CN109608460A - A kind of synthetic method of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate - Google Patents
A kind of synthetic method of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate Download PDFInfo
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- CN109608460A CN109608460A CN201811539644.2A CN201811539644A CN109608460A CN 109608460 A CN109608460 A CN 109608460A CN 201811539644 A CN201811539644 A CN 201811539644A CN 109608460 A CN109608460 A CN 109608460A
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- compound
- subunit
- dioxy
- decane
- butyl formate
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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
- C07D471/10—Spiro-condensed systems
Abstract
The present invention relates to the synthetic methods of one kind 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention divides four steps, the first step, potassium carbonate is added in anhydrous propanone by compound 1 and bromoacetonitrile first and obtains compound 2, second step, compound 2 obtain compound 3, third step under sodium borohydride effect, compound 3 is passed through cyclization inside hydrogen under nickel catalytic action and obtains compound 4,4th step, compound 4 are oxidized to compound 5, and reaction equation is as follows:
Description
Technical field
The present invention relates to the conjunctions of compound 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate
At method.
Background technique
Compound 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate (PubChem
Compound ID:131217523) and relevant derivative in pharmaceutical chemistry and organic synthesis have be widely applied.Current 1,
10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate synthetic method rarely has document report.Nagata,
Toshiaki et al. delivered similar document tetrahedron flash report (Tetrahedron Letters) 2001 a, vol. 42,
# 47, p. 8345-8349, other mentioned the synthetic route of benzenesulfonyl protection.But document route is long, raw material is not
It is easy to get, is completely unsuitable for industrialized production.It is easy to operate therefore, it is necessary to develop a raw material to be easy to get, react easily controllable, always
Body 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, easily controllable, yield higher 1 is reacted,
The synthetic method of 10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate.It mainly solves currently without suitable
The technical issues of Industrialized synthesis method.
A kind of technical solution of the present invention: 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate
Synthetic method, the present invention divides four steps, and the first step first potassium carbonate is added by compound 1 and bromoacetonitrile in anhydrous propanone and obtained
To compound 2, second step, compound 2 is dissolved in methylene chloride and obtains compound 3, third step, compound under sodium borohydride effect
3, which are dissolved in ethyl alcohol, is passed through hydrogen cyclization under nickel catalytic action and obtains compound 4, the 4th step, and compound 4 is dissolved in methylene chloride addition
Dimethyl sub-maple, DIEA and sulfur trioxide pyridine are oxidized to compound 5.Reaction equation is as follows:
First step reaction temperature is 25 DEG C, and the reaction time is 12 hours；Second step reaction temperature is 0 DEG C, and the reaction time is 1 small
When；Third step reaction temperature is 90 DEG C, 2MPa, the reaction time 24 hours；Four-step reaction temperature is 0-25 DEG C, and the reaction time is
2 hours
The Chinese paraphrase that the present invention abridges: DIEA:N, N- diisopropylethylamine；TLC: thin-layered chromatography.
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 1- tert-butyl -3- ethyl -4- oxygen subunit piperidines -1,3- dioctyl phthalate base ester and bromoacetonitrile, it is sub- to synthesize 1,10- dioxy by four steps
Base -2,7- diaza spiro [4.5] decane -7- t-butyl formate, document route more mentioned above, this method route is short, yield
Up to 50%, reaction is easy to amplify, easy to operate.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment:
Step 1: by 1- tert-butyl -3- ethyl -4- oxygen subunit piperidines -1,3- dioctyl phthalate base ester (300 g, 1.11 mol) and
Bromoacetonitrile (145.90 g, 1.22 mol) dissolves in acetone (1.5 L), then potassium carbonate (244.51 g, 1.77
Mol, 1.6 eq) it is added in reaction system and reacts 12 hours for 25 DEG C of maintenance.(petrol ether/ethyl acetate volume ratio=2/ TLC
1) end of reaction is shown.The crude product that reaction solution is concentrated under reduced pressure to give is dissolved in the water of 1L and the ethyl acetate of 1.5L, so
It is extracted afterwards with ethyl acetate (1L x 3), is concentrated under reduced pressure to give crude product after organic phase anhydrous sodium sulfate drying, gained crude product is used
Silica gel column purification (gradient elution: petrol ether/ethyl acetate~petrol ether/ethyl acetate volume ratio=10:1 ~ 2:1)
To colourless oily compound 2 (300g crude product), yield 87.42%.
1H NMR: (400MHz, CHLOROFORM-d)
δ = 4.31 (br s, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.18 - 3.89 (m, 1H), 3.38 -
3.12 (m, 2H), 3.01 - 2.73 (m, 3H), 2.64 - 2.41 (m, 1H), 1.56 - 1.35 (m, 9H),
1.33 - 1.23 (m, 3H)。
Step 2: compound 2 (265 g, 853.89 mmol) is added to methylene chloride (1.5 L), then in nitrogen
Lower 0 DEG C of dropwise addition sodium borohydride (16.15 g, 426.94 mmol) is protected to react a hour.TLC (petrol ether/ethyl acetate
Volume ratio=1/1) display end of reaction.Saturated aqueous ammonium chloride (500 mL) is added in reaction system, is then used
Ethyl acetate (500 mL x 2) extraction is concentrated under reduced pressure to give crude product after organic phase anhydrous sodium sulfate drying, and gained crude product is used
Silica gel chromatography (gradient elution: petrol ether/ethyl acetate~petrol ether/ethyl acetate volume ratio=10:1 ~ 1:
1) colourless oily compound 2 (180 g crude product), yield 86.67% are obtained.
Step 3: compound 3 (240 g, 768.34 mmol) is added in ethyl alcohol (1.5 L), then by nickel
(90.19 g, 1.54 mol) are added in reaction system, are passed through hydrogen, three times with hydrogen vacuum displacement reaction system, then
Reaction system is reacted into 24 hours under the conditions of 90 DEG C, 2 megapascal.TLC (methylene chloride/methanol volume ratio=10/1) is aobvious
Show end of reaction.Reaction solution is filtered, filtrate decompression concentration gained crude Compound 4 (180 g crude product) is colourless oily,
Yield is 86.67%.
Step 4: compound 4 (160 g, 591.88 mmol) is added in methylene chloride (1 L), then at 0 DEG C point
It Jia Ru not dimethyl sub-maple (277.47 g, 3.55 mol), DIEA (611.97 g, 4.74 mol) and sulfur trioxide pyridine network
It closes object (376.82 g, 2.37 mol).Then reaction system is reacted 2 hours at 25 DEG C.TLC (petrol ether/ethyl acetate volume
Than=0/1) display end of reaction.With water (1000mL) quenching reaction liquid, then extracted with methylene chloride (100 mL x 2),
Organic phase washes extraction twice with 1 mole of dilute hydrochloric acid (1000mLx2) again, is concentrated under reduced pressure after organic phase anhydrous sodium sulfate drying
To crude product, gained crude product silica gel chromatography (gradient elution: petrol ether/ethyl acetate~petrol ether/ethyl acetate body
Product ratio=10:1 ~ 3:1) obtain Purify conjunction object 5 (33.00 g) of yellow, yield 20.78%.
1H NMR: (400MHz, CHLOROFORM-d)
δ = 4.44 - 4.11 (m, 1H), 3.48 - 3.21 (m, 4H), 2.94 (br d, J=16.4 Hz, 1H),
2.67 (br s, 1H), 2.40 (br s, 1H), 1.88 - 1.71 (m, 1H), 1.64 (s, 1H), 1.46 -
1.37 (m, 9H)。
Claims (5)
1. one kind 1, the synthetic method of 10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate, feature
It is: includes the following steps, the first step first potassium carbonate is added by compound 1 and bromoacetonitrile in anhydrous propanone and obtains compound
2, second step, compound 2 is dissolved in methylene chloride and obtains compound 3, third step under sodium borohydride effect, and compound 3 is dissolved in second
Alcohol is passed through hydrogen cyclization under nickel catalytic action and obtains compound 4, the 4th step, and compound 4 is dissolved in methylene chloride and dimethyl is added
Sub- maple, DIEA and sulfur trioxide pyridine are oxidized to compound 5, and reaction equation is as follows:
。
2. a kind of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: 25 DEG C of the first step react 12 hours.
3. a kind of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: second step reaction temperature be 0 DEG C, the reaction time be 1 hour.
4. a kind of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: third step reaction temperature be 90 DEG C, 2MPa, the reaction time 24 hours.
5. a kind of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate according to claim 1
Synthetic method, it is characterized in that: four-step reaction temperature be 0-25 DEG C, the reaction time 2 hours.
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| CN110092790A (en) * | 2019-06-11 | 2019-08-06 | 东北农业大学 | A kind of alkaloid compound and its preparation method and application |
| CN113121537A (en) * | 2021-04-13 | 2021-07-16 | 南通药明康德医药科技有限公司 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
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| CN113121537A (en) * | 2021-04-13 | 2021-07-16 | 南通药明康德医药科技有限公司 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
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Application publication date: 20190412 |