CN102321049A - Preparation method of N-butyloxycarbonyl pyrrolidine - Google Patents
Preparation method of N-butyloxycarbonyl pyrrolidine Download PDFInfo
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- CN102321049A CN102321049A CN201110195576A CN201110195576A CN102321049A CN 102321049 A CN102321049 A CN 102321049A CN 201110195576 A CN201110195576 A CN 201110195576A CN 201110195576 A CN201110195576 A CN 201110195576A CN 102321049 A CN102321049 A CN 102321049A
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- tetramethyleneimine
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- butoxycarbonyl
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Abstract
The invention discloses a preparation method of N-butyloxycarbonyl pyrrolidine, which sequentially comprises the following steps: pyrrolidine is used as a raw material to be reacted with triphosgene in an aprotic solvent under the catalysis of organic alkali to obtain 1-pyrrolidinecarbonyl chloride, and then the 1-pyrrolidinecarbonyl chloride is reacted with sodium tert-butoxide in an aprotic solvent to obtain the N-butyloxycarbonyl pyrrolidine. The preparation method of N-butyloxycarbonyl pyrrolidine disclosed by the invention is easy to operate, the product has high purity, and the cost is low.
Description
Technical field
The present invention relates to the preparation method of organic synthesis basic raw material N-tert-butoxycarbonyl tetramethyleneimine.
Background technology
N-tert-butoxycarbonyl tetramethyleneimine is mainly used in organic synthesis, under highly basic effects such as n-Butyl Lithium, obtains various 2 bit derivants with other reagent (like ketone, aldehyde, halides etc.).Its verivate such as anticarcinogen Swainsonine, bacteriolyze property mannoside enzyme inhibitors, antimalarial drug and potential anticarcinogen febrifugine (Organic Letters, 11 (9), 1935-1938; 2009); Act on very strong histamine h1 receptor antagonist Clemastine 1 (Organic Letters, 12 (10), 2222-2225; 2010); Antitumor, antiviral Hsp90 suppressor factor (Journal of Combinatorial Chemistry, 11 (5), 860-874 with DEVELOPMENT PROSPECT; 2009, WO2008053319); AKT albumen swashs mould suppressor factor (WO2009089454).
Its verivate also is used for cationic polymerisation catalyst (Journal of the American Chemical Society, 132 (14), 5030-5032; 2010); Radical causes photocatalyst (Adv. Synth. Catal. 2008,350,2209 – 2214).
N-tert-butoxycarbonyl tetramethyleneimine is a synthesizing heterocyclic compounds important intermediate, and existing compound method has: (1) Tetrahedron Letters, 50 (46); 6244-6246,2009, (2) Letters in Organic Chemistry; 5 (2), 116-119,2008; These compound methods with industrial advantages all are to be starting raw material with the tetramethyleneimine, in different solvents, obtain N-tert-butoxycarbonyl tetramethyleneimine with the tert-Butyl dicarbonate effect, though yield is high; But because the tert-Butyl dicarbonate price is higher, so raw materials cost does not have advantage.Also have some compound methods in addition like N-tert-butoxycarbonyl pyrroles hydrogenation (Chemistry Letters, (4), 428-429; 2000) etc. do not have industrial advantages.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operate, product purity is high, cost is low method for preparing N-tert-butoxycarbonyl tetramethyleneimine.
The preparation method of N-tert-butoxycarbonyl tetramethyleneimine of the present invention in turn includes the following steps:
The first step is raw material with the tetramethyleneimine; Under 5～15 ℃ of temperature of reaction and organic base catalytic effect; In aprotic solvent, react with TRIPHOSGENE 99.5; Reaction solution gets 1-tetramethyleneimine dicarbonyl chloride through desalination, rectifying; Structural formula is like (
), and the mol ratio of used organic alkali catalyst and tetramethyleneimine is 1～1.5:1, and the mol ratio of used TRIPHOSGENE 99.5 and tetramethyleneimine is 0.4～0.3:1;
The second step 1-tetramethyleneimine dicarbonyl chloride and sodium tert-butoxide react in aprotic solvent; Control reaction temperature is at 15-25 ℃; Reaction solution gets N-tert-butoxycarbonyl tetramethyleneimine through washing, drying, rectifying; Structural formula is like (
), and the mol ratio of used sodium tert-butoxide and 1-tetramethyleneimine dicarbonyl chloride is 1.0～1.5:1.
Among the preparation method of the present invention:
Used catalyzer can be triethylamine, pyridine or tetramethyleneimine in the first step; The first step and in second step used aprotic solvent can be toluene, benzene, sherwood oil, isopropyl ether or methylene dichloride.
The present invention is raw material with the tetramethyleneimine, under organic base catalytic, makes 1-tetramethyleneimine dicarbonyl chloride with the TRIPHOSGENE 99.5 reaction; 1-tetramethyleneimine dicarbonyl chloride and sodium tert-butoxide reaction then, reaction solution gets N-tert-butoxycarbonyl tetramethyleneimine through washing, drying, rectifying, and the present invention is simple to operate; Raw material is easy to get, and cost is low, has stronger competitive power; Two step total recoverys reach more than 60%, and product quality reaches requirement.
Embodiment
Embodiment 1
Drop into toluene 400ml, TRIPHOSGENE 99.5 54.00g (0.182mol), stirring and dissolving in the there-necked flask of 1000ml; Be incubated toluene (50ml) mixed solution that drips triethylamine 61.32g (0.606mol) at 5 ℃ then, add the synthermal stirring down in back 30 minutes, drip toluene (50ml) mixed solution of tetramethyleneimine 43.03g (0.606mol) again; Added back 15 ℃ of insulation reaction 3 hours, reaction finishes back elimination solid, and solid is with the toluene wash of 50ml; Merging filtrate and washing lotion, after decompression steamed toluene, molecular distillation got 1-tetramethyleneimine dicarbonyl chloride 56.70g again; Content 98.5%, yield are 69.0%.
Drop into toluene 400ml, sodium tert-butoxide 40.36g (0.42mol) in the there-necked flask of 1000ml, stir insulation, drip toluene (50ml) solution of 1-tetramethyleneimine dicarbonyl chloride 56.10g (0.42mol) at 15 ℃; Control reaction temperature is at 25 ℃, and reaction finishes, and cools to 5 ℃ and adds the 100ml water stratification; Organic phase is washed with water to pH=7; Organic phase gets N-tert-butoxycarbonyl tetramethyleneimine 62.48g, content 98.7%, yield 85.7% through dry, underpressure distillation then.
Embodiment 2
Drop into sherwood oil 400ml, TRIPHOSGENE 99.5 60.0g (0.202mol), stirring and dissolving in the there-necked flask of 1000ml; Be incubated sherwood oil (50ml) mixed solution that drips pyridine 59.92g (0.758mol) at 5 ℃ then, add the synthermal stirring down in back 30 minutes, drip sherwood oil (50ml) mixed solution of tetramethyleneimine 43.03g (0.606mol) again; Added back 10 ℃ of insulation reaction 3 hours, reaction finishes back elimination solid, and solid is with the petroleum ether of 50ml; Merging filtrate and washing lotion, steam sherwood oil after, molecular distillation gets 1-tetramethyleneimine dicarbonyl chloride 61.88g again; Content 98.1%, yield are 75.0%.
Drop into benzene 400ml, sodium tert-butoxide 49.97g (0.52mol) in the there-necked flask of 1000ml, stir insulation, drip benzene (50ml) solution of 1-tetramethyleneimine dicarbonyl chloride 56.10g (0.42mol) at 15 ℃; Control reaction temperature is at 20 ℃, and reaction finishes, and cools to 5 ℃ and adds the 100ml water stratification; Organic phase is washed with water to pH=7; Organic phase gets N-tert-butoxycarbonyl tetramethyleneimine 64.98g, 98.5%, yield 89.0% through dry, underpressure distillation then.
Embodiment 3
Drop into methylene dichloride 400ml, TRIPHOSGENE 99.5 71.93g (0.242mol), stirring and dissolving in the there-necked flask of 1000ml; Be incubated methylene dichloride (75ml) mixed solution that drips tetramethyleneimine 64.65g (0.909mol) at 5 ℃ then, add the synthermal stirring down in back 30 minutes, drip methylene dichloride (50ml) mixed solution of tetramethyleneimine 43.03g (0.606mol) again; Added back 5 ℃ of insulation reaction 3 hours, reaction finishes back elimination solid, and solid is with the washed with dichloromethane of 50ml; Merging filtrate and washing lotion, steam methylene dichloride after, molecular distillation gets 1-tetramethyleneimine dicarbonyl chloride 58.87g again; Content 99.0%, yield are 72.0%.
Drop into isopropyl ether 400ml, sodium tert-butoxide 60.54g (0.63mol) in the there-necked flask of 1000ml, stir insulation, drip isopropyl ether (50ml) solution of 1-tetramethyleneimine dicarbonyl chloride 56.10g (0.42mol) at 15 ℃; Control reaction temperature is at 15 ℃, and reaction finishes, and cools to 5 ℃ and adds the 100ml water stratification; Organic phase is washed with water to pH=7; Organic phase gets N-tert-butoxycarbonyl tetramethyleneimine 63.59g, content 98.4%, yield 87.0% through dry, underpressure distillation then.
Claims (3)
1.N-the preparation method of tert-butoxycarbonyl tetramethyleneimine in turn includes the following steps:
The first step is raw material with the tetramethyleneimine; Under 5～15 ℃ of temperature of reaction and organic base catalytic effect; In aprotic solvent, react with TRIPHOSGENE 99.5; Reaction solution gets 1-tetramethyleneimine dicarbonyl chloride through desalination, rectifying; Structural formula is like (
), and the mol ratio of used organic alkali catalyst and tetramethyleneimine is 1～1.5:1, and the mol ratio of used TRIPHOSGENE 99.5 and tetramethyleneimine is 0.4～0.3:1;
The second step 1-tetramethyleneimine dicarbonyl chloride and sodium tert-butoxide react in aprotic solvent; Control reaction temperature is at 15-25 ℃; Reaction solution gets N-tert-butoxycarbonyl tetramethyleneimine through washing, drying, rectifying; Structural formula is like (
), and the mol ratio of used sodium tert-butoxide and 1-tetramethyleneimine dicarbonyl chloride is 1.0～1.5:1.
2. by the preparation method of the described N-tert-butoxycarbonyl of claim 1 tetramethyleneimine, it is characterized in that catalyst system therefor is in the first step: triethylamine, pyridine or tetramethyleneimine.
3. by the preparation method of the described N-tert-butoxycarbonyl of claim 1 tetramethyleneimine, it is characterized in that the first step and in second step used aprotic solvent be: toluene, benzene, sherwood oil, isopropyl ether or methylene dichloride.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110195576A CN102321049A (en) | 2011-07-13 | 2011-07-13 | Preparation method of N-butyloxycarbonyl pyrrolidine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3870707A (en) * | 1971-02-16 | 1975-03-11 | Ciba Geigy Ag | Process for the manufacture of N,N-disubstituted carbamic acid halides |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3870707A (en) * | 1971-02-16 | 1975-03-11 | Ciba Geigy Ag | Process for the manufacture of N,N-disubstituted carbamic acid halides |
Non-Patent Citations (1)
| Title |
|---|
| HARRY TILLES: "Thiolcarbamates. Preparation and Molar Refractions", 《J. AM. CHEM. SOC.》, vol. 81, 5 February 1959 (1959-02-05), pages 714 - 727, XP002431996, DOI: doi:10.1021/ja01512a052 * |
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Application publication date: 20120118 |