CN112159423A - Synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester - Google Patents

Synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester Download PDF

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CN112159423A
CN112159423A CN202011208942.0A CN202011208942A CN112159423A CN 112159423 A CN112159423 A CN 112159423A CN 202011208942 A CN202011208942 A CN 202011208942A CN 112159423 A CN112159423 A CN 112159423A
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pyridine
pyrrolo
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郦荣浩
王治国
邹成
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Kemec Shanghai Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester, belonging to the field of pharmaceutical chemistry. 7-azaindole is taken as a raw material to react with di-tert-butyl dicarbonate to synthesize 1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester, and then the tert-butyl ester reacts with n-butyl lithium, 1, 2-dibromo tetrafluoroethane reacts at low temperature to synthesize 2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester, deprotection is carried out to obtain 2-bromo-1H-pyrrolo [2,3-b ] pyridine, synthesis of 2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester, deprotection is carried out to obtain 2-bromo-1H-pyrrolo [2,3-b ] pyridine, and the 2-bromo-1H-pyrrolo [2,3-b ] pyridine reacts with bis (pinacol) borate under the catalysis of transition metal to obtain a target product. The raw materials and reagents are cheap and easy to obtain, the reaction condition is mild, the safety is high, the cost is low, and the industrial batch production is easy to realize.

Description

Synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester.
Background
1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester (also called 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine) is a pyrrolo [2,3-b ] pyridine compound, is a very important medical intermediate, has great social and economic benefits, can act on an intermediate of a candidate drug inhibitor of a MAP kinase family (also called P38 kinase), has a P38 kinase signal pathway influencing the activity of cytokines such as IL-1, IL-6, IL-8, TNF alpha and the like for regulating inflammation, and can be used for treating a plurality of chronic and acute diseases such as various inflammations and pulmonary fibrosis; also useful in the preparation of compounds that modulate receptor protein kinases (RPTKs) that regulate key signal transduction cascades that control cell growth and proliferation. Stem Cell Factor (SCF) receptor c-kit is a type III transmembrane RPTK, and abnormal expression or activation and mutation of c-kit are related to leukemia, mast cell tumor, small cell lung cancer, testicular cancer, etc. Modulation of kinase activity as appropriate for the relevant indication being treated.
There is no public report on the synthesis of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester. PCT patent WO2014/100620 a2 discloses the synthesis of similar compounds, the synthetic route is as follows:
Figure BDA0002758107310000011
wherein, condition a is sodium hydrogen (NaH), Tetrahydrofuran (THF); condition b is tert-butyl carbamate (Boc-NH)2) Cesium carbonate (Cs)2CO3) Palladium acetate (Pd (OAc)2) 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (xanthphos), 1,4-dioxane (1, 4-dioxane); with the proviso that c is tert-butyllithium (t-BuLi) or iodine (I)2) Tetrahydrofuran (THF); with the proviso that d is di-tert-butyldicarbonate (Boc)2O), 4-Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIEA), Tetrahydrofuran (THF); condition e is n-butyllithium (n-BuLi), isopropanol pinacol borate, Tetrahydrofuran (THF); the condition f is dioxane hydrochloride (HCl/1,4-dioxane), Tetrahydrofuran (THF). However, the reported method has the following disadvantages: the reaction route is as long as seven steps, the initial raw material compound 1 is not cheap, the compounds 5 to 6 are obtained, nitrogen atoms are added with tert-butyloxycarbonyl (Boc), the tert-butyloxycarbonyl (Boc) is heated in the next step of reaction and lost, and the reaction process is complicated; the reaction yield of the compound 6 to the compound 7, the n-butyl lithium hydrogen abstraction, the boric acid ester on the isopropanol pinacol boric acid ester is extremely low and is only 16 percent at room temperature overnightAnd the method has long route and low yield, and is not suitable for repetition. Therefore, it is important to find a new method with short route steps and suitable yield.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester, which comprises four steps to synthesize a target product under appropriate reaction conditions, wherein the positions of substituents are determined, the reaction steps are few, and the yield is high.
In order to achieve the above purpose, the invention provides the following technical scheme:
a synthetic method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester is disclosed, and a synthetic route is shown as the following formula:
Figure BDA0002758107310000021
the synthesis steps comprise:
1) adding the compound 1 (7-azaindole), triethylamine and 4-dimethylaminopyridine into a first organic solvent at the temperature of-5 ℃, adding di-tert-butyl dicarbonate, and reacting at room temperature for 0.5-4H to obtain a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
2) dropwise adding an alkali solution into a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) in a second organic solvent at-78 ℃, stirring for 0.5-1H at-78 ℃, dropwise adding a bromine reagent solution, and continuously reacting for 0.5-4H at-78 ℃ to obtain a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
3) adding a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) into a third organic solvent, and stirring at 15-30 ℃ for 0.5-18H to obtain a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine);
4) adding a transition metal catalyst into a fourth organic solvent containing a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine), bis-pinacol borate and alkali, and carrying out reflux reaction for 2-18H to obtain a compound 5 (1H-pyrrolo [2,3-b ] pyridine-2-pinacol borate).
Further, in the step 1), the molar ratio of the compound 1 (7-azaindole), triethylamine and 4-dimethylaminopyridine is 1: (1-4): (0.05-1).
Further, in step 1), the first organic solvent is one or a combination of two or more of tetrahydrofuran, dichloromethane, acetonitrile, toluene, dimethyl sulfoxide and N, N-dimethylformamide, and the mass volume ratio is 1: 8 to 15 (g/mL).
Further, in the step 2), the base is selected from one or a combination of more than two of n-butyl lithium, tert-butyl lithium and lithium diisopropylamide;
the bromine reagent is one or the combination of more than two of carbon tetrabromide, dibromo tetrafluoroethane and dibromo tetrachloroethane.
Further, in step 2), the molar ratio of compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester), base and bromine reagent is 1: (1-2): (1-2).
Further, in the step 2), the second organic solvent is one or a combination of more than two of diethyl ether, tetrahydrofuran and n-hexane.
Further, in step 3), the third organic solvent is one or a combination of two or more of trifluoroacetic acid, dichloromethane, boron tribromide, hydrochloric acid, dioxane, ethyl acetate, ethanol, methanol and water, and the mass-to-volume ratio is 1: 8 to 20 (g/mL).
Further, in the step 4), the alkali is potassium acetate or sodium acetate, and the catalyst is selected from Pd (PPh)3)4、Pd(dppf)Cl2、Pd(dba)2、PdCl2(PPh3)2、Pd(MeCN)2Cl2In the above-mentioned manner, the first and second substrates are,
the fourth organic solvent is selected from one of dioxane, toluene, dimethyl sulfoxide and N, N-dimethylformamide.
Further, in the step 4), the molar ratio of the compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine), the base, the bisphenonal borate and the transition metal catalyst is 1: (1-3): (1-3): (0.05-0.3).
Further, in the step 4), the reaction needs inert gas protection, and is anhydrous and oxygen-free, and the reaction temperature is 60-120 ℃.
According to the technical scheme, the synthesis method of the 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester provided by the technical scheme of the invention has the following beneficial effects:
(1) the invention provides a novel synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester based on the existing synthesis route, and the route has the advantages of short steps, proper yield, cheap and easily-obtained raw materials and reagents, mild reaction conditions, high safety, low preparation cost and easiness in industrial batch production.
(2) The invention adopts a synthesis method with higher yield and low cost to prepare the drug intermediate 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester, and provides a new specific targeted drug selection for treating related indications.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
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FIG. 1 is a nuclear magnetic hydrogen spectrum of 2-bromo-1H-pyrrolo [2,3-b ] pyridine.
FIG. 2 is a nuclear magnetic hydrogen spectrum of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Similarly, the singular forms "a," "an," or "the" do not denote a limitation of quantity, but rather denote the presence of at least one, unless the context clearly dictates otherwise. The terms "comprises," "comprising," or the like, mean that the elements or items listed before "comprises" or "comprising" encompass the features, integers, steps, operations, elements, and/or components listed after "comprising" or "comprising," and do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
The following will specifically describe the synthesis method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester in the present invention with reference to the accompanying drawings and examples. In the present disclosure, "under room temperature" means a temperature range of 10 to 30 ℃,1eq means 1 equivalent, a molar ratio of 1: 1.
in the following examples, the synthetic route for 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester is shown by the following formula:
Figure BDA0002758107310000041
the synthesis steps comprise:
1) adding the compound 1 (7-azaindole), triethylamine and 4-dimethylaminopyridine into a first organic solvent at the temperature of-5 ℃, adding di-tert-butyl dicarbonate, and reacting at room temperature for 0.5-4H to obtain a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
2) dropwise adding an alkali solution into a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) in a second organic solvent at-78 ℃, stirring for 0.5-1H at-78 ℃, dropwise adding a bromine reagent solution, and continuously reacting for 0.5-4H at-78 ℃ to obtain a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
3) adding a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) into a third organic solvent, and stirring at 15-30 ℃ for 0.5-18H to obtain a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine);
4) adding a transition metal catalyst into a fourth organic solvent containing a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine), bis-pinacol borate and alkali, and carrying out reflux reaction for 2-18H to obtain a compound 5 (1H-pyrrolo [2,3-b ] pyridine-2-pinacol borate).
Example 1
Figure BDA0002758107310000051
The first step is as follows: synthesis of Compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester)
Compound 1 (7-azaindole) (600g,5.08mol,1eq) and triethylamine (1540g,15.24mol,3eq), 4-dimethylaminopyridine (31g,0.25mol,0.05eq) were reacted in 9L of dichloromethane at-5 to 5 ℃ with di-tert-butyl dicarbonate (1220g,5.59mol,1.1eq) and then at room temperature for 4 h. After the reaction was completed, 10L of water was added for dilution, extraction was performed, and extraction with dichloromethane (10L × 2) was further performed. The organic phases were combined, dried over sodium sulfate and spin-dried to give 2 (tert-butyl 1H-pyrrolo [2,3-b ] pyridine-1-carboxylate) (1020g,4.67mol, 92, 02% yield) as a yellow oil
The second step is that: synthesis of Compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester)
Compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) (1020g,4.67mol,1eq) was dissolved in 13.8L tetrahydrofuran, cooled to-78 ℃, then 2.06L of n-butyllithium hexane solution (5.14mol,2.5M,1.1eq) was added dropwise and maintained at-78 ℃ for one hour, 2L of tetrahydrofuran solution in which 1, 1-dibromotetrafluoroethane (1420g,5.47mol,1.17eq) was dissolved was added dropwise thereto and reacted for 3 hours while maintaining the temperature, and the mixture was slowly and naturally warmed to room temperature and then treated. TLC detection raw material reaction is complete. After quenching in 20L of aqueous ammonium chloride, the THF layer was separated, the aqueous phase was extracted twice with EA (20L. multidot.2), the organic phases were combined, dried, spun-dried and slurried to give compound 3 (tert-butyl 2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate) (1210g, 4.07mol, 87.13% yield).
The third step: synthesis of Compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine)
Compound 3 (tert-butyl 2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate) (1210g, 4.07mol,1eq) was added to 5L of water, and 6.7L of a 3N aqueous hydrochloric acid solution (20.36mol,5eq) was added dropwise with stirring at room temperature for 6 hours. The mixture was cooled to 0 ℃ in an ice bath, and an aqueous ammonia solution was slowly added to make the solution cloudy. Filtering, washing the filter cake with 3L cold water, and then washing with 2L petroleum ether. The filter cake was dried under vacuum to give compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine) (746g, 3.79mol, yield 92.98%).
As shown in figure 1, compound 4 (2-bromo-1H-pyrrolo [2, 3-b)]Pyridine) nuclear magnetism1H-NMR(600MHz,DMSO)12.44(s,1H),8.19(dd,J＝4.7,1.3Hz,1H),7.89(dd,J＝7.8,1.3Hz,1H),7.07(dd,J＝7.8,4.7Hz,1H),6.58(s,1H)。
The fourth step: synthesis of Compound 5 (1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester)
Reacting compound 4 (2-bromo-1H-pyrrole [2, 3-b)]Pyridine) (746g, 3.79mol,1eq) was added to 10L of 1,4-dioxane, followed by the addition of bisphenonal borate (1150g, 4.54mol,1.2eq), potassium acetate (743g, 7.57mol,2.0eq), and then Pd (dppf)2Cl2(277g, 0.38mol,0.1eq), under argon, reflux at 90 ℃ for 12 h. And (3) detecting that the raw materials are completely reacted by a point plate, flushing ice water in reaction liquid, extracting by EA, drying, spin-drying, mixing the sample, and passing through a column. To obtain the compound 5 (1H-pyrrolo [2, 3-b)]Pyridine-2-boronic acid pinacol ester) (735g, 3.01mol, yield 79.53%).
As shown in FIG. 2, Compound 5 (1H-pyrrolo [2, 3-b)]Pyridine-2-boronic acid pinacol ester) nuclear magnetism1H-NMR(400MHz,CDCl3)10.28(s,1H),8.44(dd,J＝4.7,1.5Hz,1H),8.01(dd,J＝7.9,0.9Hz,1H),7.13–7.02(m,2H),1.39(s,12H)。
The present invention further tests the effect of the change of reaction conditions in each reaction step on the yield of the reaction product in this step, such as the key influencing factors of the reaction step 2 of compounds 2 to 3 and the reaction step 4 of compounds 4 to 5, and the specific examples and tests are shown in table 1.
TABLE 1
Figure BDA0002758107310000061
Examples 2-3 changed the equivalent of n-butyllithium in step 2 compared to example 1, with less 0.8eq of n-butyllithium, making the reaction insufficient (example 2), while too much 1.5eq of n-butyllithium increased side reactions (example 3); for the reaction step 2), 1.1eq of n-butyllithium are suitable. Moreover, the reaction needs to be strictly controlled in an anhydrous and oxygen-free environment, and the reagent or the solvent contains water, so that the lithium reagent is consumed.
Examples 4-6 varied the reaction temperature of step 2) compared to example 1, the higher the temperature, the lower the yield. The temperature determines the position of hydrogen extraction of butyl lithium and the stability of the intermediate lithium salt, and the temperature rise may extract the 3-position hydrogen of 7 azaindole, so that the intermediate lithium salt solution is more unstable, which leads to impurity change and yield reduction in the reaction step 2), and is preferably controlled at a low temperature of-78 ℃.
Compared with the example 1, the examples 7 to 9 change the reaction time of the step 4), the reaction time is increased from 2h to 12h, and the yield is gradually improved. In the process, the raw materials are continuously consumed to generate the target product. When the reaction time was increased from 12h to 18h, the yield decreased instead. The reaction is used as the name reaction of Miyaura, the reaction time is too long, the generated boric acid ester product is related to the coupling of the raw material and the remarkable increase of byproducts such as bromine removal of the raw material, and the reaction time is preferably controlled to be 12 h.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims (10)

1. A synthetic method of 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester is characterized in that a synthetic route is shown as the following formula:
Figure FDA0002758107300000011
the synthesis steps comprise:
1) adding the compound 1 (7-azaindole), triethylamine and 4-dimethylaminopyridine into a first organic solvent at the temperature of-5 ℃, adding di-tert-butyl dicarbonate, and reacting at room temperature for 0.5-4H to obtain a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
2) dropwise adding an alkali solution into a compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) in a second organic solvent at-78 ℃, stirring for 0.5-1H at-78 ℃, dropwise adding a bromine reagent solution, and continuously reacting for 0.5-4H at-78 ℃ to obtain a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester);
3) adding a compound 3 (2-bromo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester) into a third organic solvent, and stirring at 15-30 ℃ for 0.5-18H to obtain a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine);
4) adding a transition metal catalyst into a fourth organic solvent containing a compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine), bis-pinacol borate and alkali, and carrying out reflux reaction for 2-18H to obtain a compound 5 (1H-pyrrolo [2,3-b ] pyridine-2-pinacol borate).
2. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 1), the molar ratio of the compound 1 (7-azaindole), triethylamine and 4-dimethylaminopyridine is 1: (1-4): (0.05-1).
3. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 1), the first organic solvent is one or a combination of two or more of tetrahydrofuran, dichloromethane, acetonitrile, toluene, dimethyl sulfoxide and N, N-dimethylformamide, and the mass-to-volume ratio is 1: 8 to 15 (g/mL).
4. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 2), the alkali solution is one or more of a solution of n-butyl lithium, tert-butyl lithium and lithium diisopropylamide;
the bromine reagent is selected from one or the combination of more than two of carbon tetrabromide, dibromotetrafluoroethane and dibromotetrachloroethane.
5. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 2), the molar ratio of the compound 2 (1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester), the base and the bromine reagent is 1: (1-2): (1-2).
6. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 2), the second organic solvent is one or a combination of more than two of diethyl ether, tetrahydrofuran and n-hexane.
7. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 3), the third organic solvent is one or a combination of two or more of trifluoroacetic acid, dichloromethane, boron tribromide, hydrochloric acid, dioxane, ethyl acetate, ethanol, methanol and water, and the mass-to-volume ratio is 1: 8 to 20 (g/mL).
8. The 1H-pyrrolo [2,3-b ] according to claim 1]The synthesis method of pyridine-2-boronic acid pinacol ester is characterized in that in the step 4), the alkali is potassium acetate or sodium acetate; the catalyst is selected from Pd (PPh)3)4、Pd(dppf)Cl2、Pd(dba)2、PdCl2(PPh3)2、Pd(MeCN)2Cl2One of (1); the fourth organic solvent is selected from dioxygenOne of hexacyclic ring, toluene, dimethyl sulfoxide and N, N-dimethyl formamide.
9. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 4), the molar ratio of the compound 4 (2-bromo-1H-pyrrolo [2,3-b ] pyridine), the base, the bisphenonanol borate and the transition metal catalyst is 1: (1-3): (1-3): (0.05-0.3).
10. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine-2-boronic acid pinacol ester according to claim 1, wherein in the step 4), the reaction needs inert gas protection, no water or oxygen, and the reaction temperature is 60-120 ℃.
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CN104402920A (en) * 2014-11-27 2015-03-11 薛峰 Method for synthesizing 2-halogenated-3-pinacol borate-5-chloroaniline
CN105308036A (en) * 2012-12-21 2016-02-03 普莱希科公司 Compounds and methods for kinase modulation, and indications therefor
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CN102917707A (en) * 2010-05-06 2013-02-06 默沙东公司 Aza-indole derivatives useful as modulators of FAAH
EP2738172A1 (en) * 2012-11-28 2014-06-04 Almirall, S.A. New bicyclic compounds as crac channel modulators
CN105308036A (en) * 2012-12-21 2016-02-03 普莱希科公司 Compounds and methods for kinase modulation, and indications therefor
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