CN107200737B - Tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide preparation method - Google Patents
Tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide preparation method Download PDFInfo
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- CN107200737B CN107200737B CN201710512795.8A CN201710512795A CN107200737B CN 107200737 B CN107200737 B CN 107200737B CN 201710512795 A CN201710512795 A CN 201710512795A CN 107200737 B CN107200737 B CN 107200737B
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- tertbutyloxycarbonyl
- methylol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide synthetic methods, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention divides seven steps, by (2- chloro-5-nitropyridine) and malonic acid t-butyl acetate, reaction obtains compound 2 under the action of NaH in solvents tetrahydrofurane first, compound 2 obtains compound 3 under the action of trifluoroacetic acid, then compound 3 carries out hydrogenation under palladium carbon catalysis and obtains compound 4, tertbutyloxycarbonyl is carried out to compound 4 to protect to obtain compound 5, compound 5 acts on obtaining compound 6 with p-ABSA under the action of DBU, compound 6 is restored to obtain compound 7 by tetrahydrochysene lithium aluminium in tetrahydrofuran, compound 7 carries out catalytic hydrogenation under the catalysis of wet palladium carbon and obtains final compound 8.
Description
Technical field
The present invention relates to compound tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amides
Synthetic method.
Background technique
Compound tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide
(MFCD28390423) and relevant derivative has extensive use in pharmaceutical chemistry and organic synthesis.Tertiary butyloxycarbonyl at present
Base -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide synthetic method rarely has document report.Therefore, it is necessary to open
A raw material is sent out to be easy to get, it is easy to operate, react easily controllable, overall yield is suitble to, and is suitble to the synthetic method of industrialized production.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, the higher uncle of yield
Butoxy carbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide synthetic method.It mainly solves not having at present
There is the technical issues of suitable Industrialized synthesis method.
A kind of technical solution of the present invention: tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -
The synthetic method of 6- amide, it is characterized in that: the following steps are included: the first step, first by compound 1 and malonic acid t-butyl acetate
Reaction obtains compound 2, second step under the action of NaH in solvents tetrahydrofurane, and compound 2 is dissolved in methylene chloride in trifluoro
Compound 3, third step are obtained under the action of acetic acid, compound 3 is dissolved in ethyl alcohol and carries out hydrogenation under palladium carbon catalysis
Close object 4, the 4th step, by compound 4 plus tetrahydrofuran, DMAP and Boc2O carries out tertbutyloxycarbonyl to compound 4 and protects to obtain
Compound 5, the 5th step, compound 5 are dissolved in acetonitrile and act under the action of 1,5- phenodiazine -5,6- dicyano benzoquinone with p-ABSA
To compound 6, the 6th step, compound 6 is restored to obtain compound 7, the 7th step, compound 7 by tetrahydrochysene lithium aluminium in tetrahydrofuran
It is dissolved in methanol progress hydrogenation under palladium carbon catalysis and obtains final compound 8.Reaction equation is as follows:
The first step is 70 DEG C of 17 hours of reaction；Second step is in 25 DEG C of 16 hours of reaction；Third step reaction temperature is 25
DEG C, the reaction time 8 hours, palladium carbon water content 50%；4th 70 DEG C of step back flow reaction；5th step is reacted 16 hours at 25 DEG C；
6th step feeds at 0 DEG C, 25 DEG C of 16 hours of reaction；7th step, the condition of catalytic hydrogenation are 50 DEG C, 50psi, 52 hours.
The Chinese paraphrase that the present invention abridges: TFA: trifluoroacetic acid； Boc2O:Boc acid anhydrides；DMAP:4- dimethylamino naphthyridine；
THF: tetrahydrofuran；11 carbon -7- alkene of DBU:1,8- diazabicylo；P-ABSA: to acetyl-amino sulfonic acid nitrine.
Beneficial effects of the present invention: reaction process of the present invention design rationally, which employs be easy to get, can large-scale production original
Expect 2- chloro-5-nitropyridine, synthesizes tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperazine by seven steps
Pyridine -6- amide, this method route is short, and yield may be up to 31%, and reaction is easy to amplify, easy to operate.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:
Sodium hydride (50.46 g, 1.26 mol) is dissolved in batches in tetrahydrofuran (1.5 L), then room temperature is added dropwise third
Diacid t-butyl acetate (142.47 g, 756.91 mmol), stirs a hour, compound 1 is then added in batches, then
It is reacted at 70 DEG C 16 hours, TLC (petrol ether/ethyl acetate volume ratio=10/1) shows end of reaction.By reactant
System is cooled to 0 DEG C, and 1L water is added and is quenched, is then extracted with ethyl acetate (3*1L), organic phase brine It,
Then drying is concentrated to get crude Compound 2(247.5 g).
Mixture 2 (990.00 g, 3.19 mol) is dissolved in methylene chloride (5.0 L), trifluoro second is added dropwise at 0 DEG C
Sour (600 mL).16 hours are reacted at 25 DEG C.TLC (petrol ether/ethyl acetate volume ratio=5/1) shows end of reaction.
Then the pH of reaction system is adjusted to 9-10 with saturated aqueous sodium carbonate.Then with methylene chloride (1.5L*3) to system into
Row extraction.Organic phase drying is concentrated to get crude product.By crude product carry out column chromatography for separation (gradient elution: petroleum ether~petroleum ether/
Ethyl acetate volume ratio=50/1 ~ 0/1) obtain sterling compound 3(500.00 g).Yield 94.5%.
Compound 3(100.00 g, 475.76 mmol) is dissolved in ethyl alcohol (1.5 L), it is wet that water content 50% is then added
Palladium carbon (10.0 g), is replaced system with hydrogen balloon, and 25 DEG C are reacted 8 hours.TLC (petrol ether/ethyl acetate volume ratio
=5/1) end of reaction is shown.Reaction filtering, filtrate are concentrated to get crude Compound 4(320.0 g), yield: 93.3%.
By compound 4 (100.00 g, 554.94 mmol), triethylamine (112.31 g, 1.11 mol) and DMAP
(6.78 g, 55.49 mmol) are dissolved in tetrahydrofuran (1000 mL), 70 DEG C of reflux are heated to, then by Boc2O(157.45
G, 721.42 mmol) it is dissolved in tetrahydrofuran (500 mL), it is added dropwise in reflux system in 3 hours, after adding, stirring 10
Minute.TLC (petrol ether/ethyl acetate volume ratio=0/1) shows end of reaction.Reaction is down to room temperature and saturation chlorine is added
Change ammonium (5 L) to be quenched.Then it is extracted with ethyl acetate (2 L*4), organic phase is washed with saline solution, and drying is dense
Contracting obtains crude product.By crude product carry out column chromatography for separation (gradient elution: petroleum ether~petrol ether/ethyl acetate volume ratio=
50/1 ~ 0/1) sterling compound 5(111.0 g is obtained).Yield 71.4%.
By compound 5(131.30 g, 468.39 mmol) andp- ABSA(123.78 g, 515.23 mmol) it is dissolved in
In acetonitrile (1.5 L), DBU(142.62 g, 936.79 mmol is then added dropwise).16 hours are reacted at 25 DEG C.TLC (stone
Oily ether/ethyl acetate volume ratio=5/1) display end of reaction.Saturated ammonium chloride (3 L) is added into reaction solution, then uses
Ethyl acetate carries out (2 L*4) extraction.The dry concentration of organic phase.Obtained solid is washed with ethyl alcohol (1 L*3), and it is solid to obtain white
Body obtains white solid progress column chromatography for separation (gradient elution: methylene chloride/methanol volume ratio=100/1 ~ 20/1) pure
Product compound 6(93.4 g) yield: 64%.
Lithium Aluminium Hydride (15.26 g, 402.19 mmol) is dissolved in tetrahydrofuran (1.5 L), system temperature is down to 0
DEG C, then, compound 6(112.00 g, 365.63 mmol) is added in above-mentioned solution in 2 hours in batches.25
16 hours are reacted under the conditions of DEG C.TLC (petrol ether/ethyl acetate volume ratio=2/1) shows end of reaction.By reactant
System is down to 0 degree, and H is then successively added dropwise2O(15.3 mL) and 15% sodium hydrate aqueous solution (46 mL).By obtained solid mistake
Filter, and washed with ethyl acetate (2 L*4).Organic phase drying is concentrated to get compound 7 (94.5 g), yield: 97.8%.
Compound 7 (47.20 g, 178.60 mmol) is dissolved in methanol (1500 mL), water content, which is added, is
50% Pd/C(25.00 g).The hydrogen that pressure is 50 psi is then passed to, is reacted 52 hours under the conditions of 50 DEG C.TLC (stone
Oily ether/ethyl acetate volume ratio=0/1) display end of reaction.Reaction solution is filtered, filter cake washs (300 with ethyl acetate
ML*3).Organic phase is concentrated to get compound 8 (37.0 g), yield: 77.2 %.
1 MeOD δ1.27 - 1.62 (m, 9 H) 1.90 - 2.01 (m, 1 H) 2.06 - 2.17 (m, 1
H) 2.84 - 2.97 (m, 1 H) 2.98 - 3.11 (m, 1 H) 4.07 - 4.22 (m, 2 H) 4.56 (dd, J
=12.13, 3.91 Hz, 1 H) 4.64 (s, 1 H)。
Claims (8)
1. a kind of tertbutyloxycarbonyl -3- (methylol)-[1,2,3] triazole [1,5-a] piperidines -6- amide synthetic method,
Be characterized in: the following steps are included: the first step, first by compound 1 and malonic acid t-butyl acetate in solvents tetrahydrofurane
Reaction obtains compound 2, second step under the action of NaH, and compound 2 is dissolved in methylene chloride under the action of trifluoroacetic acid
Object 3, third step are closed, compound 3 is dissolved in ethyl alcohol progress hydrogenation under palladium carbon catalysis and obtains compound 4, the 4th step, by chemical combination
Object 4 plus tetrahydrofuran, DMAP and Boc2O carries out tertbutyloxycarbonyl to compound 4 and protects to obtain compound 5, the 5th step, chemical combination
Object 5 is dissolved in acetonitrile and acts on obtaining compound 6, the 6th step, the quilt in tetrahydrofuran of compound 6 with p-ABSA under the action of DBU
Tetrahydrochysene lithium aluminium restores to obtain compound 7, the 7th step, and compound 7 is dissolved in methanol progress hydrogenation under palladium carbon catalysis and obtains most
Whole compound 8；Reaction equation is as follows:
。
2. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: 70 DEG C of the first step are reacted 16 hours.
3. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: 25 DEG C of second step are reacted 16 hours.
4. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: 25 DEG C of third step are reacted 8 hours, catalyst palladium carbon water content is 50%.
5. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: 70 DEG C of back flow reactions of the 4th step.
6. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: 25 DEG C of the 5th step are reacted 16 hours.
7. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: the 6th step, feeds at 0 DEG C, 25 DEG C of 16 hours of reaction.
8. a kind of tertbutyloxycarbonyl-3- (methylol) according to claim 1-[1,2,3] triazole [1,5-a] piperidines-
The synthetic method of 6- amide, it is characterized in that: the 7th step reaction temperature is 50 DEG C, H2Pressure be 50psi, the reaction time is 52 small
When.
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| EP2687528A1 (en) * | 2012-07-17 | 2014-01-22 | Ares Trading S.A. | Fused triazole derivatives as gamma secretase modulators |
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| EP2994470B1 (en) * | 2013-05-09 | 2018-04-18 | Principia Biopharma Inc. | Pyrido[2,3-d]pyrimidine derivatives as fibroblast growth factor inhibitors |
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