CN109762007A - A kind of process synthesizing N- substitution -1,2,5,6- tetrahydropyridine -4- borate - Google Patents
A kind of process synthesizing N- substitution -1,2,5,6- tetrahydropyridine -4- borate Download PDFInfo
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- CN109762007A CN109762007A CN201910143762.XA CN201910143762A CN109762007A CN 109762007 A CN109762007 A CN 109762007A CN 201910143762 A CN201910143762 A CN 201910143762A CN 109762007 A CN109762007 A CN 109762007A
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Abstract
The present invention relates to organic compound synthetic methods.A kind of synthesis N- substitution -1, the process of 2,5,6- tetrahydropyridine -4- borates, replace -1 with N-, 2,5,6- tetrahydropyridine -4- halides are raw material, it reacts to obtain N- substitution -1 in a solvent with connection borate, cuprous halide or cuprous oxide, ligand, organic base, 2,5,6- tetrahydropyridine -4- borates.This method has originality, and easy to operate, process route is short, at low cost, and product purity is high, and reaction condition is mild, avoids previous methods using Metal Palladium coupling or high activity Grignard Reagent and cryogenic conditions, has implicit costs advantage, be suitble to industrial amplification production.
Description
Technical field
The present invention relates to the processes that a kind of synthesis N- replaces -1,2,5,6- tetrahydropyridine -4- borates, belong to drug
Intermediate synthesizes field.
Background technique
N- substitution -1,2,5,6- tetrahydropyridine structure is introduced in drug molecule often as an important structural unit
In, or for carrying out coupling reaction obtain the compound with pharmaceutical activity.Such as opioid receptor 1 (OGL1) antagonist 1
And inhibitors of fatty acid amide hydrolase 2 etc..The synthesis of these compounds usually all uses N- substitution -1,2,5,6- tetrahydro pyrrole
After the coupling of pyridine -4- borate palladium chtalyst, restore to obtain required compound.
There are mainly two types of methods for the synthesis of -1,2,5,6- tetrahydropyridine -4- borate of N- substitution at present: method one[1]Using
The higher N- of price replaces -1,2,5,6- tetrahydropyridine -4- triflates to be raw material, under catalyzing by metal palladium, with connection boron
The synthesis of acid esters coupling reaction；Method two[2]It is raw material using N- substitution -4- piperidones, with three aromatic ester of phosphorous acid, halogen
It is reacted with organic base and carbonyl is transformed into alkenyl halogen, then reacted with isopropylmagnesium chloride-lithium chloride and alkoxy borate esters
To N- substitution -1,2,5,6- tetrahydropyridine -4- borate.Its major advantage is that raw material is easy to get.But its two-step method synthesizes, and uses
Isopropyl magnesium bromide-the lithium chloride and cryogenic conditions of high activity, technique is cumbersome, and yield and purity is not high.
Bibliography: 1.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 number CN105566367.
The above method has the disadvantage in that method one is needed using expensive metal palladium catalyst, at high cost；Method two needs
Two-step reaction is wanted, and using the isopropyl magnesium bromide-lithium chloride and cryogenic conditions of high activity, cumbersome, yield and purity are not
It is high.
Summary of the invention
The purpose of the present invention is to solve above-mentioned insufficient problems, provide a kind of synthesis N- substitution -1,2,5,6- tetrahydro pyrroles
The process of pyridine -4- borate replaces -1,2,5,6- tetrahydropyridine -4- halides for raw material with N-, with connection borate, halogen
Change cuprous or cuprous oxide, ligand, organic base and reacted in reaction dissolvent and obtains N- substitution -1,2,5,6- tetrahydropyridine -4- boron
Acid esters, HPLC and 99% or more nuclear-magnetism purity.One-step synthesis method, process route is short, at low cost, and product purity is high, reaction condition
Mildly, easily operated, it is suitble to industrial applications.
Used technical solution is the present invention in order to solve the above problem: a kind of synthesis N- substitution -1,2,5,6- tetrahydro pyrrole
The process of pyridine -4- borate, it is characterised in that: the following steps are included:
Coupling reaction: by N- replace -1,2,5,6- tetrahydropyridine -4- halides, connection borate, cuprous halide or cuprous oxide,
Ligand, organic base are dissolved in reaction dissolvent, and 30 DEG C to 60 DEG C are stirred to react；After completion of the reaction, diatomite filtering reacting liquid, filter are padded
Liquid is diluted with retarder thinner, filtrate washing, then the washing of filtrate saturated common salt, is evaporated filtrate, after mixed solvent mashing filtering is added
It obtains N- and replaces -1,2,5,6- tetrahydropyridine -4- borate sterlings, HPLC and 99% or more nuclear-magnetism purity, yield 65-75%.
In the coupling reaction, N- replace -1,2,5,6- tetrahydropyridine -4- halides in, the upper substituent group of N selected from Boc,
Cbz, methyl, ethyl, isopropyl and benzyl；Halogen is selected from chlorine, bromine, iodine.
In the coupling reaction, connection borate is selected from connection boric acid pinacol ester, connection boric acid neopentyl glycol ester, connection boric acid neighbour benzene
One of two phenolic esters.
In the coupling reaction, cuprous halide is selected from one of cuprous iodide, cuprous bromide, stannous chloride.
In the coupling reaction, ligand is selected from one of triphenylphosphine, ferrocene, bis- (diphenylphosphine) propane of 1,3-.
In the coupling reaction, organic base uses lithium methoxide or tert-butyl alcohol lithium.
In the coupling reaction, reaction dissolvent is in n,N-Dimethylformamide, dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane
One kind.
In the coupling reaction, N- replaces -1,2,5,6- tetrahydropyridine -4- halides, connection borate, cuprous halide or oxygen
Change cuprous, ligand and organic alkali equivalent ratio is 1:1-1.2:0.05-0.1:0.1-0.2:2-2.2.
In the coupling reaction, retarder thinner is selected from one of ethyl acetate, methylene chloride, toluene.
In the coupling reaction, mixed solvent includes normal heptane or n-hexane and ethyl alcohol, normal heptane or n-hexane and ethyl alcohol
Mass ratio be 3-6:1.
The present invention use one-step synthesis method, process route is short, using N- replace -1,2,5,6- tetrahydropyridine -4- halides,
Connection borate, cuprous halide or cuprous oxide, ligand, organic base are raw material, and reaction raw materials are easy to get, at low cost, usually connection boric acid
Ester coupling reaction uses palladium chloride dppf for catalyst, 40,000 yuan/kilogram of price, and this method is sub- using cuprous oxide or halogenation
Copper is coupling reagent, and price is below 1,000 yuan/kilogram, and reaction condition is mild, such as the pollution of temperature, reaction process is all more friendly
Good, easily operated, product purity obtained is high, reaches 99% or more, and product industrializes high income, up to 65-75%, is suitble to
Industrial applications.
Specific embodiment
Embodiment 1
The synthesis of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate:
Under nitrogen protection, in reaction flask, by N-Boc-1,2,5,6- tetrahydropyridine -4- bromines (26.3g, 0.1mol), connection boric acid
Pinacol ester (25.4g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol), lithium methoxide
(7.2g, 0.2mol) is dissolved in n,N-Dimethylformamide (130g), and 45 DEG C to 55 DEG C of temperature control are stirred to react；GC detection has been reacted
Bi Hou pads diatomite filtering reacting liquid, elutes filter cake with toluene (50g), filtrate is diluted with toluene (50g), filtrate water
(100g) washing, layering, GC detect organic layer without n,N-Dimethylformamide, and organic layer is washed with saturated salt solution (100g), is steamed
Dry solvent is added heptane/ethyl alcohol=5:1 mashing, 20.1g white solid N-Boc-1,2,5,6- tetrahydropyridines-is obtained after filtering
4- pinacol borate, HPLC:99.2%, yield 65%.
Embodiment 2
The synthesis of N-Cbz-1,2,5,6- tetrahydropyridine -4- pinacol borate:
Under nitrogen protection, in reaction flask, by N-Cbz-1,2,5,6- tetrahydropyridine -4- iodine (34.3g, 0.1mol), connection boric acid
Pinacol ester (30.5g, 0.12mol), cuprous iodide (2.5g, 0.008mol), triphenylphosphine (4.2g, 0.016mol), methanol
Lithium (8.4g, 0.22mol) is dissolved in dimethyl sulfoxide (130g), and 40 DEG C to 50 DEG C of temperature control are stirred to react；GC detects end of reaction
Afterwards, diatomite filtering reacting liquid is padded, elutes filter cake with methylene chloride (50g), filtrate is diluted with methylene chloride (50g), and filtrate is used
Water (100g) washing, layering, GC detect organic layer without dimethyl sulfoxide, and organic layer is washed with saturated salt solution (100g), is evaporated molten
Agent is added n-hexane/ethyl alcohol=6:1 mashing, 25.7g white solid N-Cbz-1,2,5,6- tetrahydropyridine -4- is obtained after filtering
Pinacol borate, HPLC:99.5%, yield 75%.
Embodiment 3
The synthesis of N- benzyl -1,2,5,6- tetrahydropyridine -4- pinacol borate:
Under nitrogen protection, in reaction flask, by N- benzyl -1,2,5,6- tetrahydropyridine -4- bromines (25.2g, 0.1mol), connection boric acid
Bis- (diphenylphosphine) propane of pinacol ester (30.5g, 0.12mol), cuprous oxide (1.43g, 0.01mol), 1,3- (8.25g,
0.02mol), tert-butyl alcohol lithium (17.6g, 0.22mol) is dissolved in n,N-Dimethylformamide (130g), and 45 DEG C to 55 DEG C of temperature control are stirred
Mix reaction；GC is detected after completion of the reaction, pads diatomite filtering reacting liquid, elutes filter cake, filtrate toluene with toluene (50g)
(50g) dilution, filtrate water (100g) washing, layering, GC detect organic layer without n,N-Dimethylformamide, organic layer saturation
Saline solution (100g) is washed, solvent evaporated, and heptane/ethyl alcohol=3:1 mashing is added, 20.3g off-white powder N- benzyl is obtained after filtering
Base -1,2,5,6- tetrahydropyridine -4- pinacol borates, HPLC:99.6%, yield 68%.
Embodiment 4
The synthesis of N-Boc-1,2,5,6- tetrahydropyridine -4- boric acid neopentyl glycol ester:
Under nitrogen protection, in reaction flask, by N-Boc-1,2,5,6- tetrahydropyridine -4- bromines (26.3g, 0.1mol), connection boric acid
Neopentyl glycol ester (22.6g, 0.1mol), cuprous oxide (1.43g, 0.01mol), triphenylphosphine (5.24g, 0.02mol), methanol
Lithium (7.2g, 0.2mol) is dissolved in n,N-Dimethylformamide (130g), and 45 DEG C to 55 DEG C of temperature control are stirred to react；GC detection reaction
After, diatomite filtering reacting liquid is padded, elutes filter cake with toluene (50g), filtrate is diluted with toluene (50g), filtrate water
(100g) washing, layering, GC detect organic layer without n,N-Dimethylformamide, and organic layer is washed with saturated salt solution (100g), is steamed
Dry solvent is added heptane/ethyl alcohol=5:1 mashing, 21.2g white solid N-Boc-1,2,5,6- tetrahydropyridines-is obtained after filtering
4- boric acid neopentyl glycol ester, HPLC:99.8%, yield 72%.
Claims (10)
1. the process that a kind of synthesis N- replaces -1,2,5,6- tetrahydropyridine -4- borates, it is characterised in that: including following
Step: coupling reaction: by N- replace -1,2,5,6- tetrahydropyridine -4- halides, connection borate, cuprous halide or cuprous oxide,
Ligand, organic base are dissolved in reaction dissolvent, and 30 DEG C to 60 DEG C are stirred to react；After completion of the reaction, diatomite filtering reacting liquid, filter are padded
Liquid is diluted with retarder thinner, filtrate washing, then the washing of filtrate saturated common salt, is evaporated filtrate, after mixed solvent mashing filtering is added
Obtain N- substitution -1,2,5,6- tetrahydropyridine -4- borate sterling.
2. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: in coupling reaction, N- replaces in -1,2,5,6- tetrahydropyridine -4- halides, the upper substituent group of N selected from Boc,
Cbz, methyl, ethyl, isopropyl, benzyl；Halogen is selected from chlorine, bromine, iodine.
3. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: connection borate is selected from connection boric acid pinacol ester, connection boric acid neopentyl glycol ester, connection boric acid neighbour benzene in coupling reaction
One of two phenolic esters.
4. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: cuprous halide is selected from one of cuprous iodide, cuprous bromide, stannous chloride in coupling reaction.
5. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: ligand is selected from one of triphenylphosphine, ferrocene, bis- (diphenylphosphine) propane of 1,3- in coupling reaction.
6. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: organic base uses lithium methoxide or tert-butyl alcohol lithium in coupling reaction.
7. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: reaction dissolvent is in n,N-Dimethylformamide, dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane in coupling reaction
One kind.
8. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: N- replaces -1,2,5,6- tetrahydropyridine -4- halides, connection borate, cuprous halide or oxygen in coupling reaction
Change cuprous, ligand and organic alkali equivalent ratio is 1:1-1.2:0.05-0.1:0.1-0.2:2-2.2.
9. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: retarder thinner is selected from one of ethyl acetate, methylene chloride, toluene in coupling reaction.
10. a kind of synthesis N- according to claim 1 replaces the process of -1,2,5,6- tetrahydropyridine -4- borates,
It is characterized by: in coupling reaction, mixed solvent includes normal heptane or n-hexane and ethyl alcohol, normal heptane or n-hexane and ethyl alcohol
Mass ratio is 3-6:1.
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Cited By (2)
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| CN111004264A (en) * | 2019-12-28 | 2020-04-14 | 沧州普瑞东方科技有限公司 | Preparation method of N-substituted tetrahydropyridine-3/4-boric acid/ester |
| CN111171063A (en) * | 2020-01-08 | 2020-05-19 | 大连双硼医药化工有限公司 | Process method for synthesizing N-substituted piperidine-4-boric acid |
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| 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 |
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