CN107434807A - A kind of preparation method of the azaindole of 5 hydroxyl 7 - Google Patents

A kind of preparation method of the azaindole of 5 hydroxyl 7 Download PDF

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CN107434807A
CN107434807A CN201710854276.XA CN201710854276A CN107434807A CN 107434807 A CN107434807 A CN 107434807A CN 201710854276 A CN201710854276 A CN 201710854276A CN 107434807 A CN107434807 A CN 107434807A
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reaction
preparation
hydroxyls
azaindoles
compound
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庄银枪
彭少平
江辉
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Shanghai Hongbo Zhiyuan Pharmaceutical Ltd By Share Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
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    • 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

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Abstract

The invention discloses a kind of preparation method of the azaindole of 5 hydroxyl 7, the structure of the intermediate corresponds to formula III,

Description

A kind of preparation method of 5- hydroxyls -7- azaindoles
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of preparation method of 5- hydroxyls -7- azaindoles.
Background technology
ABT-199 (Venetoclax), chemical name 2- [(1H- pyrrolo-es [2,3-B] pyridine -5- bases) epoxide] -4- [4- [[2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkenyls] methyl] piperazine -1- bases]-nitrogen-[3- nitros -4- [[(tetrahydrochysene pyrroles Mutter -4- bases) methyl] amino] benzsulfamide] methyl benzoate is a kind of experimental B cell lymphoma factor -2 (BCL-2) suppression Preparation, developed jointly by AbbVie Corp. and Roche Holding Ag.BCL-2 is that one kind can prevent some cells (including lymphocyte) from withering The albumen died.ABT-199 is intended to the function of the selective depression BCL-2 factors, recovers the communication system of cell, allow cancer cell self Destroy, to reach the effect for the treatment of tumour.
FDA thinks that this medicine has in terms of the patients with chronic myelocytic leukemia with 17p deletion mutants is treated Significant curative effect.The line patients with chronic myelocytic leukemia that there are about 3-10% at present all carries this gene mutation, and is going out In existing drug-fast chronic leukemia patient, this ratio is more up to as many as 50%.
In the prior art, existing numerous patents document discloses the synthetic method on ABT-199 key intermediates III, example Such as WO2011/150016A1, WO2012/071336A1, WO2014/165044A1, CN106565706A, US2010/ 305122A1 etc. discloses multiple synthetic schemes.
Patent WO2012/071336A1 is disclosed using 5- bromo-7-azaindoles as raw material, through amido protecting, under low temperature into Boric acid hydrolyze hydroxyl substituent synthetic route.Specific reaction is as shown in scheme 1：
But the route needs to use lithium hexamethyldisilazide, butyl lithium, amplifieroperation is dangerous；Total recovery compared with It is low.
Patent WO2014/165044A1 is disclosed using 5- bromo-7-azaindoles as raw material, substitutes bromine through sodium methoxide, then pass through De-methoxy reacts to obtain hydroxylic species, through synthetic route made from condensation, specifically as shown in scheme 2：
But the dosage of the route sodium methoxide is excessive, post processing produces many waste water；Other Boron tribromide is easy to volatilize, poison Property it is big, be not easy to industrialize amplifieroperation.
Therefore, art technology needs the system for developing 5- hydroxyls-azaindole that a kind of reaction condition is gentle, yield is higher badly Preparation Method.
The content of the invention
For above-mentioned deficiency of the prior art, the technical problem to be solved in the present invention is to provide a kind of reaction condition temperature With the preparation method of, 5- hydroxyl -7- azaindoles that environment-friendly, yield is higher.
A kind of preparation method of 5- hydroxyls -7- azaindoles is provided to achieve the above object, and present invention employs following skill Art scheme：
A kind of preparation method of 5- hydroxyls -7- azaindoles, the structure of the intermediate correspond to formula III,
This method including the use of formula I compound 5- bromo-7-azaindoles as raw material,
Protected through nitrogen, hydroxylating and directly deprotect totally 2 steps reaction, finally give the 5- hydroxyl -7- azaindoles of formula III.
Preferably, this method comprises the following steps：
S1, the compound 5- bromo-7-azaindoles using formula I：
The upper protection group R of N protect to obtain the compound of formula II
Wherein R is triisopropylsilyl i.e. TIPS or tert-butyl carbonyl i.e. Boc；
S2, the compound of formula II carry out hydroxylating and directly deprotection reaction obtain under catalyst and respective ligand effect The compound of formula III：
Further, in step S1 upper protection reaction, the dosage of protection group reagent and the molar ratio of type I compound are 1:1 to 1.5:1.
Further, in step S1 upper protection reaction, reaction dissolvent is DMF, dimethyl sulfoxide, four Any of hydrogen furans, dichloromethane, acetonitrile.
Further, in step S1 upper protection reaction, reaction dissolvent is tetrahydrofuran, dichloromethane.
Further, in step S1 upper protection reaction, reaction is carried out in the presence of a base；Described alkali is uncle Any of butanol potassium, DMAP, triethylamine are a variety of.
Further, in step S1 upper protection reaction, reaction temperature is 0 DEG C to 5 DEG C.
In above-mentioned technical proposal, by the way that in the basic conditions, the compound 5- bromo-7-azaindoles of formula I are protected on N Base R protects to obtain the compound of formula II.
Further, step S2 hydroxylating and directly in deprotection reaction, the catalyst of reaction is cupric acetylacetonate Or cuprous iodide；The catalyst and the molar ratio of the compound of formula II are 0.05:1 to 0.2:1.
Further, step S2 hydroxylating and directly in deprotection reaction, corresponding part are N, N '-bis- (4- hydroxyls- 2,6- 3,5-dimethylphenyls) oxamides BHMPO or N, N '-dimethyl ethylenediamine DMEDA；The part and mole of the compound of formula II Ratio is 0.05:1 to 0.5:1.
Further, step S2 hydroxylating and direct deprotection reaction, are carried out, wherein alkali is in the presence of a base Lithium hydroxide monohydrate or potassium phosphate；The dosage of alkali is 1 with the molar ratio of the compound of formula II:1 to 5:1.
Further, in step S2 reaction, reaction temperature is 100 to 180 DEG C.
In above-mentioned technical proposal, on foregoing on the basis of protection group reaction, by the compound of formula II in catalyst and phase Answer part act under, reaction temperature control under 100-180 DEG C, alkalescence condition it is hydroxylated simultaneously, formula III can be deprotected to obtain Compound.
The beneficial effects of the present invention are：
1) synthetic method raw material is cheap and easily-available in the present invention, and cost is cheap.
2) it can be deprotected while the second one-step hydroxylation reaction of the invention, reduce reactions steps.
3) reaction condition of the present invention is gentle, environment-friendly, and yield is higher, is adapted to industrial amplification production.
Embodiment
The invention will now be further described with reference to specific embodiments, but these embodiments be only it is exemplary, it is not right The scope of the present invention forms any restrictions.Those skilled in the art, which should be understood that, is not departing from the present invention On the premise of principle, some improvements and modifications can also be made, these improvements and modifications also should be regarded as protection scope of the present invention.
In the embodiment of the present invention：
NMR：All nuclear magnetic spectrograms detect by Bruker AV400MHz NMRs, and TMS is internal standard.
MS：All mass spectrograms detect by LCMS 2020 (Shimadzu).
【Embodiment 1】
Step S1：The preparation of the bromo- 1- of 5- (triisopropylsilyl)-pyrrolo- [2,3-b] pyridine (II/TIPS)
At room temperature, into 1L there-necked flasks, add tetrahydrofuran 400ml and open stirring.The bromo- 7- nitrogen of 5- is added into reaction bulb Miscellaneous indoles (30g, 0.15mol), potassium tert-butoxide (25.6g, 0.23mol), after stirring dissolved clarification, ice salt bath cooling, interior 0 DEG C of temperature is treated, Start the tri isopropyl chlorosilane (30.8g, 0.16mol) of dropwise addition 80ml tetrahydrofurans dilution.0-5 DEG C of reaction is kept after adding 10-20 minutes.
Controlled in TLC, reaction terminates.Water 300ml is added into reaction bulb, liquid separation after stirring 15 minutes, aqueous phase methyl- tert Butyl ether (200ml*2) extracts, and merges organic phase, and saturated sodium-chloride water solution 500ml washes organic phase once, liquid separation, organic phase After anhydrous sodium sulfate drying, concentrated solvent obtains grease, adds methanol 50ml, there is solid precipitation, filters solid vacuum drying oven and dries The compound of dry formula II.
Yield：49.5g yield：92.0%.
1H NMR(400MHz,CDCl3) δ 8.204 (d, J=2Hz, 1H), 7.914 (d, J=2.4Hz, 1H), 7.237 (d, J=3.2Hz, 1H), 6.425 (d, J=3.6Hz, 1H), 1.763 (m, 3H), 1.047 (s, 9H), 1.028 (s, 9H)
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 50ml reaction bulbs, the compound (4.08g, 11.5mmol) of formula II, cupric acetylacetonate are added (0.6g, 2.3mmol), BHMPO (0.76g, 2.3mmol), Lithium hydroxide monohydrate (1.7g, 40mmol), 18ml DMSO, 4.5ml water, stirring is opened, with nitrogen displacement, be warming up to interior 130 DEG C of temperature, keeping temperature is reacted 1 hour.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), add water 100ml, is adjusted with 2N watery hydrochloric acid PH is 6, there is solid precipitation, is filtered, and aqueous phase is extracted with ethyl acetate 50ml*3, merges organic phase, respectively with water and saturation chlorination Sodium water solution is washed once, anhydrous sodium sulfate drying, and concentrated solvent obtains the compound of formula III.
Yield：1.1g, yield：72%.
1H NMR (400MHz, DMSO-d6) δ 11.265 (s, 1H), 9.052 (s, 1H), 7.823 (d, J=2.4Hz, 1H), 7.341 (t, J=2.8Hz, 1H), 7.277 (m, 1H)
【Embodiment 2】
Step S1：The preparation of the bromo- 1- of 5- (tertbutyloxycarbonyl)-pyrrolo- [2,3-b] pyridine (II/Boc)
At room temperature, into 1L there-necked flasks, add dichloromethane 500ml and open stirring.The bromo- 7- nitrogen of 5- is added into reaction bulb Miscellaneous indoles (50g, 0.25mol), DMAP DMAP (1.55g, 13mmol), triethylamine TEA (77g, 0.76mol), Stir dissolved clarification after, nitrogen displacement, ice salt bath cooling, treat interior 0 DEG C of temperature, start be added dropwise di-tert-butyl dicarbonate (60.93g, 0.28mol).0-5 DEG C is kept after adding to react 1.5 hours.
Controlled in TLC, reaction terminates.Water 500ml is added into reaction bulb, liquid separation after stirring 15 minutes, organic phase 500ml Wash, liquid separation, after organic phase anhydrous sodium sulfate drying, concentrated solvent obtains crude product, must obtain the compound of formula II after purification.
Yield：67.7g yield：89.7%.
1H NMR(400MHz,CDCl3) δ 8.449 (d, J=2.4Hz, 1H), 7.921 (d, J=2Hz, 1H), 7.575 (d, J=4Hz, 1H), 6.376 (d, J=4Hz, 1H), 1.594 (s, 3H)
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 50ml vexed tanks, the compound (4g, 13.5mmol) of addition formula II, cuprous iodide (0.256g, 1.35mmol), DMEDA (0.594g, 6.74mmol), potassium phosphate (2.86g, 13.5mmol), water 40ml, stirring is opened, uses nitrogen Gas in gas displacement vexed tank, is warming up to interior 180 DEG C of temperature, and keeping temperature is reacted 19 hours.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), and it is 6 to adjust PH with 2N watery hydrochloric acid, aqueous phase Extracted with ethyl acetate 50ml*3, merge organic phase, washed once with water and saturated sodium-chloride water solution respectively, anhydrous sodium sulfate is done Dry, concentrated solvent obtains the compound of formula III.
Yield：1.17g yield：64.6%.
【Embodiment 3】
Step S1：The preparation of the bromo- 1- of 5- (triisopropylsilyl)-pyrrolo- [2,3-b] pyridine (II/TIPS)
At room temperature, into 10L four-hole bottles, add tetrahydrofuran 4L and open stirring.The bromo- 7- azepines of 5- are added into reaction bulb Indoles (300g, 1.5mol), potassium tert-butoxide (256g, 2.3mol), after stirring dissolved clarification, ice salt bath cooling, interior 0 DEG C of temperature is treated, is started The tri isopropyl chlorosilane (308g, 1.6mol) diluted with 800ml tetrahydrofurans is added dropwise.0-5 DEG C of reaction 10-20 is kept after adding Minute.
Controlled in TLC, reaction terminates.Water 3L is added into reaction bulb, liquid separation after stirring 15 minutes, aqueous phase methyl tertbutyl Ether (2L*2) extracts, and merges organic phase, and saturated sodium-chloride water solution 5L washes organic phase once, liquid separation, organic phase anhydrous sodium sulfate After drying, concentrated solvent obtains grease, adds methanol 500ml, there is solid precipitation, filters solid vacuum drying oven and dries to obtain formula II Compound.
Yield：502g, yield：93.2%.
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 5L reaction bulbs, the compound (408g, 1.15mol) of addition formula II, cupric acetylacetonate (60g, 230mmol), BHMPO (76g, 230mmol), Lithium hydroxide monohydrate (170g, 4mol), 1.8L DMSO, 450ml water, unlatching are stirred Mix, with gas in nitrogen displacement tube sealing, be warming up to interior 130 DEG C of temperature, keeping temperature is reacted 1 hour.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), be transferred to 20L kettles, add water 10L, uses It is 6 that 2N watery hydrochloric acid, which adjusts PH, there is solid precipitation, is filtered, and aqueous phase is extracted with ethyl acetate 2L*3, merges organic phase, respectively with water and Saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, and concentrated solvent obtains the compound of formula III.
Yield：115.8g, yield：74.6%.
【Embodiment 4】
Step S1：The preparation of the bromo- 1- of 5- (tertbutyloxycarbonyl)-pyrrolo- [2,3-b] pyridine (II/Boc)
At room temperature, into 10L four-hole bottles, add dichloromethane 5L and open stirring.The bromo- 7- azepines of 5- are added into reaction bulb Indoles (500g, 2.5mol), DMAP (15.5g, 130mmol), TEA (770g, 7.6mol), after stirring dissolved clarification, nitrogen displacement, ice Salt bath cools, and treats interior 0 DEG C of temperature, starts that di-tert-butyl dicarbonate (609.3g, 2.8mol) is added dropwise.0-5 DEG C of reaction is kept after adding 1.5 hour.
Controlled in TLC, reaction terminates.Water 5L is added into reaction bulb, liquid separation after stirring 15 minutes, organic phase is washed with water 5L, Liquid separation, after organic phase anhydrous sodium sulfate drying, concentrated solvent obtains crude product, after purification formula II compound.
Yield：680g, yield：90.2%.
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 500ml vexed tanks, the compound (40g, 135mmol) of addition formula II, cuprous iodide (2.56g, 13.5mmol), DMEDA (5.94g, 67.4mmol), potassium phosphate (28.6g, 135mmol), water 400ml, stirring is opened, uses nitrogen Gas in vexed tank is replaced, is warming up to interior 180 DEG C of temperature, keeping temperature is reacted 20 hours.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), and it is 6 to adjust PH with 2N watery hydrochloric acid, aqueous phase Extracted with ethyl acetate 500ml*3, merge organic phase, washed once with water and saturated sodium-chloride water solution respectively, anhydrous sodium sulfate Dry, concentrated solvent obtains the compound of formula III.
Yield：11.8g yield：65.5%.
【Embodiment 5】
Step S1：The preparation of the bromo- 1- of 5- (triisopropylsilyl)-pyrrolo- [2,3-b] pyridine (II/TIPS)
At room temperature, into 1L there-necked flasks, add DMF 400ml and open stirring.Added into reaction bulb 5- bromo-7-azaindoles (30g, 0.15mol), potassium tert-butoxide (25.6g, 0.23mol), after stirring dissolved clarification, ice salt bath cooling, treat Interior 0 DEG C of temperature, start the tri isopropyl chlorosilane (43.3g, 0.225mol) of dropwise addition 80ml tetrahydrofurans dilution.Kept after adding 0-5 DEG C of reaction 10-20 minute.
Controlled in TLC, reaction terminates.Water 300ml is added into reaction bulb, liquid separation after stirring 15 minutes, aqueous phase methyl- tert Butyl ether (200ml*2) extracts, and merges organic phase, and saturated sodium-chloride water solution 500ml washes organic phase once, liquid separation, organic phase After anhydrous sodium sulfate drying, concentrated solvent obtains grease, adds methanol 50ml, there is solid precipitation, filters solid vacuum drying oven and dries The compound of dry formula II.
Yield：50.5g yield：93.8%.
1H NMR(400MHz,CDCl3) δ 8.204 (d, J=2Hz, 1H), 7.914 (d, J=2.4Hz, 1H), 7.237 (d, J=3.2Hz, 1H), 6.425 (d, J=3.6Hz, 1H), 1.763 (m, 3H), 1.047 (s, 9H), 1.028 (s, 9H)
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 50ml reaction bulbs, the compound (4.08g, 11.5mmol) of formula II, cupric acetylacetonate are added (0.15g, 0.575mmol), BHMPO (0.15g, 0.575mmol), Lithium hydroxide monohydrate (2.42g, 57.5mmol), 18ml's DMSO, 4.5ml water, stirring is opened, with nitrogen displacement, be warming up to interior 100 DEG C of temperature, keeping temperature is reacted 6 hours.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), add water 100ml, is adjusted with 2N watery hydrochloric acid PH is 6, there is solid precipitation, is filtered, and aqueous phase is extracted with ethyl acetate 50ml*3, merges organic phase, respectively with water and saturation chlorination Sodium water solution is washed once, anhydrous sodium sulfate drying, and concentrated solvent obtains the compound of formula III.
Yield：1.2g, yield：78.5%.
【Embodiment 6】
Step S1：The preparation of the bromo- 1- of 5- (tertbutyloxycarbonyl)-pyrrolo- [2,3-b] pyridine (II/Boc)
At room temperature, into 1L there-necked flasks, add dimethyl sulfoxide 500ml and open stirring.The bromo- 7- nitrogen of 5- is added into reaction bulb Miscellaneous indoles (50g, 0.25mol), DMAP DMAP (1.55g, 13mmol), TEA triethylamines (77g, 0.76mol), Stir dissolved clarification after, nitrogen displacement, ice salt bath cooling, treat interior 0 DEG C of temperature, start be added dropwise di-tert-butyl dicarbonate (81.75g, 0.375mol).0-5 DEG C is kept after adding to react 1.5 hours.
Controlled in TLC, reaction terminates.Water 500ml is added into reaction bulb, liquid separation after stirring 15 minutes, organic phase 500ml Wash, liquid separation, after organic phase anhydrous sodium sulfate drying, concentrated solvent obtains crude product, must obtain the compound of formula II after purification.
Yield：66.9g yield：88.6%.
Step S2：The preparation of 5- hydroxyl -7- azaindoles (III)
At room temperature, into 50ml vexed tanks, the compound (4g, 13.5mmol) of addition formula IV, cuprous iodide (0.128g, 0.675mmol), DMEDA (0.06g, 0.675mmol), potassium phosphate (2.86g, 13.5mmol), water 40ml, stirring is opened, uses nitrogen Gas in gas displacement vexed tank, is warming up to interior 160 DEG C of temperature, and keeping temperature is reacted 19 hours.
Middle control raw material reaction terminates, and stops heating, cools to room temperature (20-30 DEG C), and it is 6 to adjust PH with 2N watery hydrochloric acid, aqueous phase Extracted with ethyl acetate 50ml*3, merge organic phase, washed once with water and saturated sodium-chloride water solution respectively, anhydrous sodium sulfate is done Dry, concentrated solvent obtains the compound of formula III.
Yield：1.2g, yield：66.2%.
The part preferred embodiment of the present invention is above are only, the present invention is not limited in the content of embodiment.For ability For technical staff in domain, can there are various change and change in the concept of technical solution of the present invention, that is made appoints What changes and change, within the scope of the present invention.

Claims (10)

1. a kind of preparation method of 5- hydroxyls -7- azaindoles, the structure of the intermediate corresponds to formula III,
Characterized in that, this method including the use of formula I compound 5- bromo-7-azaindoles as raw material,
Protected through nitrogen, hydroxylating and directly deprotect totally 2 steps reaction, finally give the azaindole of 5- hydroxyls -7 of formula III.
2. the preparation method of 5- hydroxyls -7- azaindoles according to claim 1, it is characterised in that this method is included such as Lower step：
S1, the compound 5- bromo-7-azaindoles using formula I：
The upper protection group R of N protect to obtain the compound of formula II；
Wherein R is triisopropylsilyl i.e. TIPS or tert-butyl carbonyl i.e. Boc；
S2, the compound of formula II carry out hydroxylating and directly deprotection reaction obtain formula III under catalyst and respective ligand effect Compound：
3. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S1 upper guarantor In shield reaction, the dosage of protection group reagent and the molar ratio of type I compound are 1:1 to 1.5:1.
4. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S1 upper guarantor In shield reaction, reaction dissolvent is any in DMF, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile Kind.
5. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S1 upper guarantor In shield reaction, reaction is carried out in the presence of a base；Described alkali is in potassium tert-butoxide, DMAP, triethylamine It is any one or more.
6. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S1 upper guarantor In shield reaction, reaction temperature is 0 DEG C to 5 DEG C.
7. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S2 hydroxyl Change and directly in deprotection reaction, the catalyst is cupric acetylacetonate or cuprous iodide；The catalyst and the chemical combination of formula II The molar ratio of thing is 0.05:1 to 0.2:1.
8. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S2 hydroxyl Change and directly in deprotection reaction, corresponding part be N, N '-bis- (4- hydroxyls -2,6- 3,5-dimethylphenyl) oxamides or N, N ' - Dimethyl-ethylenediamine；The part and the molar ratio of the compound of formula II are 0.05:1 to 0.5:1.
9. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S2 hydroxyl Change and direct deprotection reaction, are carried out, the alkali is Lithium hydroxide monohydrate or potassium phosphate in the presence of a base；The alkali The molar ratio of dosage and the compound of formula II is 1:1 to 5:1.
10. the preparation method of 5- hydroxyls -7- azaindoles according to claim 2, it is characterised in that：Step S2 reaction In, reaction temperature is 100 to 180 DEG C.
CN201710854276.XA 2017-09-20 2017-09-20 A kind of preparation method of the azaindole of 5 hydroxyl 7 Pending CN107434807A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320516A (en) * 2018-11-30 2019-02-12 重庆三圣实业股份有限公司 A kind of how appropriate preparation method and products thereof for drawing intermediate of dimension

Citations (1)

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Publication number Priority date Publication date Assignee Title
EP1749829A1 (en) * 2005-08-05 2007-02-07 Eisai London Research Laboratories Limited JNK inhibitors

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Publication number Priority date Publication date Assignee Title
EP1749829A1 (en) * 2005-08-05 2007-02-07 Eisai London Research Laboratories Limited JNK inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHANGHUA XIA 等: "Copper-Catalyzed Hydroxylation of (Hetero)aryl Halides under Mild Conditions", 《JACS》 *
许云雷; 葛敏: "BCL-2选择性抑制剂——ABT-199的合成工艺改进", 《合成化学》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320516A (en) * 2018-11-30 2019-02-12 重庆三圣实业股份有限公司 A kind of how appropriate preparation method and products thereof for drawing intermediate of dimension

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Application publication date: 20171205