CN109970773A - A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate - Google Patents
A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate Download PDFInfo
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- CN109970773A CN109970773A CN201910265203.6A CN201910265203A CN109970773A CN 109970773 A CN109970773 A CN 109970773A CN 201910265203 A CN201910265203 A CN 201910265203A CN 109970773 A CN109970773 A CN 109970773A
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- Prior art keywords
- boc
- tetrahydropyridine
- synthetic method
- new synthetic
- pinacol
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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 a kind of N-Boc-1,2,5, the new synthetic method of 6- tetrahydropyridine -4- pinacol borate, including following three reaction steps: using 4- bromopyridine hydrochloride as starting material, the preparation bromo- N-Boc- pyridinium chloride of 4- is reacted with isobutylchloroformate or di-tert-butyl dicarbonate first, then through NaBH4Reduction preparation N-Boc piperidines -4- alkenyl bromine compounds prepares target product N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borates finally by coupling reaction occurs with connection pinacol borate.The synthetic route, raw material are easy to get, and mild condition, by-product is few, high income, are more suited to industrialization amplification.
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-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate is widely used in the synthesis of medicine intermediate.Currently,
Existing synthetic route mainly has two, such as:
Route one: WO2004/058727 uses N-Boc-4- piperidones for raw material, anti-with N- phenyl bis- (trifluoro methylsulfonimides)
3,6- dihydro -4- [[(trifluoromethyl) sulphonyl] oxygroup] -1 (2H)-pyridine carboxylic acid tert-butyl ester should be generated, then passes through coupling reaction system
Standby N-Boc-1,2,5,6- tetrahydropyridine -4- boric acid pinacol；
The route, raw material N- phenyl bis- (trifluoro methylsulfonimides) is expensive, is difficult to apply to industrialized production.
Route two: CN105566367 uses N-Boc- piperidones for raw material, through bromo alkenyl bromine compounds, then through lattice
Family name's exchange and coupling reaction prepare target product, and the route is using triphenyl phosphite and hypertoxic bromine, severe operational environment, and
And the grignard exchange reaction yield that alkenyl bromine compounds participates in is low, the cost is relatively high.
Summary of the invention
The present invention proposes a new synthetic method, route reaction condition is mild, yield phase on the basis of the above route
To higher, it is also suitable for industrialization amplification.Mainly include following three synthesis steps: being that starting is former with 4- bromopyridine hydrochloride
Material, reacts the bromo- N-Boc- pyridinium chloride of prepare compound 4- with isobutylchloroformate or di-tert-butyl dicarbonate (Boc acid anhydrides)；
Again by NaBH4Reduction prepares N-Boc piperidines -4- alkenyl bromide；Mesh is prepared finally by Suzuki-Miyaura coupling reaction
Mark product.
Specific embodiment:
[embodiment 1]
The preparation of the bromo- N-Boc- pyridinium chloride of step 1:4-
In 500mL four-hole bottle, acetonitrile 200mL is added, opens stirring and 4- bromopyridine hydrochloride 29g, 4- dimethylamino is successively added
Pyridine 0.5g, room temperature condition are slowly added to the acetonitrile solution of BOC acid anhydrides, and 40 DEG C of reaction 2h are warming up to after adding, and cooling is filtered
White solid 35g,
The preparation of step 2:N-Boc piperidines -4- alkenyl bromide
In 250mL four-hole bottle, methanol 100mL is successively added, the bromo- N-Boc- pyridinium chloride 25g of 4- is cooled to 0 DEG C, is added portionwise
Several NaBH4, insulation reaction 1h is added, after steaming methanol, obtains brown color liquid
The preparation of step 3:N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate
In four-hole bottle, a certain amount of toluene, alkenyl bromine compounds is successively added in addition, and potassium acetate is warming up to 65 DEG C after being stirred,
The toluene solution of connection pinacol borate is added dropwise, adds heat preservation 1h, cooling is filtered, and after mother liquor concentrations, petroleum ether mashing obtains target
Product.
[embodiment 2]
The preparation of the bromo- N-Boc- pyridinium chloride of step 1:4-
In 500mL four-hole bottle, addition acetonitrile is several, opens stirring and a certain amount of 4- bromopyridine hydrochloride, 4- diformazan ammonia is successively added
Yl pyridines, room temperature condition are slowly added to the acetonitrile solution of BOC acid anhydrides, 40 DEG C of reaction 2h are warming up to after adding, cooling is filtered white
The bromo- N-Boc- pyridinium chloride of color solid-like 4-
The preparation of step 2:N-Boc piperidines -4- alkenyl bromide
In 250mL four-hole bottle, a certain amount of ethyl alcohol is successively added, the bromo- N-Boc- pyridinium chloride of 4- is cooled to 0 DEG C, if being added portionwise
Dry NaBH4, insulation reaction 1h is added, after steaming methanol, obtains brown color liquid crude product N-Boc piperidines -4- alkenyl bromide
The preparation of step 3:N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate
In four-hole bottle, a certain amount of toluene, alkenyl bromine compounds is successively added in addition, and potassium acetate is warming up to 65 DEG C after being stirred,
The toluene solution of connection pinacol borate is added dropwise, adds heat preservation 1h, cooling is filtered, and after mother liquor concentrations, petroleum ether mashing obtains target
Product.
Claims (7)
1. a kind of N-Boc-1, the new synthetic method of 2,5,6- tetrahydropyridine -4- pinacol borates, it is characterised in that including with
Lower three synthesis steps:
1) using 4- bromopyridine hydrochloride as starting material, 4-dimethylaminopyridine is catalyst, in a certain amount of solvent and one
Under fixed reaction temperature, the bromo- N- of prepare compound 4- is reacted with isobutylchloroformate or di-tert-butyl dicarbonate (Boc acid anhydrides)
Boc- pyridinium chloride；
2) the bromo- N-Boc- pyridinium chloride of 4- in a solvent, passes through NaBH4Reduction prepares N-Boc piperazine under certain reaction temperature
Pyridine -4- alkenyl bromide；
3) in a certain amount of solvent, in N2Under the conditions of protection and certain reaction temperature, with Pd (dppf) Cl2For catalyst, KOAc
For alkali, N-Boc piperidines -4- alkenyl bromide and connection pinacol borate carry out Suzuki-Miyaura coupling reaction, prepare N-
Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate.
2. 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 reaction dissolvent described in step 1) is methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), acetonitrile, N, N- bis-
Methylformamide (DMF) etc.；The reaction temperature is -10~120 DEG C.
3. 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 4- bromopyridine hydrochloride described in step 1), 4-dimethylaminopyridine, the molar ratio of Boc acid anhydrides be 1:0.03~
0.05:1.0~1.05.
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 methanol, ethyl alcohol, isopropanol, DMF, THF etc.；Reaction temperature 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-Boc- pyridinium chloride of 4- described in step 2 and NaBH4Molar ratio be 1:0.5~0.55.
6. 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 reaction dissolvent described in step 3) can be dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, first
Benzene etc.；The reaction temperature is 50~140 DEG C.
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-Boc piperidines -4- alkenyl bromide described in step 3), Pd (dppf) Cl2, KOAc joins pinacol borate
Molar ratio is 1:0.01~0.05:2.5:1~1.05.
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| CN201910265203.6A CN109970773A (en) | 2019-04-03 | 2019-04-03 | A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate |
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| CN201910265203.6A CN109970773A (en) | 2019-04-03 | 2019-04-03 | A kind of new synthetic method of N-Boc-1,2,5,6- tetrahydropyridine -4- pinacol borate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526936A (en) * | 2019-09-05 | 2019-12-03 | 中昊(大连)化工研究设计院有限公司 | A kind of new synthetic method of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate |
| CN110922421A (en) * | 2019-12-17 | 2020-03-27 | 蚌埠中实化学技术有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241666A (en) * | 2010-05-12 | 2011-11-16 | 苏州艾缇克药物化学有限公司 | Method for producing hydrochloride of dopamine D4 receptor agonist A-412997 |
| 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 |
-
2019
- 2019-04-03 CN CN201910265203.6A patent/CN109970773A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241666A (en) * | 2010-05-12 | 2011-11-16 | 苏州艾缇克药物化学有限公司 | Method for producing hydrochloride of dopamine D4 receptor agonist A-412997 |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526936A (en) * | 2019-09-05 | 2019-12-03 | 中昊(大连)化工研究设计院有限公司 | A kind of new synthetic method of N- substitution -1,2,5,6- tetrahydropyridine -4- pinacol borate |
| CN110922421A (en) * | 2019-12-17 | 2020-03-27 | 蚌埠中实化学技术有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester |
| CN110922421B (en) * | 2019-12-17 | 2023-05-05 | 安徽英特美科技有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boric acid pinacol ester |
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