CN102557922A - Synthesizing method of cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid - Google Patents
Synthesizing method of cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid Download PDFInfo
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- CN102557922A CN102557922A CN2010105959295A CN201010595929A CN102557922A CN 102557922 A CN102557922 A CN 102557922A CN 2010105959295 A CN2010105959295 A CN 2010105959295A CN 201010595929 A CN201010595929 A CN 201010595929A CN 102557922 A CN102557922 A CN 102557922A
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Abstract
The invention relates to a practical synthesizing method of cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid, and is mainly used for solving the technical problem of insufficient synthetic route of cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid. The method comprises the following steps: hydrolyzing 3-methylenecyclobutanecarbonitrile 1 serving as a raw material in a sodium hydroxide aqueous solution to obtain 3-methylene cyclobutanecarboxylic acid 2; leading the compound 2 to perform an addition reaction under a concentrated hydrochloric acid condition to obtain 3-chloro-3-methyl cyclobutanecarboxylic acid 3; and hydrolyzing 3-chloro-3-methyl cyclobutanecarboxylic acid 3 in a sodium hydroxide aqueous solution to obtain cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid 4. According to the synthetic route provided by the invention, cis-3-hydroxyl-3-methylcyclobutanecarboxylic acid can be prepared quickly and conveniently.
Description
Technical field
The present invention relates to the compound method of a kind of important organic synthesis intermediate cis-3-hydroxy-3-methyl cyclobutyl formate.
Background technology
3-hydroxy-3-methyl cyclobutyl formate is a kind of important organic synthesis intermediate, on, the polymeric materials science synthetic at medicine crucial effect is arranged.Especially optically active 3-hydroxy-3-methyl cyclobutyl formate has important effect especially in medicinal design.The compound method of trans-3-hydroxy-3-methyl cyclobutyl formate have bibliographical information (
J. Am. Chem. Soc, 1966,
88, 487), the compound method of cis-3-hydroxy-3-methyl cyclobutyl formate report seldom, the therefore synthetic route of a kind of new cis-3-hydroxy-3-methyl cyclobutyl formate of necessary exploitation.
Summary of the invention
The object of the present invention is to provide the compound method of cis-3-hydroxy-3-methyl cyclobutyl formate, mainly solve the technical problem that its synthetic route lacks.We have developed a kind of synthesis technique of practicality, thus synthesizing cis that can be simple and effective-3-hydroxy-3-methyl cyclobutyl formate.
Technical scheme of the present invention: cis-3-hydroxy-3-methyl cyclobutyl formate compound method may further comprise the steps:
The first step reaction is a raw material with 3-methylene radical cyclobutyronitrile, obtains 3-methylene radical cyclobutyl formate with the aqueous sodium hydroxide solution reaction;
The reaction of second step, 3-methylene radical cyclobutyl formate and concentrated hydrochloric acid reaction generate 3-chloro-3-methyl cyclobutyl formate;
Three-step reaction is under the aqueous sodium hydroxide solution condition, and the acid hydrolysis of 3-chloro-3-methyl cyclobutylmethyl obtains cis-3-hydroxy-3-methyl cyclobutyl formate.
Reaction formula is following:
The first step reaction, aqueous sodium hydroxide solution concentration is 1.0mol/L; Temperature of reaction is 80-100 ℃; Reaction times is 4～6 hours.
The reaction of second step, temperature of reaction is 25 ℃; Reaction times is 1～2 hour.
Three-step reaction, the concentration of aqueous sodium hydroxide solution are 1.0mol/L, and temperature of reaction is 25 ℃, and the reaction times is 12～16 hours.
Beneficial effect of the present invention: the invention provides a kind of simple and effective synthetic route, synthesized a kind of important organic synthesis intermediate cis-3-hydroxy-3-methyl cyclobutyl formate.This technology is three-step reaction altogether, and total recovery can reach 40%.This compound can generate corresponding amide with the amine reaction.
Embodiment
Following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content:
? 
。
Synthesizing of 1:3-methylene radical cyclobutyl formate.
Embodiment 1
With 3-methylene radical cyclobutyronitrile
1(40 g, 0.43 mol) is dissolved in sodium hydroxide (860 mL, the 1.0 mol/L) aqueous solution, and this mixture is warming up to 80 ℃, reacts 6 hours.The reaction solution cool to room temperature is transferred the pH=1 of solution with concentrated hydrochloric acid, and with dichloromethane extraction (1 L*2), the merging organic phase is used the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-methylene radical cyclobutyl formate
2(42 g, 87.5%);
Proton nmr spectra (DMSO
,400 MHz),
δPpm:4.70-4.80 (m, 2H); 3.00-3.10 (m, 1H); 2.75-2.85 (m, 4H).
Embodiment 2
With 3-methylene radical cyclobutyronitrile
1(40 g, 0.43 mol) is dissolved in sodium hydroxide (860 mL, the 1.0 mol/L) aqueous solution, and this mixture is warming up to 90 ℃, reacts 5 hours.The reaction solution cool to room temperature is transferred the pH=1 of solution with concentrated hydrochloric acid, and with dichloromethane extraction (1 L*2), the merging organic phase is used the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-methylene radical cyclobutyl formate
2(44.5 g, 91.7%).
Embodiment 3
With 3-methylene radical cyclobutyronitrile
1(40 g, 0.43 mol) is dissolved in sodium hydroxide (860 mL, the 1.0 mol/L) aqueous solution, and this mixture is warming up to 100 ℃, reacts 4 hours.The reaction solution cool to room temperature is transferred the pH=1 of solution with concentrated hydrochloric acid, and with dichloromethane extraction (1 L*2), the merging organic phase is used the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-methylene radical cyclobutyl formate
2(43 g, 88.4%).
Synthesizing of 2:3-chloro-3-methyl cyclobutyl formate.
Embodiment 4
Under 25 ℃, 3-methylene basic ring fourth formic acid
2(48 g, 0.43 mol) joins in the concentrated hydrochloric acid of 300 mL slowly, stirs 1 hour; With dichloromethane extraction (500 mL*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-chloro-3-methyl cyclobutyl formate
3(59 g, 93%);
Proton nmr spectra (DMSO
,400 MHz),
δPpm:2.90-3.30 (m, 1H); 2.45-2.70 (m, 4H); 1.65-1.75 (d, 3H).
Embodiment 5
Under 25 ℃, 3-methylene radical cyclobutyl formate
2(50 g, 0.45 mol) joins in the concentrated hydrochloric acid of 350mL slowly, stirs 1.5 hours; With dichloromethane extraction (500 mL*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-chloro-3-methyl cyclobutyl formate
3(60 g, 91%).
Embodiment 6
Under 25 ℃, 3-methylene radical cyclobutyl formate
2(50 g, 0.45 mol) joins in the concentrated hydrochloric acid of 350mL slowly, stirs 2 hours; With dichloromethane extraction (500 mL*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain 3-chloro-3-methyl cyclobutyl formate
3(62 g, 94%).
3: cis-3-hydroxy-3-methyl cyclobutyl formate synthetic.
Embodiment 7
With 3-chloro-3-methyl cyclobutyl formate
3(50 g, 0.34 mol) is dissolved in sodium hydroxide (700 mL, the 1.0 mol/L) aqueous solution; This mixture was stirred 12 hours down at 25 ℃, and reaction solution extracts once with ETHYLE ACETATE (200 mL), and water is transferred pH=1 with concentrated hydrochloric acid; With chloroform extraction (1 L*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain cis-3-hydroxy-3-methyl cyclobutyl formate
4(20g, 46%);
Proton nmr spectra (CDCl
3,400 MHz),
δPpm:5.00 (s, 1H); 2.45-2.60 (m, 1H); 2.00-2.20 (m, 4H); 1.18 (s, 3H).
Embodiment 8
With 3-chloro-3-methyl cyclobutyl formate
3(50g, (700mL is 1.0mol/L) in the aqueous solution 0.34mol) to be dissolved in sodium hydroxide; This mixture was stirred 15 hours down at 25 ℃, and reaction solution extracts once with ETHYLE ACETATE (200mL), and water is transferred pH=1 with concentrated hydrochloric acid; With chloroform extraction (1 L*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain cis-3-hydroxy-3-methyl cyclobutyl formate
4(20g, 46%).
Embodiment 9
With 3-chloro-3-methyl cyclobutyl formate
3(50g, (700mL is 1.0mol/L) in the aqueous solution 0.34mol) to be dissolved in sodium hydroxide; This mixture was stirred 16 hours down at 25 ℃, and reaction solution extracts once with ETHYLE ACETATE (200mL), and water is transferred pH=1 with concentrated hydrochloric acid; With chloroform extraction (1 L*3); Merge organic phase and use the saturated common salt water washing again, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain cis-3-hydroxy-3-methyl cyclobutyl formate
4(21g, 48%).
4: compound 6 synthetic
Embodiment 10
With cis-3-hydroxy-3-methyl cyclobutyl formate
4(1.3g, 10mmol), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3, (3.8g 10mmol) is dissolved in the THF (20mL) 25 to 3-tetramethyl-urea phosphofluoric acid ester
oC stirred 10 minutes down, aniline
5(1.1g, 12mmol), (2.0g 20mmol) adds in the above-mentioned reaction system triethylamine, continues to stir two hours, and reaction solution concentrates, and column chromatography obtains compound
6(1.85g, 90%);
Proton nmr spectra (DMSO
,400 MHz),
δPpm:7.60-7.70 (m, 2H); 7.20-7.30 (m, 2H); 6.95-7.00 (m, 1H); 2.40-2.50 (m, 1H); 2.05-2.25 (m, 4H); 1.20 (s, 3H).
5: compound 8 synthetic
Embodiment 11
With cis-3-hydroxy-3-methyl cyclobutyl formate
4(1.3g, 10mmol), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3, (3.8g 10mmol) is dissolved in the THF (20mL) 25 to 3-tetramethyl-urea phosphofluoric acid ester
oC stirred 10 minutes down, m-anisidine
7(1.5g, 12mmol), (2.0g 20mmol) adds in the above-mentioned reaction system triethylamine, continues to stir two hours, and reaction solution concentrates, and column chromatography obtains compound
8(1.95g, 83%);
Proton nmr spectra (DMSO
,400 MHz),
δPpm:7.25-7.30 (m, 1H); 7.10-7.20 (m, 2H); 6.75-6.85 (m, 1H); 2.35-2.45 (m, 1H); 2.00-2.25 (m, 4H); 1.19 (s, 3H).
Claims (4)
1. the compound method of cis-3-hydroxy-3-methyl cyclobutyl formate may further comprise the steps:
The first step reaction is a raw material with 3-methylene radical cyclobutyronitrile, obtains 3-methylene radical cyclobutyl formate with the aqueous sodium hydroxide solution reaction;
The reaction of second step, 3-methylene radical cyclobutyl formate and concentrated hydrochloric acid reaction generate 3-chloro-3-methyl cyclobutyl formate;
Three-step reaction is under the aqueous sodium hydroxide solution condition, and the acid hydrolysis of 3-chloro-3-methyl cyclobutylmethyl obtains cis-3-hydroxy-3-methyl cyclobutyl formate.
2. the compound method of cis according to claim 1-3-hydroxy-3-methyl cyclobutyl formate is characterized in that, the first step reaction, and aqueous sodium hydroxide solution concentration is 1.0 mol/L, and temperature of reaction is 80-100 ℃, and the reaction times is 4～6 hours.
3. the compound method of cis according to claim 1-3-hydroxy-3-methyl cyclobutyl formate is characterized in that, the reaction of second step, and temperature of reaction is 25 ℃, the reaction times is 1～2 hour.
4. the compound method of cis according to claim 1-3-hydroxy-3-methyl cyclobutyl formate is characterized in that, three-step reaction, and aqueous sodium hydroxide solution concentration is 1.0mol/L, temperature of reaction is 25 ℃; Reaction times is 12～16 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999103A (en) * | 2021-11-26 | 2022-02-01 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of alpha-hydroxy-cyclobutane carboxylic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3852322A (en) * | 1973-06-15 | 1974-12-03 | Pfizer | Process for citric acid production and intermediates therefor |
| CN1407967A (en) * | 1999-12-08 | 2003-04-02 | 沃尼尔·朗伯公司 | Stereoselective synthesis of cyclic amino acids |
-
2010
- 2010-12-20 CN CN2010105959295A patent/CN102557922A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3852322A (en) * | 1973-06-15 | 1974-12-03 | Pfizer | Process for citric acid production and intermediates therefor |
| CN1407967A (en) * | 1999-12-08 | 2003-04-02 | 沃尼尔·朗伯公司 | Stereoselective synthesis of cyclic amino acids |
Non-Patent Citations (1)
| Title |
|---|
| E. P. BLANCHARD ET AL.: "Bicyclo[1.1.0]butane Chemistry. I. The Synthesis and Reactions of 3-Methylbicyclo[1.1.0]butanecarbonitriles", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999103A (en) * | 2021-11-26 | 2022-02-01 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of alpha-hydroxy-cyclobutane carboxylic acid |
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Application publication date: 20120711 |