CN109762007B - Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester - Google Patents
Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester Download PDFInfo
- Publication number
- CN109762007B CN109762007B CN201910143762.XA CN201910143762A CN109762007B CN 109762007 B CN109762007 B CN 109762007B CN 201910143762 A CN201910143762 A CN 201910143762A CN 109762007 B CN109762007 B CN 109762007B
- Authority
- CN
- China
- Prior art keywords
- tetrahydropyridine
- substituted
- synthesizing
- acid ester
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a method for synthesizing organic compounds. A process for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate includes such steps as reaction of N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide with diborate, cuprous halide or cuprous oxide, ligand and organic alkali in solvent to obtain N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate. The method has the advantages of originality, simple and convenient operation, short process route, low cost, high product purity and mild reaction conditions, avoids the adoption of metal palladium coupling or high-activity Grignard reagent and low-temperature conditions in the traditional method, has potential cost advantage and is suitable for industrial amplification production.
Description
Technical Field
The invention relates to a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester, belonging to the field of synthesis of pharmaceutical intermediates.
Background
The N-substituted-1, 2,5, 6-tetrahydropyridine structure is often introduced into a drug molecule as an important structural unit or used to perform a coupling reaction to obtain a compound having pharmaceutical activity. Such as opioid receptor 1(OGL1) antagonist 1 and fatty acid amide hydrolase inhibitor 2. The synthesis of the compounds usually adopts palladium-catalyzed coupling of N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate ester, and then reduction is carried out to obtain the required compounds.
Currently, two methods are mainly used for synthesizing the N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate ester: method 1[1]The N-substituted-1, 2,5, 6-tetrahydropyridine-4-trifluoromethanesulfonate with high price is taken as a raw material and is synthesized by coupling reaction with diborate ester under the catalysis of metal palladium; method two[2]The method adopts N-substituted-4-piperidone as a raw material, reacts with triaryl phosphite, halogen and organic base to convert carbonyl into alkenyl halide, and then reacts with isopropyl magnesium chloride-lithium chloride and alkoxy borate to obtain N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate. Its main advantage is easily available raw material. But the synthesis is carried out by a two-step method, high-activity isopropyl magnesium bromide-lithium chloride is used, the low-temperature condition is adopted, the process is complicated, and the yield and the purity are not high.
Reference documents: gerfaud, T.; martin, c.; bouquet, k.; talano, s.;Millois-Barbuis, C.；Musicki,B.；Boiteau,J.；Cardinaud,I.Organic Process Research and Development.2017,21,631-640.
2. chinese patent CN201610014644.5, publication No. CN 105566367.
The above method has the following disadvantages: in the first method, an expensive metal palladium catalyst is used, so that the cost is high; the second method needs two steps of reaction, uses high-activity isopropyl magnesium bromide-lithium chloride and low-temperature conditions, and has the disadvantages of complex operation and low yield and purity.
Disclosure of Invention
The invention aims to solve the problems of the defects and provides a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate, wherein an N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide is used as a raw material and reacts with diborate, cuprous halide or cuprous oxide, a ligand and an organic base in a reaction solvent to obtain the N-substituted-1, 2,5, 6-tetrahydropyridine-4-borate, and the HPLC and nuclear magnetic purity is more than 99%. The one-step synthesis method has the advantages of short process route, low cost, high product purity, mild reaction conditions, easy operation and suitability for industrial application.
The technical scheme adopted by the invention for solving the problems is as follows: a process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester is characterized by comprising the following steps: the method comprises the following steps:
coupling reaction: dissolving N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate ester, cuprous halide or cuprous oxide, ligand and organic base in a reaction solvent, and stirring for reaction at 30-60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, diluting the filtrate by using a diluting solvent, washing the filtrate by using water, washing the filtrate by using saturated salt solution, evaporating the filtrate to dryness, adding a mixed solvent, pulping and filtering to obtain the pure N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester, wherein the purity of HPLC (high performance liquid chromatography) and nuclear magnetism is more than 99%, and the yield is 65-75%.
In the coupling reaction, in an N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, a substituent on N is selected from Boc, Cbz, methyl, ethyl, isopropyl and benzyl; the halogen is selected from chlorine, bromine and iodine.
In the coupling reaction, the diborate is selected from one of pinacol diborate, neopentyl glycol diborate and phthalic acid diphenol diborate.
In the coupling reaction, cuprous halide is selected from one of cuprous iodide, cuprous bromide and cuprous chloride.
In the coupling reaction, the ligand is selected from one of triphenylphosphine, ferrocene and 1, 3-bis (diphenylphosphino) propane.
In the coupling reaction, the organic base adopts lithium methoxide or lithium tert-butoxide.
In the coupling reaction, the reaction solvent is selected from one of N, N-dimethylformamide, dimethyl sulfoxide and 1, 4-dioxane.
In the coupling reaction, N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, and the equivalent ratio of the ligand to the organic base are 1:1-1.2:0.05-0.1:0.1-0.2: 2-2.2.
In the coupling reaction, the diluting solvent is selected from one of ethyl acetate, dichloromethane and toluene.
In the coupling reaction, the mixed solvent comprises n-heptane or n-hexane and ethanol, and the mass ratio of the n-heptane or the n-hexane to the ethanol is 3-6: 1.
The method adopts a one-step synthesis method, has short process route, adopts N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, ligand and organic base as raw materials, has easily obtained reaction raw materials and low cost, usually adopts palladium chloride dppf as a catalyst in the diborate coupling reaction, and has the selling price of 4 ten thousand yuan/kg, but the method adopts cuprous oxide or cuprous halide as a coupling reagent, the selling price is lower than 1 thousand yuan/kg, the reaction conditions are mild, such as temperature, pollution in the reaction process and the like, the method is friendly and easy to operate, the prepared product has high purity which is more than 99 percent, the industrial yield of the product is high and can reach 65-75 percent, and the method is suitable for industrial application.
Detailed description of the preferred embodiments
Example 1
Synthesis of N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-Boc-1,2,5, 6-tetrahydropyridine-4-bromine (26.3g, 0.1mol), pinacol diboron (25.4g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol) and lithium methoxide (7.2g, 0.2mol) in N, N-dimethylformamide (130g) in a reaction bottle, and controlling the temperature to be 45-55 ℃ to stir for reaction; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for the absence of N, N-dimethylformamide and was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 5:1 was added and slurried, 20.1g of white solid N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained after filtration, HPLC: 99.2%, yield 65%.
Example 2
Synthesis of N-Cbz-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-Cbz-1,2,5, 6-tetrahydropyridine-4-iodine (34.3g, 0.1mol), pinacol diboron (30.5g, 0.12mol), cuprous iodide (2.5g, 0.008mol), triphenylphosphine (4.2g, 0.016mol) and lithium methoxide (8.4g, 0.22mol) in dimethyl sulfoxide (130g) in a reaction bottle, and controlling the temperature to be 40-50 ℃ to stir for reaction; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with dichloromethane (50g), the filtrate was diluted with dichloromethane (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for no dimethylsulfoxide, the organic layer was washed with saturated brine (100g), the solvent was evaporated, N-hexane/ethanol (6: 1) was added and slurried, and after filtration, 25.7g of white solid N-Cbz-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained, with HPLC: 99.5% and yield of 75%.
Example 3
Synthesis of N-benzyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester:
under the protection of nitrogen, dissolving N-benzyl-1, 2,5, 6-tetrahydropyridine-4-bromine (25.2g, 0.1mol), pinacol diboron (30.5g, 0.12mol), cuprous oxide (1.43g, 0.01mol), 1, 3-bis (diphenylphosphino) propane (8.25g, 0.02mol) and lithium tert-butoxide (17.6g, 0.22mol) in N, N-dimethylformamide (130g) in a reaction bottle, and stirring to react at the temperature of 45-55 ℃; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), the layers were separated, the organic layer was checked by GC for the absence of N, N-dimethylformamide and was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 3:1 was added and slurried, 20.3g of white-like solid N-benzyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was obtained after filtration, HPLC: 99.6%, yield 68%.
Example 4
Synthesis of N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid neopentyl glycol ester:
under the protection of nitrogen, dissolving N-Boc-1,2,5, 6-tetrahydropyridine-4-bromine (26.3g, 0.1mol), neopentyl glycol diborate (22.6g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol) and lithium methoxide (7.2g, 0.2mol) in N, N-dimethylformamide (130g) in a reaction bottle, and stirring to react at the temperature of 45-55 ℃; after the reaction was completed by GC assay, the reaction solution was filtered through celite, the filter cake was rinsed with toluene (50g), the filtrate was diluted with toluene (50g), the filtrate was washed with water (100g), and the layers were separated, and GC assay showed that the organic layer had no N, N-dimethylformamide, and the organic layer was washed with saturated brine (100g), the solvent was evaporated, heptane/ethanol 5:1 was added and the mixture was slurried, and after filtration, 21.2g of white solid N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid neopentyl glycol ester was obtained, with HPLC 99.8%, and the yield 72%.
Claims (10)
1. A process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester is characterized by comprising the following steps: the method comprises the following steps: coupling reaction: dissolving N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate ester, cuprous halide or cuprous oxide, ligand and organic base in a reaction solvent, and stirring for reaction at 30-60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, diluting the filtrate by using a diluting solvent, washing the filtrate by using water, washing the filtrate by using saturated salt solution, evaporating the filtrate to dryness, adding a mixed solvent, pulping and filtering to obtain the pure N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester.
2. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, in the N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, a substituent on N is selected from Boc, Cbz, methyl, ethyl, isopropyl and benzyl; the halogen is selected from chlorine, bromine and iodine.
3. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the diborate is selected from one of pinacol diborate, neopentyl glycol diborate and catechol diborate.
4. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the cuprous halide is selected from one of cuprous iodide, cuprous bromide and cuprous chloride.
5. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the ligand is selected from one of triphenylphosphine, ferrocene and 1, 3-bis (diphenylphosphino) propane.
6. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the organic base adopts lithium methoxide or lithium tert-butoxide.
7. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the reaction solvent is selected from one of N, N-dimethylformamide, dimethyl sulfoxide and 1, 4-dioxane.
8. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, N-substituted-1, 2,5, 6-tetrahydropyridine-4-halide, diborate, cuprous halide or cuprous oxide, and the equivalent ratio of the ligand to the organic base are 1:1-1.2:0.05-0.1:0.1-0.2: 2-2.2.
9. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the diluting solvent is selected from one of ethyl acetate, dichloromethane and toluene.
10. The process for synthesizing an N-substituted-1, 2,5, 6-tetrahydropyridine-4-boronic acid ester according to claim 1, wherein: in the coupling reaction, the mixed solvent comprises n-heptane or n-hexane and ethanol, and the mass ratio of the n-heptane or the n-hexane to the ethanol is 3-6: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910143762.XA CN109762007B (en) | 2019-02-27 | 2019-02-27 | Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910143762.XA CN109762007B (en) | 2019-02-27 | 2019-02-27 | Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109762007A CN109762007A (en) | 2019-05-17 |
| CN109762007B true CN109762007B (en) | 2021-05-11 |
Family
ID=66456795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910143762.XA Active CN109762007B (en) | 2019-02-27 | 2019-02-27 | Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109762007B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004264B (en) * | 2019-12-28 | 2022-05-17 | 沧州普瑞东方科技有限公司 | Preparation method of N-substituted tetrahydropyridine-3/4-boric acid/ester |
| CN111171063B (en) * | 2020-01-08 | 2022-06-14 | 大连双硼医药化工有限公司 | Process method for synthesizing N-substituted piperidine-4-boric acid |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863911A (en) * | 2010-04-13 | 2010-10-20 | 艾琪康医药科技（上海）有限公司 | A process for preparing 1-R1-3, 4-dehydro-3 or 4-R6-piperidine |
| EP2606052B1 (en) * | 2010-08-20 | 2016-06-01 | Research Triangle Institute | Nicotinic receptor compounds |
| CN105503924B (en) * | 2016-01-11 | 2017-05-31 | 沧州普瑞东方科技有限公司 | A kind of synthesis N replaces the method for the borate of 1,2,3,6 tetrahydropyridine 5 |
| CN105566368B (en) * | 2016-01-11 | 2017-09-15 | 沧州普瑞东方科技有限公司 | A kind of method of the borate of synthesis N substituted piperidines 4 |
| CN105566367B (en) * | 2016-01-11 | 2017-10-13 | 沧州普瑞东方科技有限公司 | A kind of synthesis N replaces the method for the borate of 1,2,5,6 tetrahydropyridine 4 |
-
2019
- 2019-02-27 CN CN201910143762.XA patent/CN109762007B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN109762007A (en) | 2019-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109762007B (en) | Process method for synthesizing N-substituted-1, 2,5, 6-tetrahydropyridine-4-boric acid ester | |
| CN103992212A (en) | Synthesis method for cis-benvitimod, and applications of cis-benvitimod | |
| CN104130188B (en) | The preparation method of 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine | |
| CN104892623A (en) | Preparation method for isosorbide 5-mononitrate | |
| Lysén et al. | Palladium on activated carbon-A recyclable catalyst for Suzuki-Miyaura cross-coupling of aryl chlorides in water | |
| Xie et al. | Cobalt‐Catalyzed Oxidative Dimerization of 2‐Phenylpyridine Derivatives | |
| CN110183450B (en) | Synthetic method of 2-arylindazolo maleimide fused polycyclic compound | |
| CN101775035B (en) | Synthesis of class of amino acid type amphoteric water-soluble chiral phosphine ligand and application thereof in asymmetric catalytic hydrogenation | |
| CN107602399B (en) | Preparation method of enkephalinase inhibitor intermediate | |
| Schultz et al. | Palladium (II) complexes with chelating P, O-ligands as catalysts for the heck reaction | |
| CN104860980B (en) | It is a kind of to be used to synthesize intermediate of Ezetimibe and its preparation method and application | |
| CN108299340B (en) | Method for synthesizing 2-fluoro-N-substituted aryl acetamide compound | |
| CN105968030A (en) | Preparation method of Sitagliptin midbody of beta-amino acid | |
| CN111484436A (en) | Method for introducing isopentenyl group to C3 position of indole | |
| CN111484437A (en) | Method for introducing tertiary isopentenyl group to C3 position of indole | |
| CN105985316A (en) | Preparation method for trelagliptin and salt thereof | |
| CN108947801B (en) | Preparation of biphenyldicarboxylic acid by coupling of 4-chlorobenzoic acid in ionic liquid | |
| CN111087405B (en) | Method for asymmetrically synthesizing amaryllidaceae alkaloid (+) -gamma-lycorane | |
| CN112266364A (en) | Preparation method of tetrahydroquinoxaline compound | |
| CN101143331B (en) | Non-palladium catalyst system used for coupling reaction | |
| CN112194559A (en) | Synthesis method of chiral and achiral 2,2' -dihalogenated biaryl compounds | |
| CN107445879B (en) | Preparation method of Latricinib intermediate | |
| CN107382782A (en) | A kind of synthetic method of polyaryl substituted naphthol derivative | |
| CN107353267A (en) | A kind of method for synthesizing substituted furan | |
| CN107602602A (en) | A kind of synthetic method of the pinacol borate of 3 cyanopyridine 5 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |