CN102731373B - Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib) - Google Patents
Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib) Download PDFInfo
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- CN102731373B CN102731373B CN2012102497397A CN201210249739A CN102731373B CN 102731373 B CN102731373 B CN 102731373B CN 2012102497397 A CN2012102497397 A CN 2012102497397A CN 201210249739 A CN201210249739 A CN 201210249739A CN 102731373 B CN102731373 B CN 102731373B
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- CKQOYZZVGLARQG-UHFFFAOYSA-N CC(C)(C)OC(Nc(cc1)cc(-c2ncccc2)c1Cl)=O Chemical compound CC(C)(C)OC(Nc(cc1)cc(-c2ncccc2)c1Cl)=O CKQOYZZVGLARQG-UHFFFAOYSA-N 0.000 description 1
- QWVLHTCIAZPQAY-UHFFFAOYSA-N Nc(cc1)cc(-c2ncccc2)c1Cl Chemical compound Nc(cc1)cc(-c2ncccc2)c1Cl QWVLHTCIAZPQAY-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the field of synthesis of drug intermediates, in particular to an intermediate of antitumor drug GDC-0449 (vismodegib) and a synthesis method of the intermediate. The synthesis method is characterized by comprising the following steps: with parachlorobenzoic-acid as a raw material, firstly carrying out iodination and then carrying out a rearrangement reaction under the action of diphenylphosphoryl azide; reacting with coupled boronic acid pinacol ester; and finally carrying out coupling reaction with 2-bromopyridine; and removing protecting groups to finally obtain the intermediate of GDC-0449. The preparation method provided by the invention has the following advantages: the raw material is cheap, the reaction conditions are moderate, the yield of each reaction is high, and the total yield is high up to 54.7%; and therefore the preparation method is suitable for large-scale preparation.
Description
Technical field
The present invention relates to the synthetic field of medicine and intermediate thereof, be specifically related to the chloro-3-of the chloro-N-[4-of 2-(2-pyridyl) phenyl]-intermediate and the synthetic method thereof of 4-(methylsulfonyl) benzamide (GDC-0449).
Background technology
The chloro-3-of the chloro-N-[4-of a kind of novel targeted antitumor drug Vismodegib(2-(2-pyridyl) phenyl]-4-(methylsulfonyl) benzamide, GDC-0449) be a kind of new small molecule inhibitors of hedgehog path, IC
50For 3nm, can effectively treat basal cell naevus syndrome and progressive stage rodent cancer (BCC).Vismodegib is in Nikkei U.S. FDA approval listing January 30 in 2012.The chloro-3-of 4-(2-pyridyl) aniline is the key intermediate of synthetic Vismodegib in addition.
For the Vismodegib(Compound I) preparation, patent WO2009126863 report related compound method is as follows:
Reagent and condition: (a) H
2SO
4, NaNO
2, H
2O, KI, yield: 73%; (b) 2-bromopyridine, ZnCl
2, tetrahydrofuran (THF) (THF), toluene, isopropylmagnesium chloride (i-PrMgCl), two triphenyl phosphorus palladium chloride (PdCl
2(PPh
3)
2), triphenylphosphine (PPh
3), yield: 72%; (c) Fe, ethanol (EtOH), acetic acid (AcOH), yield: 94%; (d) triethylamine, methylene dichloride (DCM).
This synthetic method has the following disadvantages: raw materials cost is high, and reaction conditions is gentle not, prepares on a large scale yield unstable etc.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, possess the chloro-3-of 4-(2-pyridyl) aniline (II) and synthetic method Vismodegib(I) that extensive preparation is worth.Mainly solve existing Vismodegib and the chloro-3-of 4-(2-pyridyl) aniline preparation method raw materials cost high, reaction conditions is not very gentle, prepares on a large scale the technical problems such as yield is unstable.
The present invention be take Chlorodracylic acid and is raw material, and raw materials cost reduces, and iodide reaction occurs and obtain compound VI I; Under the diphenyl phosphate azide effect, rearrangement reaction occurring, obtains compound VI II again; With coupling boric acid pinacol ester generation boration, react and obtain Compound I X; With 2-bromopyridine generation linked reaction, obtain compounds X I; Slough protecting group and obtain midbody compound II, Compound I I can obtain Vismodegib at alkaline condition generation amidate action.
Reaction process comprises:
Midbody compound II can obtain Compound I at alkaline condition generation amidate action.
While wherein by compound VI, preparing compound VI I, iodo reagent is preferably NaIO
4And KI, the vitriol oil is made solvent, wherein compound VI: NaIO
4: the mol ratio of KI is preferably 1.0: 0.25～and 0.5: 0.75～1.5.Temperature of reaction gets final product in room temperature, and preferred temperature of reaction is 15～40 ℃.
While by compound VI I, preparing compound VI II, the preferred triethylamine of alkali or DIPEA; Preferred toluene/the trimethyl carbinol of solvent or the trimethyl carbinol.
While by compound VI I, preparing compound VI II, compound VI I: diphenyl phosphate azide (DPPA): the mol ratio of alkali is preferably 1.0: 1.0～and 1.5: 1.0～2.0; Temperature of reaction is preferably 80～110 ℃.
While by compound VI II, preparing Compound I X, the preferred Potassium ethanoate of alkali, salt of wormwood or sodium bicarbonate; Catalyzer is [1,1 ＇-bis-(diphenylphosphino) ferrocene] palladium chloride (Pd (dppf) Cl
2) or tetrakis triphenylphosphine palladium (Pd (PPh
3)
4); The preferred tetrahydrofuran (THF) of solvent, methyl-sulphoxide (DMSO) or DMF (DMF).
While by compound VI II, preparing Compound I X, compound VI II: coupling boric acid pinacol ester: alkali: the mol ratio of catalyzer is preferably 1: 1.0～and 1.5: 1.0～4.0: 0.02～0.10; Temperature of reaction is preferably 100～150 ℃.
While by Compound I X, preparing compounds X I, the preferred Potassium ethanoate of alkali, salt of wormwood, cesium carbonate or sodium bicarbonate; Catalyzer is [1,1 ＇-bis-(diphenylphosphino) ferrocene] palladium chloride or tetrakis triphenylphosphine palladium preferably; Preferred tetrahydrofuran (THF)/the water of solvent, methyl-sulphoxide, glycol dimethyl ether (DME)/water or DMF; Temperature of reaction is preferably 85～150 ℃; Compound I X: compounds X: alkali: the mol ratio of catalyzer is preferably 1: 1.0～and 1.5: 1.0～4.0: 0.02～0.10.
While by compounds X I, preparing Compound I I, acid is hydrochloric acid or trifluoroacetic acid preferably; The preferred tetrahydrofuran (THF) of solvent, methylene dichloride or ethyl acetate.
While by Compound I I, preparing Compound I, the preferred triethylamine of alkali; The preferred tetrahydrofuran (THF) of solvent or methylene dichloride.
Preparation method's raw material of the present invention is cheap, the reaction conditions gentleness, and every step productive rate is all higher, and total recovery can reach 54.2%, and is applicable to extensive preparation.
Embodiment
Embodiment 1
The preparation of intermediate II
Compound VI I's is synthetic:
In the 1L four-hole bottle, add compound VI (313.1g, 2.0mol, 1.0eq.), with the 5L concentrated sulfuric acid dissolution, add NaIO
4(188.2g, 0.9mol, 0.45eq.), treat that solid dissolves fully, by part, slowly adds KI (365g, 2.2mol, 1.1eq.) under room temperature, and reaction solution is purple darkly, controls temperature of reaction 25-30 ℃, finishes, and room temperature reaction 2h, after reacting completely.Reaction solution slowly in impouring 20kg trash ice, is stirred, and a large amount of solids are separated out, and filter, and filter cake washes with water, petroleum ether, after oven dry compound VI I white solid 410g, yield 72.7%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：13.35(bs，1H)，8.38(d，J＝2.0Hz，1H)，7.91(dd,J=8.3，2.0Hz，1H)，7.69(d，J＝8.3Hz，1H)。
Compound VI II's is synthetic:
In the 1L four-hole bottle, add compound VI I(331.3g, 1.17mol, 1.0eq.), the 5L trimethyl carbinol (t-BuOH) dissolves, and adds DPPA(322.8g, 1.17mol, 1.0eq.), Et
3N(119.4g, 1.17mol, 1.0eq.), finish, back flow reaction 8h, reaction finishes.Reaction solution is concentrated, and gained oily matter dissolves with EA, the salt water washing, and anhydrous sodium sulfate drying, recrystallization (PE/EA), obtain compound VI II white solid 347g, yield 84%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：9.58(bs，1H)，8.12(s，1H)，7.43(s，1H)，7.42(s，1H)，1.47(s，9H)。
Compound I X's is synthetic:
In the 5L four-hole bottle, add compound VI II (339.1g, 0.96mol, 1.0eq.), dissolve with 3L DMSO, add successively afterwards coupling pinacol borate (244.2g, 0.96mol, 1.0eq.), Potassium ethanoate (282.6g, 2.88mol, 3.0eq.), Pd (dppf) Cl
2(35.1g, 48mmol, 0.05eq.), finish, and is heated to 110 ℃ of reaction 4h, after reaction finishes.Reaction solution is cooled to room temperature, by its impouring 9L water, adds 8LEA, separatory, and organic phase, washing twice, the saturated common salt water washing, dried over sodium sulfate, recrystallization (PE/EA) obtains Compound I X white crystal 307.7g, yield 90.5%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：9.44(bs，1H)，7.82(d，J=2.6Hz，1H)，7.47(dd，J＝2.6，8.7Hz，1H)，7.28(d，J＝8.7Hz，1H)，1.46(s，9H)，1.31(s，12H)。
Compounds X I's is synthetic:
In the 5L four-hole bottle, add Compound I X (231.2g, 0.65mol, 1.0eq.), dissolve with 2LDME, add successively afterwards compounds X (123.9g, 0.78mol, 1.2eq.), NaHCO
3(164.8g, 1.96mol, 3.0eq.), 1L water, Pd (PPh
3)
4(38.1g, 30mmol, 0.05eq.), finish, back flow reaction 10h under nitrogen protection, and reaction finishes.Question response liquid is cooled to room temperature, adds wherein DCM, the layering separatory,, merge organic phase, anhydrous sodium sulfate drying, recrystallization (PE/EA), obtain compounds X I white solid 200g, yield 100%.
1HNMR(400MHz,CDCl3)δ(ppm)：8.72(m，1H)，7.60-7.80(m，1H)，7.68(d，1H)，7.60(m，1H)，7.38-7.46(m,2H)，7.29-7.33(m，1H)，6.69(s，1H)，1.51(s,9H)。
Compound I I's is synthetic:
In the 5L four-hole bottle, add compounds X I (200g, 660mmol, 1.0eq.), dissolve with 2LDCM, add 500mLTFA under 0 ℃, room temperature reaction 2h, reaction finishes.After concentrated, with the PE washing, obtain Compound I I white solid 132.7g, purity: 98%, yield 99%.
1HNMR(400MHz,CDCl3)δ(ppm)：8.71(m，1H)，7.76-7.80(m，1H)，7.69(d，1H)，7.28-7.32(m，1H)，7.24(d，J＝8.5Hz，1H)，6.95(d，J＝2.9Hz，1H)，6.68(dd，J＝8.5Hz，2.8Hz，1H)，3.45(bs，2H)。
Embodiment 2
Synthesizing of Compound I:
In the 2L four-hole bottle, add Compound I I (81g, 400mmol, 1.0eq.), 800mLDCM, add triethylamine (Et
3N) (60g, 600mmol, 1.5eq.), slowly add compounds X II (120g, 480mmol, 1.2eq.) afterwards under ice bath, control temperature 0-5 ℃, finish, and room temperature reaction 30min, reaction finishes.Recrystallization (PE/EA), obtain white solid 165.3g, yield 99%.Purity: 99%.
1H?NMR(400MHz，CDCl3)δ(ppm)：9.58(bs，1H)，8.43(d，J＝4.7Hz,1H)，8.03(dd，J＝2.6，8.7Hz，1H)，7.90(d，J＝1.6Hz,1H)，7.67-7.78(m，4H)，7.60(d，J＝8.0Hz,1H)，7.51(d，J＝8.8Hz,1H)，7.23-7.24(m，1H)，3.01(s，3H)。
Embodiment 3
Compound VI I's is synthetic:
In the 1L four-hole bottle, add compound VI (313.1g, 2.0mol, 1.0eq.), with the 5L concentrated sulfuric acid dissolution, add NaIO
4(104.5g, 0.49mol, 0.25eq.), treat that solid dissolves fully, by part, slowly adds KI (248.8g, 1.50mol, 0.75eq.) under room temperature, and reaction solution is purple darkly, controls temperature of reaction 25-40 ℃, finishes, and room temperature reaction 3h, after reacting completely.Reaction solution slowly in impouring 18kg trash ice, is stirred, and a large amount of solids are separated out, and filter, and filter cake washes with water, petroleum ether, after oven dry compound VI I white solid 400g, yield 70.9%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：13.35(bs，1H)，8.38(d，J＝2.0Hz，1H)，7.91(dd,J＝8.3，2.0Hz，1H)，7.69(d，J＝8.3Hz，1H)。
Compound VI II's is synthetic:
In the 1L four-hole bottle, add compound VI I(331.3g, 1.17mol, 1.0eq.), toluene 4L and the trimethyl carbinol (t-BuOH) 1L dissolves, and adds DPPA(484.2g, 1.755mol, 1.5eq.), N, N-diisopropylethylamine (DIPEA) (226.8g, 1.775mol, 1.5eq.), finish, back flow reaction 7h, reaction finishes.Reaction solution is concentrated, and gained oily matter dissolves with EA, the salt water washing, and anhydrous sodium sulfate drying, recrystallization (PE/EA), obtain compound VI II white solid 340.8g, yield 82.5%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：9.58(bs，1H)，8.12(s，1H)，7.43(s，1H)，7.42(s，1H)，1.47(s，9H)。
Compound I X's is synthetic:
In the 5L four-hole bottle, add compound VI II (339.1g, 0.96mol, 1.0eq.), dissolve with 3LDMF, add successively afterwards coupling pinacol borate (317.4g, 1.248mol, 1.3eq.), salt of wormwood (199.0g, 1.44mol, 1.5eq.), Pd (PPh
3)
4(88.7g, 76.8mmol, 0.8eq.), finish, and is heated to 120 ℃ of reaction 4h, after reaction finishes.Reaction solution is cooled to room temperature, by its impouring 9L water, adds 8L EA, separatory, and organic phase, washing twice, the saturated common salt water washing, dried over sodium sulfate, recrystallization (PE/EA) obtains Compound I X white crystal 304.6g, yield 89.5%.
1HNMR(400MHz,DMSO-d
6)δ(ppm)：9.44(bs，1H)，7.82(d，J=2.6Hz，1H)，7.47(dd,J＝2.6,8.7Hz，1H)，7.28(d，J＝8.7Hz，1H)，1.46(s，9H)，1.31(s，12H)。
Compounds X I's is synthetic:
In the 5L four-hole bottle, add Compound I X (231.2g, 0.65mol, 1.0eq.), dissolve with 2LDMF, add successively afterwards compounds X (123.9g, 0.78mol, 1.2eq.), NaHCO
3(164.8g, 1.96mol, 3.0eq.), 1L water, Pd (dppf) Cl
2(8.78g, 12mmol, 0.02eq.), finish, under nitrogen protection, and 110 ℃ of reaction 10h, reaction finishes.Question response liquid is cooled to room temperature, adds wherein DCM, the layering separatory,, merge organic phase, anhydrous sodium sulfate drying, recrystallization (PE/EA), obtain compounds X I white solid 200g, yield 100%.
1HNMR(400MHz,CDCl3)δ(ppm)：8.72(m，1H)，7.60-7.80(m，1H)，7.68(d，1H)，7.60(m，1H)，7.38-7.46(m,2H)，7.29-7.33(m，1H)，6.69(s，1H)，1.51(s,9H)。
Synthesizing of Compound I:
In the 2L four-hole bottle, add compounds X I (200g, 660mmol, 1.0eq.), add 400mL hydrochloric acid under 0 ℃, room temperature reaction 2h, reaction finishes.By 50%NaOH aqueous solution adjustment pH value, add 2L EA, separatory, organic phase, washing twice, the saturated common salt water washing, anhydrous sodium sulfate drying, the concentrated Compound I white solid 132.7g that to obtain, purity: 98%, yield 99%.
1HNMR(400MHz,CDCl3)δ(ppm)：8.71(m，1H)，7.76-7.80(m，1H)，7.69(d，1H)，7.28-7.32(m，1H)，7.24(d，J＝8.5Hz，1H)，6.95(d，J＝2.9Hz，1H)，6.68(dd，J＝2.8，8.5Hz，1H)，3.45(bs，2H)。
Claims (10)
1. the preparation method of a midbody compound (II) comprising:
Wherein iodo reagent is NaIO
4And KI.
2. the preparation method of a compound (I) comprising:
Wherein iodo reagent is NaIO
4And KI.
3. claim 1 or 2 preparation method, while wherein by compound VI, preparing compound VI I, iodo reagent is NaIO
4And KI, the vitriol oil is made solvent, wherein compound VI: NaIO
4: the mol ratio of KI is 1.0: 0.25～0.5: 0.75～1.5.
4. claim 1 or 2 preparation method, while wherein by compound VI I, preparing compound VI II, alkali is triethylamine or DIPEA; Solvent is toluene/trimethyl carbinol or the trimethyl carbinol.
5. claim 1 or 2 preparation method, while wherein by compound VI I, preparing compound VI II, compound VI I: diphenyl phosphate azide: the mol ratio of alkali is 1.0: 1.0～1.5: 1.0～2.0.
6. claim 1 or 2 preparation method, while wherein by compound VI II, preparing Compound I X, alkali is Potassium ethanoate, salt of wormwood or sodium bicarbonate; Catalyzer is [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or tetrakis triphenylphosphine palladium; Solvent is tetrahydrofuran (THF), methyl-sulphoxide or DMF.
7. claim 1 or 2 preparation method, while wherein by compound VI II, preparing Compound I X, compound VI II: coupling boric acid pinacol ester: alkali: the mol ratio of catalyzer is 1: 1.0～1.5: 1.0～4.0: 0.02～0.10.
8. claim 1 or 2 preparation method, while wherein by Compound I X, preparing compounds X I, alkali is Potassium ethanoate, salt of wormwood, cesium carbonate or sodium bicarbonate; Catalyzer is [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or tetrakis triphenylphosphine palladium; Solvent is tetrahydrofuran (THF)/water, methyl-sulphoxide, glycol dimethyl ether/water or DMF; Temperature of reaction is 80～150 ℃; Compound I X: compounds X: alkali: the mol ratio of catalyzer is 1: 1.0～1.5: 1.0～4.0: 0.02～0.10.
9. claim 1 or 2 preparation method, while wherein by compounds X I, preparing Compound I I, acid is hydrochloric acid or trifluoroacetic acid; Solvent is tetrahydrofuran (THF), methylene dichloride or ethyl acetate.
10. the preparation method of claim 2, while wherein by Compound I I, preparing Compound I, alkali is triethylamine; Solvent is tetrahydrofuran (THF) or methylene dichloride.
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| CN103910672B (en) * | 2013-01-08 | 2016-10-05 | 连云港润众制药有限公司 | The preparation method of Vismodegib |
| CN103910671B (en) * | 2013-01-08 | 2016-08-10 | 正大天晴药业集团股份有限公司 | Vismodegib and the preparation method of intermediate thereof |
| WO2014147504A2 (en) * | 2013-03-22 | 2014-09-25 | Shilpa Medicare Limited | Process for preparation of 2-chloro-n-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide solid forms |
| CN103214456B (en) * | 2013-04-20 | 2015-02-25 | 郎恒元 | Benzimidazole compound with antitumour activity as well as preparation method and application thereof |
| CN103254124A (en) * | 2013-04-23 | 2013-08-21 | 镇江圣安医药有限公司 | N-[4-chloro-3-(pyridinyl-2-radical)phenyl]-2-chloro-4(methylsulfonyl)-benzamide derivative and application thereof |
| CN104496889A (en) * | 2014-11-20 | 2015-04-08 | 成都平和安康医药科技有限公司 | Industrialized synthetic method of vismodegib |
| CN104926714B (en) * | 2015-07-02 | 2017-07-28 | 天津大学 | The preparation method of 2 chlorine N (4 chlorine 3 (2 pyridine radicals) phenyl) 4 methyl sulfone phenylbenzamaides |
| KR102610930B1 (en) * | 2016-08-24 | 2023-12-08 | (주)아모레퍼시픽 | COMPOSITION FOR SKIN-WHITENING COMPRISING 3-CHLORO-N-[TRANS-4-(METHYLAMINO)CYCLOHEXYL]-N-[[3-(4-PYRIDINYL)PHENYL]METHYL]BENZO[b]THIOPHENE-2-CARBOXAMIDE |
| CN108003091B (en) * | 2017-12-04 | 2018-09-14 | 南京天越星生物技术有限公司 | A method of vismodegib is prepared using microchannel reaction unit |
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| WO2011014888A1 (en) * | 2009-07-31 | 2011-02-03 | Selexagen Therapeutics | Novel hedgehog inhibitors |
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