CN105294442A - Preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester - Google Patents
Preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester Download PDFInfo
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Abstract
The invention relates to a preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester, and mainly solves the technical problem that a method suitable for industrial synthesis does not exist at present. The preparation method comprises the following six steps: firstly, reacting a compound (1) and bromoform under an alkaline condition to obtain a compound (2); secondly, reacting the compound (2) and lithium methide to obtain a compound (3); thirdly, illuminating the compound (3) and diacetyl by a high-pressure mercury lamp to obtain a compound (4); fourthly, treating with sodium hypochlorite to obtain a compound (5); fifthly, reacting the compound (5) and thionyl chloride to obtain a compound (6); and finally, treating the compound (6) under the effect of methanol to obtain a compound (7) which is a final product. A reaction formula is as shown in the specification, and the acquired bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester is a useful midbody or product for synthesis of many drugs.
Description
Technical field
The present invention relates to the synthetic method of dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate (CAS:115913-32-1).
Background technology
Dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.Current dicyclo [1.1.1] pentane-1, the synthesis of 3-dimethyl dicarboxylate is mainly raw material with New cyclobutane derivative, synthesize dicyclo [1.1.1] pentane by alkylated reaction, this route yield is lower, and there is significant limitation in exploitation derived molecules.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is applicable to.
Summary of the invention
The object of the invention is exploitation one to have raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method of dicyclo [1.1.1] pentane-1, the 3-dimethyl dicarboxylate that yield is higher.Mainly solve the technical problem not being applicable to Industrialized synthesis method at present.
Technical scheme of the present invention: the preparation method of a kind of dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate, comprise the following steps, the present invention divides six steps, first, by compound
1under sodium hydroxide solution condition, compound is obtained with bromofom
2; Then compound is obtained with lithium methide effect
3; Then under the high voltage mercury lamp radiation of 80W to 150W, compound is arrived with diacetyl
4; Compound is obtained with process under clorox room temperature
5; Then compound is obtained by reacting with sulfur oxychloride
6, final compound
6the finished product compound is obtained under methyl alcohol effect
7, reaction formula is as follows:
In above-mentioned reaction, the first step reaction chloroform consumption is 2 equivalents; Second step reaction lithium methide consumption 1.5 equivalent; Three-step reaction diacetyl consumption 2 equivalent; Four-step reaction clorox consumption is 2 equivalents.
Beneficial effect of the present invention: a kind of method that the invention provides synthesis dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate, compared with traditional method, the method route is short, and yield can up to 10.5%, and reaction is easy to amplify, easy to operate, be suitable for the molecule synthesizing other derived structures.
Embodiment
Reaction formula of the present invention is as follows:
。
Embodiment 1:a, by compound 1 (100g, 0.8mol) be preced with-6 ethers (5g) and tetramethyl ethylene ketone (8g) to be dissolved in (400g) in bromofom to drip sodium hydroxide (mass percentage concentration 30% with 18-at 10 DEG C to 25 DEG C, 1.0L) the aqueous solution, then this reaction system at room temperature stirs 24 hours.TLC (petrol ether/ethyl acetate=10/1, volume ratio, lower same) display reaction end.After reaction system is concentrated, obtain compound 2 sterling (168g) through chromatography (petrol ether/ethyl acetate=5/1 to 1/1), yield 70.7%.
δ3.301(s,4H),1.061(s,2H).
B, compound 2 (101g, 0.338mol) to be dissolved in tetrahydrofuran (THF) (200mL), at-30 DEG C to-40 DEG C, to drip the tetrahydrofuran solution (1.6M, 600mL) of lithium methide.After dropping terminates, reaction system is slowly raised to stirring at room temperature 2 lab scale.Obtain the solution of compound 2, be directly used in next step reaction.
C, in the solution of the compound 2 obtained, add diacetyl (35mL), control temperature at 15 DEG C at 25 DEG C, reaction 16 hours under the medium pressure mercury lamp of 80W to 150W irradiates.Reaction system is directly concentrated obtains crude product, obtains compound 4 sterling (23g), yield 43% with normal hexane recrystallization.
δ2.391(s,6H),2.130(s,6H)。
D, by compound 4(23g) dissolve (100mL) in dioxane, be then added drop-wise in chlorine bleach liquor (1L) at 10 DEG C-15 DEG C, continue stirring 4 hours, then add Sulfothiorine (6g).Reaction system chloroform (400mL × 3) washs.Aqueous phase concentrated hydrochloric acid is acidified to pH<1, then uses ethyl acetate (500mL × 3) to extract.After combined ethyl acetate extraction phase, with guarantor and brine It, after anhydrous sodium sulfate drying, filtering and concentrating obtains compound 5(11.5g), yield 50%.
δ2.391(s,6H)。
E, compound 5 (11.5g, 73.7mmol) is dissolved in sulfur oxychloride (200mL), back flow reaction 5 hours.TLC (petrol ether/ethyl acetate=10/1) display reaction terminates.The direct concentrating under reduced pressure of reaction system obtains compound 6, and is directly used in next step reaction.
F, compound obtained in the previous step 6 crude product are directly dissolved in methyl alcohol (200mL), reflux 4 lab scale, obtain the crude product of compound 7 after concentrated.The sterling (12.2g) of compound 7 is obtained, yield 90% with sherwood oil recrystallization.
δ3.595(s,6H),2.225(s,6H)。
Embodiment 2:a, by compound 1 (500g, 4mol) be preced with-6 ethers (25g) and tetramethyl ethylene ketone (40g) to be dissolved in (2kg) in bromofom at 10 DEG C to 25 DEG C, to drip sodium hydroxide (mass percentage concentration 30%, the 5.0L) aqueous solution with 18-. then this reaction system at room temperature stirs 24 hours.TLC (petrol ether/ethyl acetate=10/1) display reaction terminates.After reaction system is concentrated, obtain compound 2 sterling (840g) through chromatography (petrol ether/ethyl acetate=5/1 to 1/1), yield 70.7%.
δ3.301(s,4H),1.061(s,2H)。
B, compound 2 (505g, 1.69mol) to be dissolved in tetrahydrofuran (THF) (800mL), at-30 DEG C to-40 DEG C, to drip the tetrahydrofuran solution (1.6M, 3.0L) of lithium methide.After dropping terminates, reaction system is slowly raised to stirring at room temperature 2 lab scale.Obtain the solution of compound 2, be directly used in next step reaction.
C, in the solution of the compound 2 obtained, add diacetyl (150mL), control temperature at 15 DEG C at 25 DEG C, reaction 16 hours under the medium pressure mercury lamp of 80W to 150W irradiates.Reaction system is directly concentrated obtains crude product, obtains compound 4 sterling (115g), yield 43% with normal hexane recrystallization.
δ2.391(s,6H),2.130(s,6H)。
D, by compound 4(115g) dissolve (500mL) in dioxane, be then added drop-wise in chlorine bleach liquor (5L) at 10 DEG C-15 DEG C, continue stirring 4 hours, then add Sulfothiorine (30g).Reaction system chloroform (1.5L × 3) washs.Aqueous phase concentrated hydrochloric acid is acidified to pH<1, then uses ethyl acetate (1.5L × 3) to extract.After merging EtOAc extraction phase, with guarantor and brine It, after anhydrous sodium sulfate drying, filtering and concentrating obtains compound 5(57.5g), yield 50%.
δ2.391(s,6H)。
E, compound 5 (57.5g, 0.36mol) is dissolved in sulfur oxychloride (800mL), back flow reaction 5 hours.TLC (petrol ether/ethyl acetate=10/1) display reaction terminates.The direct concentrating under reduced pressure of reaction system obtains compound 6, and is directly used in next step reaction.
F, compound obtained in the previous step 6 crude product are directly dissolved in methyl alcohol (200mL), reflux 4 lab scale, obtain the crude product of compound 7 after concentrated.The sterling (61g) of compound 7 is obtained, yield 90% with sherwood oil recrystallization.
δ3.595(s,6H),2.225(s,6H)。
Claims (3)
1. the preparation method of dicyclo [1.1.1] pentane-1, a 3-dimethyl dicarboxylate, is characterized in that comprising the following steps: first, by compound
1under sodium hydroxide solution, compound is obtained by reacting with bromofom
2; Then compound is obtained with lithium methide effect
3; Then under high voltage mercury lamp radiation, compound is obtained with diacetyl
4; Compound is obtained with process under clorox room temperature
5; Then compound is obtained by reacting with sulfur oxychloride
6, final compound
6the finished product compound is obtained under methyl alcohol effect
7,reaction formula is as follows:
。
2. the preparation method of a kind of dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate according to claim 1, is characterized in that the 3rd step is reacted under the high voltage mercury lamp radiation of 80W to 150W.
3. the preparation method of a kind of dicyclo [1.1.1] pentane-1,3-dimethyl dicarboxylate according to claim 1, is characterized in that the first step reaction chloroform consumption is 2 equivalents; Second step reaction lithium methide consumption 1.5 equivalent; Three-step reaction diacetyl consumption 2 equivalent; Four-step reaction clorox consumption is 2 equivalents.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109661399A (en) * | 2016-08-23 | 2019-04-19 | 芝诺罗耶尔蒂里程碑有限责任公司 | Cross-coupling methods |
| CN110759840A (en) * | 2019-09-25 | 2020-02-07 | 爱斯特（成都）生物制药股份有限公司 | Synthesis method of 1, 1-dibromo-2, 2-bis (chloromethyl) cyclopropane |
| WO2023037935A1 (en) * | 2021-09-13 | 2023-03-16 | 富士フイルム株式会社 | Method for producing 1,3-disubstituted bicyclo[1.1.1]pentane by photoreaction |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759563A (en) * | 2009-12-29 | 2010-06-30 | 大连凯飞精细化工有限公司 | Method for selectively reducing 2,5-dioxo-bicyclo-[2,2,2] octane-1,4-dicarboxylic acid ester |
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- 2014-06-03 CN CN201410241169.6A patent/CN105294442A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759563A (en) * | 2009-12-29 | 2010-06-30 | 大连凯飞精细化工有限公司 | Method for selectively reducing 2,5-dioxo-bicyclo-[2,2,2] octane-1,4-dicarboxylic acid ester |
Non-Patent Citations (2)
| Title |
|---|
| KASZYNSKI, PIOTR和MICHL, JOSEF: "A practical photochemical synthesis of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| PELLICCIARI, ROBERTO等: "(S)-(+)-2-(3-Carboxybicyclo[1.1.1]pentyl)- glycine, a Structurally New Group I Metabotropic Glutamate Receptor Antagonist", 《J. MED. CHEM.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109661399A (en) * | 2016-08-23 | 2019-04-19 | 芝诺罗耶尔蒂里程碑有限责任公司 | Cross-coupling methods |
| CN109661399B (en) * | 2016-08-23 | 2021-09-07 | 里科瑞尔姆Ip控股有限责任公司 | Cross-coupling method |
| CN110759840A (en) * | 2019-09-25 | 2020-02-07 | 爱斯特（成都）生物制药股份有限公司 | Synthesis method of 1, 1-dibromo-2, 2-bis (chloromethyl) cyclopropane |
| CN110759840B (en) * | 2019-09-25 | 2021-06-01 | 爱斯特（成都）生物制药股份有限公司 | Synthesis method of 1, 1-dibromo-2, 2-bis (chloromethyl) cyclopropane |
| WO2023037935A1 (en) * | 2021-09-13 | 2023-03-16 | 富士フイルム株式会社 | Method for producing 1,3-disubstituted bicyclo[1.1.1]pentane by photoreaction |
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