CN110642880B - Preparation method of nitrogen unsubstituted pyrazole and indazole boric acid - Google Patents

Preparation method of nitrogen unsubstituted pyrazole and indazole boric acid Download PDF

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CN110642880B
CN110642880B CN201910961281.XA CN201910961281A CN110642880B CN 110642880 B CN110642880 B CN 110642880B CN 201910961281 A CN201910961281 A CN 201910961281A CN 110642880 B CN110642880 B CN 110642880B
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indazole
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覃永俊
杨兵
朱志平
夏志强
张建华
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Changsha Luxing Bio Chem Tech Co ltd
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Abstract

A preparation method of nitrogen unsubstituted pyrazole or indazole boric acid comprises the steps of dissolving nitrogen unsubstituted halogenated pyrazole and derivatives thereof or nitrogen unsubstituted halogenated indazole and derivatives thereof and triisopropyl chlorosilane in an organic solvent for reaction to generate triisopropyl silicon-based protected halogenated pyrazole or halogenated indazole compounds, then carrying out lithium-bromine exchange reaction with n-butyl lithium, adding boric acid ester to introduce boron atoms, and obtaining the nitrogen unsubstituted pyrazole or indazole boric acid with high yield after hydrolysis.

Description

Preparation method of nitrogen unsubstituted pyrazole and indazole boric acid
Technical Field
The invention relates to a preparation method of pyrazole and indazole boric acid, in particular to a preparation method of nitrogen unsubstituted pyrazole and indazole boric acid.
Background
Synthesis of Nitrogen unsubstituted Pyrazoles and indazoles boronic acid Compounds in the treatment of leukemia (see Xiaoning Deng, Barun Okram, Qiang Ding, Jianning Zhang, et al, Expanding the Diversity of A llosteric Bcr-Abl Inhibitors J. Med. chem.2010,53, 6934-6946), liver cancer (see M. Emilia Di France sco, Salvaza Avolo, Marco Pompei, et al, Synthesis an anti-viral properties of non 7-heterocyclic cultured 7-deaza-adenosine nucleic acid Inhibitors of Hepatis C NS5 polymerase biological 5B&Medicinal Chem istry 20(2012) 4801-; ASTEX THERAPEUTIC LIMITED; THE E INSTITUTE OF CANCER RESEARCH ROYAL CANCER HOS PITAL; CANCER RESEARCH TECHNOLOGY LIMITED; ASTRAZENECA AB; WO 2008/75110; (2008) (ii) a (A1) Antibacterial (see Min Teng, Mark T. Hilgers, Mark L. cunningham, Allen Borchardt, et al., Identification of Bacter)ia-Selective Th reunyl-tRNA synthetic inhibition by Structure-Based Design, J.Me d.chem.2013,56,1748-]heptanes as novel a7 neuronal nicotini c receptor(NNR)ligands,Bioorganic&The protein kinase inhibitor has wide application in fields such as Medicinal Chemistry Letters 20(2010) 3636-3639) and the like, and also has application in protein kinase inhibitors (see 1. Fabricio Giordanetto a, Andrea)
Figure BDA0002229002700000011
et al.，Discovery of phosphoinositide 3-kinas es(PI3K)p110b isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one,an effective antithrombotic ag ent without associated bleeding and insulin resistance，Bioorganic&Medicinal Chemistry Letters 22(2012)6671–6676；2.Yike Ni a,Ariamala Gopalsamy，et al.，Identification and SAR of a new series of thieno[3,2-d]pyrimidines as Tpl 2kinase inhibitors，Bioorganic&Medicinal Chemistry Letters 21(2011)5952–5956；3.Jonathan M.Large a,Jane E.Torr，et al.，Preparation and evaluationof trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors.3-Hydr oxyphenol analogues and bioisosteric replacements，Bioorganic&The synthesis of Medicinal Ch entity 19(2011) 836-.
The Suzuki coupling method (see 1.Gary A. Molander, Sarah L. J. Trice, et al., Scope of the Palladium-catalyst Aryl Borylation reaction Bis-Boronic Acid, J.Am. chem. Soc.2012,134, 11667-11673; 2. Patent; Kelly, Martha; Lee, Younghe; Liu, Bin; Fujimo to, Ted; Freund, Joel; Dorsey, Bruce D.; Flynn, Gary A.; Husain, Arifa; US 2006/270686; (A1)) is currently widely used for the synthesis of most of nitrogen-unsubstituted pyrazole and indazole Boronic Acid compounds. Furthermore, the nitrogen of the nitrogen-unsubstituted pyrazole is not protected, and the lithium-bromine exchange synthesis method is directly carried out by using n-butyllithium (see Patent; Basilea pharmaceutical AG; U.S. Pat. No. 2,21980; 2004; B1)), the reaction needs to add one more equivalent of n-butyllithium to consume nitrogen and hydrogen, and the method has the disadvantages of more impurities, low yield and difficult purification.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects in the prior art and provides a preparation method of nitrogen unsubstituted pyrazole and indazole boric acid, which is simple to operate, cheap in raw materials, convenient to purify products and easy to industrially produce.
The technical scheme adopted by the invention for solving the technical problems is as follows: a method for preparing nitrogen unsubstituted pyrazole and indazole boronic acids comprising the steps of:
(1) dissolving nitrogen unsubstituted halogenated pyrazole and derivatives thereof or nitrogen unsubstituted halogenated indazole and derivatives thereof and triisopropyl chlorosilane in an organic solvent for reaction to generate triisopropyl silicon-based protected halogenated pyrazole or halogenated indazole compounds;
(2) and (2) carrying out lithium-bromine exchange reaction on the triisopropyl silicon-based protected halogenated pyrazole or halogenated indazole compound obtained in the step (1) and n-butyllithium, introducing boron atoms into a triester borate reagent for reaction, and carrying out acidic hydrolysis on the obtained reaction product to obtain the nitrogen unsubstituted pyrazole or indazole boric acid.
Further, the organic solvent is tetrahydrofuran or dichloromethane.
Further, the acid-binding agent used for protecting substituted halogenated pyrazole or halogenated indazole nitrogen by using triisopropyl chlorosilane as a protection reagent is triethylamine, pyridine or tertiary amine.
Further, the boric acid triester reagent is triisopropyl borate or trimethyl borate.
Further, the pH of the acidic hydrolysis is 5 to 6.
Further, the acidic aqueous solution used for acidic hydrolysis is a dilute hydrochloric acid, a dilute sulfuric acid or an ammonium chloride solution.
The principle of the invention is as follows:
Figure BDA0002229002700000031
in the above reaction formula, R1Is a substituent on the pyrazole ring, X is a halogen atom bromine or iodine, R2Is a substituent on the indazole ring, Et3N is acid-binding agent triethylamine; n-BuLi is n-butyllithium and TIPB is a reagent of boric acid triester.
The invention has the beneficial effects that: the method provides the preparation method of the nitrogen unsubstituted pyrazole and indazole boric acid, which is simple to operate, cheap in raw materials, convenient to purify products, high in yield and easy for industrial production.
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FIG. 1 is a NMR spectrum of 4-bromo-1- (triisopropylsilyl) -1H-pyrazole which is an intermediate obtained in example 1;
FIG. 2 is a NMR spectrum of 1H-pyrazole-4-boronic acid, a product obtained in example 1;
FIG. 3 is a NMR spectrum of 4-bromo-3-methyl-1- (triisopropylsilyl) -1H-pyrazole which is an intermediate obtained in example 3;
FIG. 4 is a NMR spectrum of 3-methyl-1H-pyrazole-4-boronic acid obtained in example 3;
FIG. 5 is a NMR spectrum of 4-bromo-1- (triisopropylsilyl) -1H-indazole, an intermediate obtained in example 4;
FIG. 6 is a NMR spectrum of indazole-4-boronic acid, a product obtained in example 4;
FIG. 7 is a NMR spectrum of 5-bromo-1- (triisopropylsilyl) -1H-indazole, an intermediate obtained in example 5;
FIG. 8 is a NMR spectrum of indazole-5-boronic acid, a product obtained in example 5;
FIG. 9 is a NMR spectrum of 6-bromo-1- (triisopropylsilyl) -1H-indazole, an intermediate obtained in example 6;
FIG. 10 is a NMR spectrum of indazole-6-boronic acid, a product obtained in example 6.
Detailed Description
The present invention will be further described with reference to the following examples.
The chemical reagents used in the examples of the present invention, unless otherwise specified, are commercially available in a conventional manner.
Example 1
This example is the synthesis of 1H-pyrazole-4-boronic acid, comprising the following steps:
Figure BDA0002229002700000041
(1) at room temperature, dissolving 15.6 g (0.1mol) of 4-bromopyrazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 10.2 g (0.1mol) of triethylamine in 200 ml of dichloromethane, heating and carrying out micro-reflux reaction for about 72 hours, monitoring by a point plate until the reaction is finished, cooling to room temperature, filtering, concentrating the product, and recrystallizing to obtain 24.8 g of intermediate product 4-bromo-1- (triisopropylsilyl) -1H-pyrazole with the yield of 81.8%, wherein reference figure 1 is a nuclear magnetic resonance spectrum of the product 4-bromo-1- (triisopropylsilyl) -1H-pyrazole obtained in the embodiment;
1H-NMR(400MHz,CDCl3)δ:7.71(1H,s)，7.61(1H,s)，1.53(3H,m),1.11(18H,J＝7.6Hz)；
(2) adding 24.8 g of the intermediate product 4-bromo-1- (triisopropylsilyl) -1H-pyrazole obtained in the step (1) and 19.2 g (0.1mol) of triisopropyl borate into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding 40 ml (0.1mol) of 2.5M n-butyllithium solution, maintaining the reaction temperature at minus 78 ℃ or so, stirring at room temperature for half an hour after dropwise adding is finished, slowly heating to minus 20 ℃, adding 100 ml of ammonium chloride aqueous solution to quench the reaction system, adjusting the pH value of the reaction system to 5-6, extracting with ethyl acetate, drying, and recrystallizing to obtain 6.6 g of the product.
The yield of the target product 1H-pyrazole-4-boronic acid in the example is 72%, and the NMR spectrum of the product 1H-pyrazole-4-boronic acid obtained in the example is shown in FIG. 2;
1H-NMR(400MHz,DMSO-d6)δ:7.71(2H,s)，7.87(2H,brs)，12.79(1H,s)。
example 2
This example is the synthesis of 1H-pyrazole-4-boronic acid, comprising the following steps:
Figure BDA0002229002700000051
(1) at room temperature, dissolving 19.4 g (0.1mol) of 4-iodopyrazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 7.9 g (0.1mol) of pyridine in 200 ml of dichloromethane, heating and carrying out micro-reflux reaction for about 48 hours, monitoring by a point plate until the reaction is finished, cooling to room temperature, filtering, concentrating the product, and then recrystallizing to obtain 30.8 g of intermediate product 4-iodo-1- (triisopropylsilyl) -1H-pyrazole with the yield of 88%;
(2) adding 30.8 g of the intermediate product 4-iodo-1- (triisopropylsilyl) -1H-pyrazole obtained in the step (1) and 19.9 g (0.1mol) of triisopropyl borate into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding 40 ml (0.1mol) of 2.5M n-butyllithium solution, maintaining the reaction temperature at minus 78 ℃ or so, stirring at room temperature for half an hour after dropwise adding is finished, slowly heating to minus 20 ℃, adding 100 ml of ammonium chloride aqueous solution to quench the reaction system, adjusting the pH value of the reaction system to 5-6, extracting with ethyl acetate, drying, and recrystallizing to obtain 6.6 g of the product.
The yield of the target product 1H-pyrazole-4-boronic acid in the embodiment is 72%, and the NMR detection pattern is consistent with that in the embodiment 1;1H-NMR(400MHz,DMSO-d6)δ:7.71(2H,s)，7.87(2H,brs)，12.79(1H,s)。
example 3
This example is the synthesis of 3-methyl-1H-pyrazole-4-boronic acid, comprising the following steps:
Figure BDA0002229002700000052
(1) at room temperature, 16.1 g (0.1mol) of 3-methyl-4-bromopyrazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 10.2 g (0.1mol) of triethylamine are dissolved in 200 ml of dichloromethane, the mixture is heated and subjected to micro-reflux reaction for about 72 hours, a point plate monitors the reaction until the reaction is finished, the reaction product is cooled to room temperature, filtered, and recrystallized after the product is concentrated to obtain 27.3 g of intermediate product 4-bromo-3-methyl-1- (triisopropylsilyl) -1H-pyrazole, and the yield is 86.1%.
FIG. 3 is the NMR spectrum of 4-bromo-3-methyl-1- (triisopropylsilyl) -1H-pyrazole as the intermediate obtained in this example;
1H-NMR(400MHz,CDCl3)δ:7.53(1H,s)，2.27(3H,s)，1.50(3H,m),1.10(18H,d，J＝7.6Hz)；
(2) adding 27.3 g of the intermediate product 4-bromo-3-methyl-1- (triisopropylsilyl) -1H-pyrazole obtained in the step (1) and 10.5 g (0.1mol) of trimethyl borate into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding 2.5M n-butyllithium solution (40 ml and 0.1mol), maintaining the reaction temperature to minus 78 ℃ or so, stirring at room temperature for half an hour after dropwise addition is finished, slowly heating to minus 20 ℃, adding 100 ml of ammonium chloride aqueous solution to quench the reaction system, adjusting the pH value of the system to 5-6, extracting with ethyl acetate, drying, and recrystallizing to obtain 10.1 g of the product.
The yield of the target product 3-methyl-1H-pyrazole-4-boronic acid in the example is 80.1%, and FIG. 4 is a nuclear magnetic resonance spectrum of the product 3-methyl-1H-pyrazole-4-boronic acid obtained in the example;
1H-NMR(400MHz,DMSO-d6)δ:7.71(1H,s)，7.52(2H,brs)，2.29(3H,s)，12.44(1H,brs)。
example 4
This example is the synthesis of indazole-4-boronic acid, comprising the following steps:
Figure BDA0002229002700000061
(1) at room temperature, 19.7 g (0.1mol) of 4-bromoindazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 10.2 g (0.1mol) of triethylamine are dissolved in 200 ml of dichloromethane, heated and subjected to a micro reflux reaction for about 72 hours, a point plate monitors until the reaction is finished, the temperature is cooled to room temperature, the product is filtered, concentrated and then recrystallized to obtain 30.4 g of intermediate product 4-bromo-1- (triisopropylsilyl) -1H-indazole, and the yield is 86.1%.
FIG. 5 shows the NMR spectrum of 4-bromo-1- (triisopropylsilyl) -1H-indazole obtained in this example;
1H-NMR(400MHz,CDCl3)δ:8.24(1H,s)，7.50(1H,d，J＝8.4Hz)，7.28(1H,t，J1＝7.6Hz，J2＝8.4Hz),7.19(1H,d，J＝7.6Hz)，1.79(3H,m)，1.14(18H,d，J＝7.2Hz)；
(2) adding 24.8 g of the intermediate product 4-bromo-1- (triisopropylsilyl) -1H-indazole obtained in the step (1) and 23.1 g (0.1mol) of tri-n-butyl borate into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding 40 ml (0.1mol) of 2.5M n-butyllithium solution, maintaining the reaction temperature at minus 78 ℃ or so, stirring at room temperature for half an hour after dropwise adding is finished, slowly heating to minus 20 ℃, adding 100 ml of ammonium chloride aqueous solution to quench the reaction system, adjusting the pH value of the reaction system to 5-6, extracting with ethyl acetate, drying, and recrystallizing to obtain 6.6 g of the product.
The yield of the target indazole-4-boronic acid product of this example is 72%, and FIG. 6 is a nuclear magnetic resonance spectrum of the indazole-4-boronic acid product obtained in this example;
1H-NMR(400MHz,DMSO-d6)δ:8.29(1H,s)，8.18(2H,brs)，7.60(1H,d，J＝7.2Hz)，7.58(1H,d，J＝7.6Hz)，7.33(1H,d，J1＝7.2Hz,J2＝7.6Hz,)，12.95(1H,brs)。
example 5
This example is the synthesis of indazole-5-boronic acid, comprising the following steps:
Figure BDA0002229002700000071
(1) at room temperature, 19.7 g (0.1mol) of 5-bromoindazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 10.2 g (0.1mol) of triethylamine are dissolved in 200 ml of dichloromethane, heated and subjected to micro-reflux reaction for about 72 hours, a point plate monitors until the reaction is finished, the temperature is cooled to room temperature, the product is filtered, concentrated and recrystallized to obtain 31.1 g of intermediate product 5-bromo-1- (triisopropylsilyl) -1H-indazole, and the yield is 88.1%.
FIG. 7 is the NMR spectrum of 5-bromo-1- (triisopropylsilyl) -1H-indazole product obtained in this example;
1H-NMR(400MHz,CDCl3)δ:8.17(1H,s)，7.89(1H,s)，7.41(1H,t，J1＝8Hz，J2＝5.6Hz),7.19(1H,d，J＝7.6Hz)，1.79(3H,m)，1.14(18H,d，J＝7.2Hz)；
(2) adding the intermediate product 5-bromo-1- (triisopropylsilyl) -1H-indazole (24.8 g) obtained in the step (1) and tri-n-propyl borate (19.2 g, 0.1mol) into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding a 2.5M n-butyllithium solution (40 ml, 0.1mol), maintaining the reaction temperature at minus 78 or so, stirring at room temperature for half an hour after dropwise adding is finished, slowly heating to minus 20 ℃, adding 100 ml of an aqueous solution to quench the reaction system, adjusting the pH value to 5-6 by 2M hydrochloric acid, extracting by ethyl acetate, drying, and recrystallizing to obtain 6.6 g of a product,
the yield of the target indazole-5-boronic acid product of this example was 72%.
FIG. 8 is a NMR spectrum of indazole-5-boronic acid obtained in the present example;
1H-NMR(400MHz,DMSO-d6)δ:8.24(1H,s)，8.07(1H,s)，7.95(2H,brs)7.75(1H,d,J＝8.4Hz),7.46(1H,d,J＝8.4Hz),13.02(1H,brs)。
example 6
This example is the synthesis of indazole-6-boronic acid, comprising the following steps:
Figure BDA0002229002700000081
(1) at room temperature, 19.7 g (0.1mol) of 6-bromoindazole, 19.3 g (0.1mol) of triisopropylchlorosilane and 10.2 g (0.1mol) of triethylamine are dissolved in 200 ml of tetrahydrofuran, the mixture is heated and subjected to a micro reflux reaction for about 72 hours, a point plate monitors the reaction until the reaction is finished, the reaction is cooled to room temperature, the reaction product is filtered, and the product is concentrated and then recrystallized to obtain 29.7 g of intermediate product 6-bromo-1- (triisopropylsilyl) -1H-indazole, wherein the yield is 84.1%.
FIG. 9 shows the NMR spectrum of 6-bromo-1- (triisopropylsilyl) -1H-indazole, an intermediate obtained in this example;
1H-NMR(400MHz,CDCl3)δ:8.19(1H,s)，7.71(1H,s)，7.61(1H,d，J＝8.4Hz),7.25(1H,d，J1＝8.4Hz)，1.76(3H,m)，1.14(18H,d，J＝7.6Hz)。
(2) adding 29.7 g of intermediate 6-bromo-1- (triisopropylsilyl) -1H-indazole obtained in the step (1) and 19.2 g (0.1mol) of triisopropyl borate into a reaction bottle, cooling to minus 78 ℃ under the protection of nitrogen, dropwise adding 40 ml (0.1mol) of 2.5M n-butyllithium solution, maintaining the reaction temperature at minus 78 ℃ or so, stirring for half an hour at room temperature after dropwise adding is finished, slowly heating to minus 20 ℃, adding 100 ml of aqueous solution to quench the reaction system, adjusting the pH value of the system to 5-6 by 1M dilute sulfuric acid, extracting with ethyl acetate, drying, and recrystallizing to obtain 10.6 g of a product.
The yield of the target indazole-6-boronic acid product of this example was 77.9%.
FIG. 10 is a NMR spectrum of indazole-6-boronic acid, a product obtained in this example;
1H-NMR(400MHz,DMSO-d6)δ:7.51(1H,d，J＝8.4Hz)，7.68(1H,d，J＝8Hz)，7.99(1H,s)，8.03(1H,s)，8.10(2H,brs)，13.10(1H,brs)。

Claims (6)

1. a method for preparing nitrogen unsubstituted pyrazole and indazole boronic acids, comprising the steps of:
(1) dissolving nitrogen unsubstituted halogenated pyrazole or nitrogen unsubstituted halogenated indazole and triisopropyl chlorosilane in an organic solvent for reaction to generate triisopropyl silicon-based protected halogenated pyrazole or halogenated indazole compounds; the halogen atoms in the nitrogen unsubstituted halogenated pyrazole or nitrogen unsubstituted halogenated indazole are bromine and iodine;
(2) and (2) carrying out exchange reaction on the triisopropyl silicon-based protected halogenated pyrazole or halogenated indazole compound obtained in the step (1) and n-butyllithium, introducing boron atoms into a boric acid triester reagent for reaction, and carrying out acidic hydrolysis on the obtained reaction product to obtain nitrogen unsubstituted pyrazole or indazole boric acid.
2. A process for the preparation of nitrogen unsubstituted pyrazole and indazole boronic acids according to claim 1, characterized in that: the organic solvent is tetrahydrofuran or dichloromethane.
3. The process for the preparation of the nitrogen unsubstituted pyrazole and indazole boronic acids according to claims 1 and 2, characterized in that: the acid-binding agent used for protecting nitrogen unsubstituted halogenated pyrazole or nitrogen unsubstituted halogenated indazole nitrogen by using triisopropyl chlorosilane as a protection reagent is pyridine or tertiary amine.
4. The method of making nitrogen unsubstituted pyrazole and indazole boronic acids according to claim 1, wherein said boronic acid triester reagent is triisopropyl borate or trimethyl borate.
5. A process for the preparation of nitrogen unsubstituted pyrazole and indazole boronic acids according to claim 1, characterized in that: the pH of the acidic hydrolysis = 5-6.
6. A process for the preparation of nitrogen unsubstituted pyrazole and indazole boronic acids according to claim 1, characterized in that: the acidic aqueous solution used for the acidic hydrolysis is dilute hydrochloric acid, dilute sulfuric acid or ammonium chloride solution.
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