CN102731373A - Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib) - Google Patents

Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib) Download PDF

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CN102731373A
CN102731373A CN2012102497397A CN201210249739A CN102731373A CN 102731373 A CN102731373 A CN 102731373A CN 2012102497397 A CN2012102497397 A CN 2012102497397A CN 201210249739 A CN201210249739 A CN 201210249739A CN 102731373 A CN102731373 A CN 102731373A
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CN102731373B (en
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朱经纬
毛俊
杨民民
吴希罕
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PHARMABLOCK (NANJING) R&D CO., LTD.
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NANJING MEDICAL STONE AND MEDICINE RESEARCH AND DEVELOPMENT Co Ltd
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    • 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

Antitumor drug GDC-0449 intermediates preparation
Technical field
The present invention relates to the synthetic field of medicine and midbody thereof, be specifically related to the midbody and the compound method thereof of 2-chloro-N-[4-chloro-3-(2-pyridyl) phenyl]-4-(methylsulfonyl) BM (GDC-0449).
Background technology
(2-chloro-N-[4-chloro-3-(2-pyridyl) phenyl]-4-(methylsulfonyl) BM GDC-0449) is a kind of new small molecule inhibitors of hedgehog path, IC to a kind of novel targeted antitumor drug Vismodegib 50Be 3nm, can effectively treat basal cell naevus syndrome and progressive stage rodent cancer (BCC).Vismodegib is in Nikkei drugs approved by FDA listing January 30 in 2012.4-chloro-3-(2-pyridyl) aniline is the key intermediate of synthetic Vismodegib in addition.
For the preparation of Vismodegib (compound I), patent WO2009126863 report related compound method is following:
Figure BDA00001905294000011
Reagent and condition: (a) H 2SO 4, NaNO 2, H 2O, KI, yield: 73%; (b) 2-bromopyridine, ZnCl 2, 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).
Not enough below this compound method exists: raw materials cost is high, and reaction conditions is gentle inadequately, mass preparation yield instability etc.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, possess 4-chloro-3-(2-pyridyl) aniline (II) that mass preparation is worth and the compound method of Vismodegib (I).It is high mainly to solve existing Vismodegib and 4-chloro-3-(2-pyridyl) aniline preparation method raw materials cost, and reaction conditions is not very gentle, technical problems such as mass preparation yield instability.
The present invention is raw material with the Chlorodracylic acid, and raw materials cost reduces, and iodide reaction takes place obtain compound VI I; Rearrangement reaction takes place under the diphenyl phosphate azide effect again, obtains compound VIII; Obtain compound I X with the reaction of coupling boric acid pinacol ester generation boration; Obtain compounds X I with 2-bromopyridine generation linked reaction; Slough the protection base and obtain midbody compound II, compound I I can obtain Vismodegib at alkaline condition generation amidate action.
Reaction process comprises:
Figure BDA00001905294000021
Midbody compound II can obtain compound I at alkaline condition generation amidate action.
Figure BDA00001905294000022
When wherein preparing compound VI I by compound VI, 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 ℃.
When preparing compound VIII by compound VI I, preferred triethylamine of alkali or N, N-diisopropylethylamine; Preferred toluene/the trimethyl carbinol of solvent or the trimethyl carbinol.
When preparing compound VIII by compound VI I, 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 ℃.
When preparing compound I X by compound VIII, the preferred Potassium ethanoate of alkali, salt of wormwood or sodium hydrogencarbonate; Catalyzer is [1,1 ＇-two (diphenylphosphino) ferrocene] palladium chloride (Pd (dppf) Cl 2) or tetrakis triphenylphosphine palladium (Pd (PPh 3) 4); The preferred THF of solvent, methyl-sulphoxide (DMSO) or N, dinethylformamide (DMF).
When preparing compound I X by compound VIII, compound VIII: 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 ℃.
When preparing compounds X I by compound I X, the preferred Potassium ethanoate of alkali, salt of wormwood, cesium carbonate or sodium hydrogencarbonate; Preferred [1,1 ＇-two (diphenylphosphino) ferrocene] palladium chloride or the tetrakis triphenylphosphine palladium of catalyzer; Preferred THF/the water of solvent, methyl-sulphoxide, glycol dimethyl ether (DME)/water or N, dinethylformamide; 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.
When preparing compound I I by compounds X I, preferred hydrochloric acid of acid or trifluoroacetic acid; The preferred THF of solvent, methylene dichloride or ETHYLE ACETATE.
When preparing compound I by compound I I, the preferred triethylamine of alkali; Preferred THF of solvent or methylene dichloride.
Preparing method's raw material of the present invention is cheap, and reaction conditions is gentle, and per step productive rate is all than higher, and total recovery can reach 54.2%, and suitable mass preparation.
Embodiment
Embodiment 1
The preparation of intermediate II
Compound VI I's is synthetic:
(313.1g, 2.0mol 1.0eq.), with the 5L concentrated sulfuric acid dissolution, add NaIO to add compound VI in the 1L four-hole bottle 4(188.2g, 0.9mol 0.45eq.), treat that solid dissolves fully, under the room temperature by part slowly add KI (1.1eq.), reaction solution is purple darkly for 365g, 2.2mol, control reaction temperature 25-30 ℃, finish, room temperature reaction 2h is after reacting completely.Reaction solution slowly in the impouring 20kg trash ice, is stirred, and a large amount of solids are separated out, and filter, and filter cake use water washing, and petroleum ether must compound VI I white solid 410g after the oven dry, 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)。
Synthesizing of compound VIII:
Figure BDA00001905294000041
In the 1L four-hole bottle, and adding compound VI I (331.3g, 1.17mol, 1.0eq.), the 5L trimethyl carbinol (t-BuOH) dissolving, adding DPPA (322.8g, 1.17mol, 1.0eq.), Et 3N (119.4g, 1.17mol 1.0eq.), finish, back flow reaction 8h, and reaction finishes.Reaction solution concentrates, and gained oily matter dissolves with EA, brine wash, and anhydrous sodium sulfate drying, recrystallization (PE/EA) gets compound VIII 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:
Figure BDA00001905294000042
(339.1g, 0.96mol 1.0eq.), dissolve with 3L DMSO in the 5L four-hole bottle, to add compound VIII; Add successively afterwards coupling boric acid pinacol ester (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 are heated to 110 ℃ of reaction 4h, after reaction finishes.Reaction solution is cooled to room temperature, in 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) gets 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:
Figure BDA00001905294000051
In the 5L four-hole bottle, add compound I X (231.2g, 0.65mol, 1.0eq.), with the 2LDME dissolving, 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, nitrogen protection refluxed reaction 10h, and reaction finishes.Question response liquid is cooled to room temperature, to wherein adding DCM, the layering separatory,, merge organic phase, anhydrous sodium sulfate drying, recrystallization (PE/EA), 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:
Figure BDA00001905294000052
(1.0eq.), with the 2LDCM dissolving, 0 ℃ adds 500mLTFA down for 200g, 660mmol, and room temperature reaction 2h reacts and finishes in the 5L four-hole bottle, to add compounds X I.After concentrating,, get compound I I white solid 132.7g, purity with the PE washing: 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:
Figure BDA00001905294000053
(1.0eq.), 800mLDCM adds triethylamine (Et for 81g, 400mmol to add compound I I in the 2L four-hole bottle 3N) (1.5eq.), (120g, 480mmol 1.2eq.), controlled temperature 0-5 ℃, finish room temperature reaction 30min, reaction end slowly to add compounds X II afterwards under the ice bath for 60g, 600mmol.Recrystallization (PE/EA) gets 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:
Figure BDA00001905294000061
(313.1g, 2.0mol 1.0eq.), with the 5L concentrated sulfuric acid dissolution, add NaIO to add compound VI in the 1L four-hole bottle 4(104.5g, 0.49mol 0.25eq.), treat that solid dissolves fully, under the room temperature by part slowly add KI (0.75eq.), reaction solution is purple darkly for 248.8g, 1.50mol, control reaction temperature 25-40 ℃, finish, room temperature reaction 3h is after reacting completely.Reaction solution slowly in the impouring 18kg trash ice, is stirred, and a large amount of solids are separated out, and filter, and filter cake use water washing, and petroleum ether must compound VI I white solid 400g after the oven dry, 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)。
Synthesizing of compound VIII:
Figure BDA00001905294000062
In the 1L four-hole bottle, and adding compound VI I (331.3g, 1.17mol, 1.0eq.); The toluene 4L and the trimethyl carbinol (t-BuOH) 1L dissolving, and adding DPPA (484.2g, 1.755mol, 1.5eq.); N, and N-diisopropylethylamine (DIPEA) (226.8g, 1.775mol, 1.5eq.); Finish, back flow reaction 7h, reaction finishes.Reaction solution concentrates, and gained oily matter dissolves with EA, brine wash, and anhydrous sodium sulfate drying, recrystallization (PE/EA) gets compound VIII 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:
Figure BDA00001905294000071
In the 5L four-hole bottle, add compound VIII (339.1g, 0.96mol, 1.0eq.), with 3LDMF dissolving, add successively afterwards coupling boric acid pinacol ester (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 are heated to 120 ℃ of reaction 4h, after reaction finishes.Reaction solution is cooled to room temperature, in 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) gets 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:
Figure BDA00001905294000072
In the 5L four-hole bottle, add compound I X (231.2g, 0.65mol, 1.0eq.), with the 2LDMF dissolving, 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 the nitrogen protection, and 110 ℃ of reaction 10h, reaction finishes.Question response liquid is cooled to room temperature, to wherein adding DCM, the layering separatory,, merge organic phase, anhydrous sodium sulfate drying, recrystallization (PE/EA), 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:
Figure BDA00001905294000073
(1.0eq.), 0 ℃ adds 400mL hydrochloric acid down, room temperature reaction 2h, reaction end for 200g, 660mmol in the 2L four-hole bottle, to add compounds X I.Adjust pH value with the 50%NaOH aqueous solution, add 2L EA, separatory, organic phase, washing twice, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrated compound 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＝2.8，8.5Hz，1H)，3.45(bs，2H)。

Claims (10)

1. the preparation method of a midbody compound (II) comprising:
Figure FDA00001905293900011
2. the preparation method of a compound (I) comprising:
Figure FDA00001905293900012
3. claim 1 or 2 preparation method, when wherein preparing compound VI I by compound VI, 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, when wherein preparing compound VIII by compound VI I, alkali is triethylamine or N, the N-diisopropylethylamine; Solvent is the toluene/trimethyl carbinol or the trimethyl carbinol.
5. claim 1 or 2 preparation method, when wherein preparing compound VIII by compound VI I, 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, when wherein preparing compound I X by compound VIII, alkali is Potassium ethanoate, salt of wormwood or sodium hydrogencarbonate; Catalyzer is [1,1 ＇-two (diphenylphosphino) ferrocene] palladium chloride or tetrakis triphenylphosphine palladium; Solvent is THF, methyl-sulphoxide or N, dinethylformamide.
7. claim 1 or 2 preparation method, when wherein preparing compound I X by compound VIII, compound VIII: 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, when wherein preparing compounds X I by compound I X, alkali is Potassium ethanoate, salt of wormwood, cesium carbonate or sodium hydrogencarbonate; Catalyzer is [1,1 ＇-two (diphenylphosphino) ferrocene] palladium chloride or tetrakis triphenylphosphine palladium; Solvent is THF/water, methyl-sulphoxide, glycol dimethyl ether/water or N, dinethylformamide; 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, when wherein preparing compound I I by compounds X I, acid is hydrochloric acid or trifluoroacetic acid; Solvent is THF, methylene dichloride or ETHYLE ACETATE.
10. the preparation method of claim 2, when wherein preparing compound I by compound I I, alkali is triethylamine; Solvent is 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
CN103910672A (en) * 2013-01-08 2014-07-09 连云港润众制药有限公司 Preparation method for vismodegib
CN103910671A (en) * 2013-01-08 2014-07-09 正大天晴药业集团股份有限公司 Preparation method for vismodegib and intermediate of vismodegib
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CN103214456B (en) * 2013-04-20 2015-02-25 郎恒元 Benzimidazole compound with antitumour activity as well as preparation method and application thereof
CN103214456A (en) * 2013-04-20 2013-07-24 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
CN104926714A (en) * 2015-07-02 2015-09-23 天津大学 Preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide
CN109890383A (en) * 2016-08-24 2019-06-14 株式会社爱茉莉太平洋 Include the chloro- N- of 3- [trans- -4-(methylamino) cyclohexyl]-N- [[3-(4- pyridyl group) phenyl] methyl] composition for whitening skin of benzo [b] thiophene-2-carboxamide derivatives
CN108003091A (en) * 2017-12-04 2018-05-08 南京天越星生物技术有限公司 A kind of method that vismodegib is prepared using microchannel reaction unit
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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