add in the mixed solution of THF (20ml) and dehydrated alcohol (80ml).Add 2,4-dichloro pyrimidine (25.6g, 0.172mol) under room temperature, be heated to the 20h that refluxes.Reaction is complete is cooled to room temperature, and filter, filter cake dehydrated alcohol (20ml × 2) washs.Merging filtrate, is evaporated to the mixed solvent adding isopropyl ether (60ml) and toluene (30ml) after doing, stirring at room temperature 1h, filters, and obtains faint yellow solid 7 (6.2g, 75.5%), HPLC:99% after filtration cakes torrefaction.
mp173-175℃。
1HNMR(400MHz，DMSO-d6)δ：2.62(s，3H)，3.43(s，3H)，4.06(s，3H)，6.24(d，J＝6.0Hz，1H)，6.87(dd，J＝8.8、2.0Hz，1H)，7.49(d，J＝0.8Hz，1H)，7.31(dd，J＝8.8Hz、0.8Hz 1H)，7.93(d，J＝6.0Hz，1H)。MS(m/z)：288(M+H)。
Claims (10)
1. the intermediate compound III of pazopanib hydrochloride or an IIIa,
2. the preparation method of the intermediate compound III of pazopanib hydrochloride as claimed in claim 1, it comprises the following step:
Step (1): in protic solvent, under alkali-metal effect, carries out condensation reaction as follows by Compound II per and paraformaldehyde;
Step (2): the material obtain step (1) and reductive agent carry out reduction reaction;
3. preparation method as claimed in claim 2, is characterized in that: in step (1), after basic metal is dissolved in protic solvent entirely, add Compound II per, then adds paraformaldehyde and carry out condensation reaction.
4. preparation method as claimed in claim 2, is characterized in that: in step (1), and described protic solvent is one or more in methyl alcohol, ethanol, Virahol and butanols.
5. preparation method as claimed in claim 2, it is characterized in that: in step (1), described basic metal is sodium and/or potassium; The mol ratio of basic metal and Compound II per is 1:1 ~ 20:1.
6. preparation method as claimed in claim 2, is characterized in that: described paraformaldehyde participates in reaction with the suspension liquid form of the protic solvent of paraformaldehyde.
7. preparation method as claimed in claim 2, is characterized in that: described paraformaldehyde and the mol ratio of Compound II per are 1:1 ~ 10:1.
8. preparation method as claimed in claim 2, is characterized in that: the temperature of described condensation reaction is 0 ~ 100 DEG C.
9. preparation method as claimed in claim 2, is characterized in that: in step (2), and described reductive agent is one or more in sodium borohydride, tetrahydrochysene lithium aluminium, ammonium formiate, formic acid and hydrogen; Described reductive agent and the mol ratio of Compound II per are 0.1:1 ~ 10:1.
10. preparation method as claimed in claim 2, it is characterized in that: in step (2), the temperature of described reduction reaction is 0 ~ 100 DEG C.
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| WO2011050159A1 (en) * | 2009-10-23 | 2011-04-28 | Glaxo Wellcome Manufacturing Pte Ltd | Compositions and processes |
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| Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor;Philip A. Harris et al;《Journal of Medicinal Chemistry 》;20080712;第51卷;4632-4640 * |
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