CN117500789A - Preparation method of pyridine borate - Google Patents

Preparation method of pyridine borate Download PDF

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Publication number
CN117500789A
CN117500789A CN202180099449.6A CN202180099449A CN117500789A CN 117500789 A CN117500789 A CN 117500789A CN 202180099449 A CN202180099449 A CN 202180099449A CN 117500789 A CN117500789 A CN 117500789A
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Prior art keywords
preparation
tetramethyl
dimethyl
dioxaborolan
pyridine
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CN202180099449.6A
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Inventor
胡范
周鑫洁
张宇辰
胡海文
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention provides a preparation method of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine, which can reduce the consumption of boric acid ester, reduce the cost and three wastes and ensure that the effective content of the product is higher.

Description

Preparation method of pyridine borate Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an intermediate pyridine borate of a GLP-1 receptor agonist.
Background
(S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1, 4)]-dioxino [2,3-g]Isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid dihydrochloride, a non-peptide small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, having the formula C 50 H 49 Cl 4 N 3 O 6 The molecular weight is 929.76. (S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1, 4)]-dioxino [2,3-g]Isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid dihydrochloride contains four chiral centers, wherein (S) -2-amino-3- [4- (2, 3-dimethylpyridin-4-yl) phenyl]Methyl propionate diacid salt introduces the last chiral center for synthesis and is a key intermediate in the preparation process.
CN102378574a discloses a method for synthesizing (S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] -dioxino [2,3-g ] isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid free base, wherein specifically (S) -3- (4-bromo-phenyl) -2-tert-butoxycarbonylamino-propionic acid methyl ester VI is prepared from (S) -3- (4-bromo-phenyl) -2-tert-butoxycarbonylamino-propionic acid methyl ester VI as starting material by 3 steps of Suzuki coupling, deprotection, etc. to obtain (S) -2-amino-3- [4- (2, 3-dimethylpyridin-4-yl) phenyl ] propionic acid methyl ester dihydrochloride (IV). In the method, column chromatography separation and purification are needed, the total yield is only 49%, the price of the compound IX is more expensive, and only gram-grade raw materials are supplied in the market, so that the industrialized application is difficult.
In order to realize the industrial application, related researchers re-develop two synthetic routes suitable for industrialization, as shown below, two new processes both use an intermediate 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (namely, a compound III), the preparation of the compound III in the literature (WO 2015153720A 1) also uses the compound IX as a raw material, and the coupling with di (pinacol) diboron is influenced by the yield of the compound IX, and the method is not suitable for the industrial application.
In two newly developed routes, 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (compound III) is prepared by using relatively cheap and easily available pyridine nitrogen oxide XIII as a raw material and carrying out coupling reaction with di (pinacolato) diboron, wherein in the reaction, the di (pinacolato) diboron is used as a deoxidizing reagent and a coupling reagent, so that the consumption of the di (pinacolato) diboron is larger (more than 2 equivalents), the cost is about 33%, the compound III is a high-consumption material, the selling price is higher, and the whole process cost is directly influenced. In addition, a large amount of boric acid waste residues generated by using di (pinacolato) diboron bring great pressure to post-treatment. Therefore, further optimization is needed, and a more efficient method is sought to prepare the compound III, so that the consumption of boric acid ester is reduced, the cost is lowered, and three wastes are reduced.
Disclosure of Invention
The invention provides a novel method for preparing 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (compound III), which reduces the consumption of boric acid ester, lowers the cost and reduces three wastes.
The invention provides a method for preparing 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (compound III), which comprises the following steps:
1) Deoxidizing the compound XIII under the action of a reducing agent to generate an intermediate A;
2) The intermediate A and di (pinacolato) diboron are subjected to coupling reaction under the action of organic acid salt and a catalyst to generate a compound III.
As a specific embodiment, the reducing agent used in the step 1) is selected from Fe, fe/NH 4 Cl, fe/AcOH, fe/HCl, zn/AcOH or PCl 3 。
As a specific embodiment, the reducing agent used in step 1) is preferably Fe/NH 4 Cl。
As a specific embodiment, the reaction solvent used in the step 1) is selected from a mixed solution of water and any one of methanol, ethanol, n-propanol and tetrahydrofuran.
As a specific embodiment, the reaction solvent used in step 1) is preferably ethanol/water.
As a specific embodiment, the molar feed ratio of compound XIII to reducing agent in step 1) is 1:1.5 to 1:5.
as a specific embodiment, the molar feed ratio of compound XIII to reducing agent in step 1) is preferably 1: 2-1: 3.
as a specific embodiment, the step 1) may be carried out after completion of the reaction.
In a specific embodiment, the post-treatment method in the step 1) is that after the reaction is finished, the filtering, concentrating to remove the organic solvent, extracting to remove the water phase, drying the organic phase, filtering and concentrating; wherein the extraction reagent is selected from dichloromethane or ethyl acetate; the dry reagent is sodium sulfate.
As a specific embodiment, the reaction solvent of step 2) is selected from xylene or toluene.
As a specific embodiment, the reaction solvent of step 2) is preferably xylene.
As a specific embodiment, the catalyst in step 2) is selected from palladium catalyst or a mixed system of palladium catalyst and organophosphorus ligand; the palladium catalyst is selected from Pd 2 (dba) 3 ，PdCl 2 (PPh 3 ) 2 ，Pd(OAc) 2 The organophosphorus ligand is selected from PCy 3 ，PPh 3 ，n-Bu 3 P，P(OMe) 3 One or two or more of them.
As a specific embodiment, the catalyst in step 2) is preferably Pd 2 (dba) 3 And PCy 3 And (3) a mixed system.
As a specific embodiment, the organic acid salt used in the step 2) is selected from potassium acetate, sodium acetate, potassium oxalate, sodium citrate, potassium L-tartrate, sodium L-tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate.
As a specific embodiment, the organic acid salt used in the step 2) is preferably potassium acetate.
As a specific embodiment, the feeding mole ratio of the compound A to the di (pinacolato) diboron in the step 2) is 1:1-1:1.2.
As a specific embodiment, the reaction temperature of the step 2) is selected from 90 to 130 ℃.
As a specific embodiment, the reaction of step 2) should be followed by a post-treatment.
As a specific implementation mode, the post-treatment method of the step 2) is that after the reaction is finished, adding an organic solvent, stirring, filtering out insoluble matters, adding an acid solution into the filtrate, removing the organic layer, washing the acid water layer, regulating the pH of the acid water layer to 8-9 by using a dilute alkali solution, filtering, and drying to obtain a solid compound III; wherein the organic solvent is selected from any one of heptane, n-hexane and cyclohexane; the washing reagent is selected from dichloromethane or ethyl acetate.
The beneficial effects of the invention are as follows: by changing the deoxidizing method, deoxidizing with reducing agent and then coupling reaction, the use level of di (pinacolato) diboron can be reduced by more than half, thus greatly reducing the cost of raw materials. Meanwhile, the post-treatment is simplified, and the product with higher purity can be obtained, so that the effective content of the product is higher.
Detailed Description
The experimental method without specific conditions noted in the embodiments of the present invention is generally conventional conditions or conditions suggested by the manufacturer of the raw materials or goods; reagents of unspecified origin are typically conventional reagents commercially available or may be prepared from known reagents by conventional methods.
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 preparation of Compound III
Compound XIII (20 g,126.9mmol,1 eq), iron powder (17.56 g,317.26mmol,2.5 eq), ammonium chloride (20.4 g,317.25mmol,2.5 eq), 6ml water, 60ml methanol were added to the reaction flask and reacted for 5h at 65℃under nitrogen. After the reaction, the iron-removed powder was filtered off with suction, ethanol was removed by spinning, 50ml of water was added, and dichloromethane (3X 80 ml) was added for extraction. Saturated brine (2X 100 ml), dried over anhydrous sodium sulfate, and dried by spinning to give 16.09g of a yellow liquid. The yield was 89.5% and the purity was 99.8%.
Intermediate A (11.74 g,82.91mmol,1 eq) was added to toluene followed by bis (pinacolato) diboron (23.16 g,91.2mmol,1.1 eq) followed by potassium acetate (24.41 g,248.73mmol,3 eq), pd 2 (dba) 3 (152mg，0.17mmol，0.002eq)，PCy 3 (186 mg,0.66mmol,0.008 eq). And (3) nitrogen protection and reaction at 100 ℃. After the reaction is finished, cooling to room temperature, adding heptane for dilution, stirring for 1h, filtering, adding 2N diluted hydrochloric acid into the solution for extraction, washing with dichloromethane twice, adding saturated sodium carbonate into the water phase for regulating the pH to 8-9, filtering and drying to obtain 21.12g of white solid. The yield thereof was found to be 94% and the purity thereof was found to be 99%.
Example 2
Compound XIII (20 g,126.9mmol,1 eq), iron powder (17.56 g,317.26mmol,2.5 eq), acetic acid (19.05 g,317.25mmol,2.5 eq), 6ml water, 60ml methanol were added to the reaction flask and reacted for 5h at 65℃under nitrogen. After the reaction, the iron powder was removed by suction filtration, ethanol was removed by rotation, and 50ml of water was added thereto, followed by extraction with methylene chloride. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and dried by spinning to give 13.48g of a yellow liquid. Yield 75.0% and purity 98.8%.
Intermediate A (11.74 g,82.91mmol,1 eq) was added to toluene followed by bis (pinacolato) diboron (23.16 g,91.2mmol,1.1 eq) followed by potassium acetate (24.41 g,248.73mmol,3 eq), pd 2 (dba) 3 (152mg，0.17mmol，0.002eq)，PCy 3 (186 mg,0.66mmol,0.008 eq). And (3) nitrogen protection and reaction at 100 ℃. After the reaction is finished, cooling to room temperature, adding heptane for dilution, stirring for 1h, filtering, adding 2N diluted hydrochloric acid into the solution for extraction, washing with dichloromethane twice, adding saturated sodium carbonate into the water phase for regulating the pH to 8-9, filtering and drying to obtain 21.12g of white solid. The yield thereof was found to be 94% and the purity thereof was found to be 99%.
Example 3
Compound XIII (20 g,126.9mmol,1 eq), iron powder (17.56 g,317.26mmol,2.5 eq), ammonium chloride (20.4 g,317.25mmol,2.5 eq), 6ml water, 60ml methanol were added to the reaction flask and reacted for 5h at 65℃under nitrogen. After the reaction, the iron powder was removed by suction filtration, ethanol was removed by rotation, and 50ml of water was added thereto, followed by extraction with methylene chloride. Saturated brine (2X 100 ml), dried over anhydrous sodium sulfate, and dried by spinning to give 16.09g of a yellow liquid. The yield was 89.5% and the purity was 99.8%.
Intermediate A (11.74 g,82.91mmol,1 eq) was added to toluene followed by bis (pinacolato) diboron (23.16 g,91.2mmol,1.1 eq) followed by potassium acetate (24.41 g,248.73mmol,3 eq), pdCl 2 (PPh 3 ) 2 (1.19 g,1.7mmol,0.02 eq). And (3) nitrogen protection and reaction at 100 ℃. After the reaction, cooling to room temperature, adding heptane (80 ml) for dilution, stirring for 1h, filtering, adding 2N diluted hydrochloric acid (3X 100 ml) into the solution for extraction, washing with dichloromethane (50 ml) twice, adding saturated sodium carbonate into the aqueous phase for regulating the pH to 8-9, filtering and drying to obtain 21.56g of white solid. The yield was 96% and the purity was 99.2%.
The above embodiments are only for understanding the method and core idea of the present invention, and do not limit the scope of the present invention. It will be apparent to those skilled in the art that any possible variations or substitutions can be made without departing from the spirit of the invention.

Claims (9)

  1. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine comprising the steps of:
    1) Deoxidizing the compound XIII under the action of a reducing agent to generate an intermediate A;
    2) The intermediate A and di (pinacolato) diboron are subjected to coupling reaction under the action of organic acid salt and a catalyst to generate a compound III.
  2. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine as defined in claim 1, wherein the reducing agent in step 1) is selected from the group consisting of Fe/NH 4 Cl, fe/AcOH, fe/HCl, zn/AcOH or PCl 3 Preferably Fe/NH 4 Cl；
    And/or the reaction solvent in the step 1) is selected from a mixed solution of any one of methanol, ethanol, n-propanol and tetrahydrofuran and water, preferably an ethanol/water solution.
  3. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine as defined in claim 1, wherein the molar ratio of compound XIII to reducing agent in step 1) is 1:1.5 to 1:5, preferably 1: 2-1: 3.
  4. a process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to claim 1, wherein the reaction solvent of step 2) is xylene or toluene, preferably xylene.
  5. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to claim 1, wherein the catalyst added in step 2) is selected from palladium catalyst or a mixed system of palladium catalyst and organophosphorus ligand; the palladium catalyst is selected from Pd 2 (dba) 3 ，PdCl 2 (PPh 3 ) 2 ，Pd(OAc) 2 The organophosphorus ligand is selected from PCy 3 ，PPh 3 ，n-Bu 3 P，P(OMe) 3 One or more of them, preferably Pd 2 (dba) 3 And PCy 3 And (3) a mixed system.
  6. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to claim 1, wherein the organic acid salt added in step 2) is selected from potassium acetate, sodium acetate, potassium oxalate, sodium citrate, potassium L-tartrate, sodium L-tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, sodium maleate, preferably potassium acetate.
  7. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to claim 1, wherein the molar ratio of compound a to di (pinacolato) diboron in step 2) is from 1:1 to 1:1.2;
    and/or the reaction temperature of the step 2) is 90-130 ℃.
  8. A process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to claim 1, wherein step 1) and/or step 2) is/are completed and may be subjected to a post-treatment.
  9. Use of a process for the preparation of 2, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine according to any one of claims 1 to 8 for the preparation of (S) -2- (3S, 8S) -3- (4- (3, 4-dichlorobenzyloxy) phenyl-7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] -dioxino [2,3-g ] isoquinoline-8-carboxamido) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionic acid.
CN202180099449.6A 2021-06-17 2021-09-26 Preparation method of pyridine borate Pending CN117500789A (en)

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CN202110670498 2021-06-17
CN2021106704982 2021-06-17
PCT/CN2021/120522 WO2022262143A1 (en) 2021-06-17 2021-09-26 Method for preparing pyridine borate

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WO2010114824A1 (en) * 2009-03-30 2010-10-07 Transtech Pharma Inc Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
CN117466884A (en) * 2017-07-13 2024-01-30 德州大学系统董事会 Heterocyclic compounds or salts thereof as ATR kinase inhibitors, pharmaceutical compositions containing same and uses thereof
WO2019103060A1 (en) * 2017-11-22 2019-05-31 第一三共株式会社 Condensed tricyclic compound
EP4163271A4 (en) * 2020-05-28 2024-07-17 Hangzhou Zhongmeihuadong Pharmaceutical Co Ltd Method for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof
TW202206412A (en) * 2020-05-28 2022-02-16 美商維特衛治療有限責任公司 Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof
EP4159719A4 (en) * 2020-05-28 2024-07-17 Hangzhou Zhongmeihuadong Pharmaceutical Co Ltd Preparation method for (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)methyl propionate diacid salt

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