CN110526936A - A kind of new synthetic method of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate - Google Patents
A kind of new synthetic method of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate Download PDFInfo
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- CN110526936A CN110526936A CN201910834824.1A CN201910834824A CN110526936A CN 110526936 A CN110526936 A CN 110526936A CN 201910834824 A CN201910834824 A CN 201910834824A CN 110526936 A CN110526936 A CN 110526936A
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- tetrahydropyridine
- substitution
- reaction
- pinacol
- pinacol borate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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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
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The invention discloses the new synthetic methods that a kind of N- replaces -1,2,5,6- tetrahydropyridine -4- pinacol borates, including following three reaction steps: firstly, with 4- bromopyridine hydrochloride and clR1The reaction preparation bromo- N- substitution-pyridinium chloride of 4-, then through NaBH4Reduction preparation N- substitution-piperidines -4- alkenyl bromine compounds, prepares target product N- finally by Grignard and methoxyl group pinacol borate and replaces -1,2,5,6- tetrahydropyridine -4- pinacol borates.This synthetic route has versatility good, and raw material is cheap and easy to get, and reaction condition is mild, and by-product is few, the advantages such as high income, and product economy is high, and the market competitiveness is strong, is suitable for industrialized production.(wherein R1=-Boc；-Cbz；-Bz；-Bn；-Fmoc；-Me；-Et；-iPr；-Ph).
Description
Technical field
The present invention relates to a kind of N-Boc-1, the new synthetic method of 2,5,6- tetrahydropyridine -4- pinacol borates belongs to
Medicine intermediate synthesis technical field.
Background technique
N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate is widely used in the synthesis of medicine intermediate.Mesh
Before, synthetic method is mainly using N- substitution-piperidones as starting material, and cost of material is high, and reaction process often needs expensive
Palladium catalyst or need condition of ultralow temperature to react, process conditions are harsh, cause product cost higher, are highly detrimental to industry
Metaplasia produces, and now mainly has following four principal synthetic routes.
Route one: it is first starting material by N- substitution-piperidones, prepares dibromo compound through bromination reaction, then DBU
At alkenyl bromine after debrominate, alkenyl bromine replaces -1,2,5,6- by chlorination palladium-catalyzed reaction preparation N- with connection pinacol borate again
Tetrahydropyridine -4- pinacol borate.The synthetic route cost of material is higher, and bromination reaction operating environment is poor, palladium catalyst valence
Lattice are expensive, and product yield is high, deficiency in economic performance.
Route two: generation is reacted using N- substitution-piperidones as starting material with expensive trifluoromethane sulfonic acid class compound
Intermediate, then target product is obtained by palladium catalysed cross coupling reaction with connection pinacol borate, raw material used in the reaction, catalysis
Agent price is high, and reaction efficiency is low, needs condition of ultralow temperature, is highly detrimental to industrialized production, and product economy is not high, and market is competing
It is weak to strive power.
Route three: generating intermediate using N- substitution-piperidones as starting material and tolysulfonyl hydrazine reaction, then with butyl lithium and
Methoxyl group pinacol borate reacts to obtain target product.This method main problem is that cost of material is higher, and atom utilization is low,
Ton consumption is big, and butyl lithium is extremely inflammable, there is very big security risk in production.
Route four: generating intermediate using N- substitution-piperidones as starting material and tolysulfonyl hydrazine reaction, then with grignard
Reagent and methoxyl group pinacol borate react to obtain target product.Although the route avoids the use of butyl lithium, but same
Sample there are atom utilizations low, the more expensive problem of cost of material.
Summary of the invention
In view of the above problems, the present invention provides a kind of improved synthetic route, raw material is cheap and easy to get, avoids expensive catalysis
The use of agent, reaction condition is mild, and safe operation is simple, versatile.
1) first step uses cheap 4- bromopyridine hydrochloride for starting material, triethylamine (Et3It N is) catalyst, with one
Serial R1Chloro thing in a certain amount of solvent and certain reaction temperature under, reaction preparation the bromo- N- substitution-chlorination pyrrole of 4-
Pyridine.
2) second step, the bromo- N- substitution-pyridinium chloride of 4- pass through NaBH in certain solvent4Reduction, in certain reaction
At a temperature of, prepare N- substituted piperidine -4- alkenyl bromide.
3) third step, in a certain amount of solvent, in N2Under the conditions of protection and certain reaction temperature, using isopropyl bromide as lattice
Family name's reagent and N- substituted piperidine -4- alkenyl bromide carry out grignard exchange reaction, then react with methoxyl group pinacol borate,
Prepare N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate.Three step total recoverys 60~70%, NMR purity 98% with
On.
Further, in the above scheme, in the first step, starting material is-Boc；-Cbz；-Bz；-Bn；-Fmoc；-
Me；-Et；The chloro thing of-Ph.
Further, in the above scheme, in the first step, the reaction dissolvent is ethyl acetate, chlorobenzene, Isosorbide-5-Nitrae-dioxy six
Ring, methylene chloride, n,N-Dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile；
Further, in the above scheme, in the first step, the reaction temperature is -20~150 DEG C.
Further, in the above scheme, in the first step, 4- bromopyridine hydrochloride, Et3N, R1The molar ratio of chloro thing is
1:1.0~2.0:1.0~1.8.
Further, in the above scheme, in second step, the solvent can be ethyl alcohol, isopropanol, methanol, chlorobenzene, two
Chlorobenzene, THF, DMF.
Further, in the above scheme, in second step, reaction temperature is -30~120 DEG C.
Further, in the above scheme, in second step, the bromo- N- substitution-pyridinium chloride of the 4- and NaBH4Mole
Than for 1:0.5~1.5.
Further, in the above scheme, in third step, the reaction dissolvent can be ether, THF, toluene, diformazan
Benzene.
Further, in the above scheme, in third step, the reaction temperature is -30~100 DEG C.
Further, in the above scheme, in third step, the N- substituted piperidine -4- alkenyl bromide, isopropyl bromide,
The molar ratio of methoxyl group pinacol borate is 1:1~1.5:1~1.8.
Advantageous effect of the invention:
This synthetic route, raw material is cheap and easy to get, and reaction condition is mild, and by-product is few, and high income is more suited to industrialized production,
Replace the preparation of -1,2,5,6- tetrahydropyridine -4- pinacol borates that there is versatility, stable product quality, economy effect N-
Beneficial high, the market competitiveness is strong.
Example is embodied:
The preparation of [embodiment 1] N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate
In 250ml four-hole bottle, 19.45g (0.1mol) 4- bromopyridine hydrochloride, several 15.02g are first added in the first step
Then 100ml chlorobenzene is added in (0.11mol) tertbutyloxycarbonyl chlorine, open stirring, is warming up to 40 DEG C, and 11.13g is added dropwise
(0.11mol) Et3N, insulation reaction 2h~3h.TLC is detected after reaction, filters out solid, is then depressurized organic phase and is revolved
It steams, 50ml toluene and 100ml saturated common salt water washing is added after solvent evaporated, is evaporated organic phase and obtains the bromo- N-Boc- chlorination of 4-
Pyridine, yield 85%.
In 250ml four-hole bottle, the bromo- N-Boc- pyridinium chloride of 29.46g (0.1mol) 4- is added in second step, 120ml ethyl alcohol,
It is cooled to 0 DEG C, 4.16g(0.11mol is added portionwise) NaBH4, insulation reaction 8h is added, then revolving removes ethyl alcohol, obtains pale brown
Color liquid crude product N-Boc piperidines -4- alkenyl bromide, yield 92%.
Third step, by 26.21g (0.1mol) N-Boc piperidines -4- alkenyl bromide and 12.9g (0.105mol) isopropyl
Bromine carries out grignard exchange reaction in tetrahydrofuran, then, under nitrogen protection, under the conditions of 0 DEG C, by 19.03g (0.11mol)
Methoxyl group pinacol borate is added drop-wise in grignard reaction liquid, and insulation reaction 4h then heats to back flow reaction 1h.It has reacted
To finish, 10ml is added, 10% dilute hydrochloric acid is quenched, and after steaming solvent, the mashing of 120ml ethyl alcohol is added, filters out white solid and obtains 26.9g,
Yield 87%.
The preparation of [embodiment 2] N-Bn-1,2,5,6- tetrahydropyridine -4- pinacol borate
In 250ml four-hole bottle, 19.45g (0.1mol) 4- bromopyridine hydrochloride and 13.3g (0.105mol) is first added in the first step
Then 100ml methylene chloride is added in benzyl chloride, open stirring, is warming up to 20 DEG C, and 11.13g (0.11mol) Et is added dropwise3N is protected
Temperature reaction 4h~6h, TLC detection after reaction, filter out solid, then organic phase vacuum rotary steam, are added after solvent evaporated
50ml toluene and 100ml saturated common salt water washing are evaporated organic phase and obtain the bromo- N-Boc- pyridinium chloride of 4-, yield 83%.
In 250ml four-hole bottle, the bromo- N-Bn- pyridinium chloride of 28.46g (0.1mol) 4- is added in second step, 150ml ethyl alcohol,
It is cooled to 0 DEG C, 4.16g(0.11mol is added portionwise) NaBH4, insulation reaction 6h is added, ethyl alcohol is then rotated out, obtains brown color
Liquid crude product N-Bn piperidines -4- alkenyl bromide, yield 87%.
Third step, by 25.15g (0.1mol) N-Bn piperidines -4- alkenyl bromide and 13.5g (0.11mol) isopropyl bromide
Grignard exchange reaction is carried out in tetrahydrofuran, then, under nitrogen protection, under the conditions of 0 DEG C, by 20.76g (0.12mol) first
Oxygroup pinacol borate is added drop-wise in reaction solution, is reacted 2h, is then heated to back flow reaction 1h, to end of reaction, is added
15ml, 10% dilute hydrochloric acid is quenched, and after steaming solvent, the mashing of 150ml methanol is added, filters out white solid and obtains 25.44g, yield
85%.
The preparation of [embodiment 3] N-Et-1,2,5,6- tetrahydropyridine -4- pinacol borate
In 250ml four-hole bottle, 19.45g (0.1mol) 4- bromopyridine hydrochloride is first added in the first step, 120ml methylene chloride,
15.18g (0.15mol) Et3N opens stirring, chloroethanes gas is slowly introducing under the conditions of -10 DEG C, detects reaction knot to TLC
Shu Hou stops ventilation, and then by organic phase vacuum rotary steam, 60ml ethyl acetate and 120ml saturated common salt are added after solvent evaporated
Water washing is evaporated organic phase and obtains the bromo- N-Boc- pyridinium chloride of 4-, yield 82%.
In 250ml four-hole bottle, the bromo- N-Et- pyridinium chloride of 22.25g (0.1mol) 4- is added in second step, 100ml ethyl alcohol,
It is cooled to 0 DEG C, 4.16g(0.11mol is added portionwise) NaBH4, insulation reaction 4h is added, after steaming methanol, obtains weak yellow liquid
Crude product N-Boc piperidines -4- alkenyl bromide, yield 93%.
Third step, by 19.1g(0.1mol) N-Et piperidines -4- alkenyl bromide and 12.9g (0.105mol) isopropyl bromide
Grignard exchange reaction is carried out in tetrahydrofuran, then, under nitrogen protection, under the conditions of 0 DEG C, by 19.03g (0.11mol) first
Oxygroup pinacol borate is added drop-wise in reaction solution, and insulation reaction 4h then heats to back flow reaction 2h.End of reaction is added
20ml, 10% dilute hydrochloric acid is quenched, and after steaming solvent, continues to be warming up to 120 DEG C of vacuum distillations obtaining the mesh of 18.73g weak yellow liquid
Mark product, yield 79%.
Claims (7)
1. the new synthetic method that a kind of N- replaces -1,2,5,6- tetrahydropyridine -4- pinacol borates, it is characterised in that including with
Lower three synthesis steps:
Using 4- bromopyridine hydrochloride as starting material, triethylamine (Et3It N is) catalyst, with a series of R1Chloro thing a certain amount of
Solvent in and certain reaction temperature under, prepare the bromo- N- substitution-pyridinium chloride of compound 4-；
The bromo- N- substitution-pyridinium chloride of 4- passes through NaBH in a certain amount of solvent4Reduction, under certain reaction temperature, preparation
N- substituted piperidine -4- alkenyl bromide；
In a certain amount of solvent, in N2Under the conditions of protection and certain reaction temperature, replace by Grignard Reagent and N- of isopropyl bromide
Piperidines -4- alkenyl bromide carries out grignard exchange reaction, then reacts with methoxyl group pinacol borate, prepares N- substitution -
1,2,5,6- tetrahydropyridine -4- pinacol borate.
2. a kind of synthesis of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate is newly square according to claim 1
Method, it is characterised in that reaction dissolvent described in step 1) is ethyl acetate, chlorobenzene, Isosorbide-5-Nitrae-dioxane, methylene chloride, N, N- diformazan
Base formamide (DMF), tetrahydrofuran (THF), acetonitrile, the reaction temperature are -10~100 DEG C.
3. a kind of synthesis of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate is newly square according to claim 1
Method, it is characterised in that 4- bromopyridine hydrochloride, Et described in step 1)3N and R1The molar ratio of chloro thing be 1:1.0~1.5:1.0~
1.5。
4. a kind of N-Boc-1 according to claim 1, the new synthetic method of 2,5,6- tetrahydropyridine -4- pinacol borates,
It is characterized in that solvent described in step 2 can be ethyl alcohol, isopropanol, methanol, chlorobenzene, dichloro-benzenes, THF, DMF, reaction temperature
It is -30~120 DEG C.
5. a kind of N-Boc-1 according to claim 1, the new synthetic method of 2,5,6- tetrahydropyridine -4- pinacol borates,
It is characterized in that the bromo- N- substitution-pyridinium chloride of 4- described in step 2 and NaBH4Molar ratio be 1:0.5~1.2.
6. a kind of synthesis of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate is newly square according to claim 1
Method, it is characterised in that reaction dissolvent described in step 3) can be ether, THF, toluene, dimethylbenzene, the reaction temperature be -10~
100℃。
7. a kind of N-Boc-1 according to claim 1, the new synthetic method of 2,5,6- tetrahydropyridine -4- pinacol borates,
It is characterized in that N- substituted piperidine -4- alkenyl bromide, isopropyl bromide described in step 3) and methoxyl group pinacol borate rub
You are than being 1:1~1.5:1~1.8.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566367A (en) * | 2016-01-11 | 2016-05-11 | 沧州普瑞东方科技有限公司 | Synthesis method of N-substituted-1,2,5,6-tetrahydropyridine-4-borate |
| CN109485666A (en) * | 2018-12-14 | 2019-03-19 | 中昊(大连)化工研究设计院有限公司 | A kind of preparation method of ene boric acid pinacol ester |
| CN109970773A (en) * | 2019-04-03 | 2019-07-05 | 中昊(大连)化工研究设计院有限公司 | A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566367A (en) * | 2016-01-11 | 2016-05-11 | 沧州普瑞东方科技有限公司 | Synthesis method of N-substituted-1,2,5,6-tetrahydropyridine-4-borate |
| CN109485666A (en) * | 2018-12-14 | 2019-03-19 | 中昊(大连)化工研究设计院有限公司 | A kind of preparation method of ene boric acid pinacol ester |
| CN109970773A (en) * | 2019-04-03 | 2019-07-05 | 中昊(大连)化工研究设计院有限公司 | A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate |
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Application publication date: 20191203 |