CN104356109A - Preparation method of 2-(( 4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate - Google Patents
Preparation method of 2-(( 4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate Download PDFInfo
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- CN104356109A CN104356109A CN201410633271.0A CN201410633271A CN104356109A CN 104356109 A CN104356109 A CN 104356109A CN 201410633271 A CN201410633271 A CN 201410633271A CN 104356109 A CN104356109 A CN 104356109A
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 2-((4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate. The method comprises the following steps: carrying out bromination cyclization reaction on 3-((substituted-oxyformyl)oxy)-5-hexenoate (II) with a bromination reagent in an organic solvent in the presence of an inorganic alkali to obtain 2-((4R,6S)-6-bromoethyl-2-oxo-1,3-dioxyhexacyclo-4-yl)acetate (III), and carrying out ketalation reaction with a ketalation reagent in the presence of protonic acid to obtain the 2-((4R,6S)-6-bromoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate (I). The compound is a key chiral intermediate for preparing statin hypolipidemic drugs. The method has the advantages of accessible raw material, mild conditions and low cost, and is simple to operate and convenient for industrial production.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, this compound can be used as the synthesis of important drugs synthesis of chiral intermediate for statins antilipemic medicine.
Background technology
2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester is a kind of chemical industry synthetic intermediate, can be used for the synthesis of statins antilipemic drugs.Its structural formula is as shown in the formula shown in (I):
In formula, R is C
1-C
8alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl.
US Patent No. 5278313 disclose with (
s)-4-bromo-3-hydroxybutyrate methyl esters is that raw material and tert.-butyl acetate carry out Claisen condensation, then through diethyl methoxyl group boron/sodium borohydride cis-selectivity reduction and ketalization preparation 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) method of tert.-butyl acetate (I).
But the reaction of these method first two steps is all carried out under low temperature (-78 DEG C) and anhydrous and oxygen-free condition, severe reaction conditions, and employs expensive inflammable and explosive diethyl methoxyl group boron in reduction reaction, makes troubles to industrial production.
Chinese patent CN103614430 and document Chinese Journal of Pharmaceuticals 2013,44 (10): 975-977 report another kind of with (
s)-4-bromo-3-hydroxybutyrate methyl esters is that raw material and tert.-butyl acetate carry out Claisen condensation, then through biological reducing and ketalization preparation 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) method of tert.-butyl acetate (I).
This method uses candidiasis Magnotiae IF0705 as the carbonyl of reductive agent reduction Claisen condensation product, but this bacterial classification commercial-free source.
Above-mentioned two kinds of methods, are all unfavorable for large-scale industrial production.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of 2-((4 is provided
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) high efficiency preparation method of acetic ester (compound (I)), to be applicable to suitability for industrialized production.
2-((4 provided by the invention
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester (I), concrete steps are:
(1) carry out bromo cyclization in organic solvent with brominated reagent in the presence of an inorganic base by compound (II): 3-((replacing oxygen formyl) oxygen)-5-hexene acid esters, obtain compound (III): 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) acetic ester (III);
(2) compound (III) carries out ketal reaction with ketalization reagent under the existence of protonic acid, obtains target compound (I): 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester;
Its synthetic route is:
R, R in formula ' be identical or different C
1-C
8alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl.
In the present invention, starting material compound (II) can be prepared with reference to world patent WO2003053950 or Chinese patent CN101735272.
In the present invention, when preparing compound (III) by compound (II), the oxyhydroxide that the mineral alkali used is basic metal or alkaline-earth metal, carbonate, phosphoric acid salt or C
1-C
4alcoxyl salt, as salt of wormwood, potassiumphosphate, sodium ethylate etc.; Use brominated reagent to be bromine,
n-bromo acetamide,
n-bromo-succinimide, 1,3-bis-bromo-5,5-dimethyl hydantion,
n,N-dibromo-benzene sulphonamide; The organic solvent used is for halo or alkyl polyhalides hydrocarbon are as methylene dichloride, chloroform, monosubstituted or polysubstituted aromatic hydrocarbons is as toluene, chlorobenzene, symmetrical, asymmetric ether or cyclic ethers are as ether, methyl tertiary butyl ether, tetrahydrofuran (THF), acetonitrile, or the mixed solvent of above-mentioned solvent composition, these solvents are cheap and easy to get.In reaction, the mol ratio of compound (II), brominated reagent, alkali is 1:1 ~ 5:1 ~ 5, and temperature of reaction is-80 ~ 0 DEG C, and when the reaction times is 10 ~ 120 minutes, reaction can be carried out smoothly.The compound (III) of reaction gained is directly used in next step without the need to separation and purification.
In the present invention, when preparing compound (I) by compound (III), the protonic acid used is hydrogenchloride, sulfuric acid, C
1-C
6alkylsulphonic acid, monosubstituted or polysubstituted aryl sulfonic acid or camphorsulfonic acid.The ketalization reagent used is acetone, the mixture of 2,2-dimethylpropanes or both arbitrary proportions.The mol ratio of compound (III), protonic acid and ketalization examination is 1:0.01 ~ 1:5 ~ 500, and at 0 ~ 50 DEG C, reaction can obtain compound (I) for 6 ~ 72 hours.
Top condition in the present invention is:
When preparing compound (III) by compound (II), the solvent used is methylene dichloride, and alkali is salt of wormwood, and brominated reagent is bromine.The mol ratio of compound (II), mineral alkali and brominated reagent is 1:1.5 ~ 2.5:1.5 ~ 2.5, and temperature of reaction is-40 ~-20 DEG C, and the reaction times is 30 ~ 60 minutes.
When preparing compound (I) by compound (III), the acid used is tosic acid or methanesulfonic; The ketalization reagent used is acetone.Compound (III), mol ratio that is sour and ketalization reagent are 1:0.5 ~ 1:20 ~ 100, and temperature of reaction is 25 ~ 35 DEG C, 24-48 hours reaction times.
The inventive method, raw material is easy to get, and reaction conditions is gentle, easy and simple to handle, product purity high, is applicable to suitability for industrialized production.
Embodiment
Following examples illustrate content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1
By 3-((tertiary fourth oxygen formyl) oxygen)-5-hexenoic acid methyl ester, (1.22 g) are dissolved in methylene dichloride (20 mL), and (1.38 g), and (1.6 g) to drip bromine under stirring in-40 DEG C to add salt of wormwood, drip and finish, insulated and stirred 45 minutes, reaction is finished, and adds 10% sodium sulfite solution (10 mL), reaction solution dichloromethane extraction, merge organic phase, saturated sodium bicarbonate solution washs, anhydrous sodium sulfate drying, concentrated, obtain pale yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate crude product.
By this oily matter and acetone, (10 g) put in reaction flask, (0.90 g), stirs 36 hours in 25 DEG C, and reaction is finished to add tosic acid monohydrate, add saturated sodium bicarbonate solution (10 mL), concentrating under reduced pressure acetone, residual solution is extracted with ethyl acetate, and merges organic phase, use 10% sodium sulfite solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, obtain yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate (1.16 g, 82%).
Embodiment 2
By 3-((tertiary fourth oxygen formyl) oxygen)-5-hexenoic acid methyl ester, (1.22 g) are dissolved in methylene dichloride (20 mL), and (1.60 g), and (1.60 g) to drip bromine under stirring in-20 DEG C to add potassiumphosphate, drip and finish, insulated and stirred 1 hour, reaction is finished, and adds 10% sodium sulfite solution (10 mL), reaction solution dichloromethane extraction, merge organic phase, saturated sodium bicarbonate solution washs, anhydrous sodium sulfate drying, concentrated, obtain pale yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate crude product.
By this oily matter and 2,2-dimethoxypropane, (15 g) put in reaction flask, and (0.40 g) to add methanesulfonic, stir 40 hours in 25 DEG C, reaction is finished, and adds saturated sodium bicarbonate solution (10 mL), concentrating under reduced pressure 2,2-Propanal dimethyl acetal, residual solution is extracted with ethyl acetate, and merges organic phase, use 10% sodium sulfite solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, obtain yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate (0.80 g, 57%).
Embodiment 3
By 3-((tertiary fourth oxygen formyl) the oxygen)-5-hexenoic acid tert-butyl ester, (1.43 g) are dissolved in acetonitrile (20 mL), and (1.00 g), adds under stirring in-40 DEG C in batches to add sodium carbonate
n(1.78 g) for-bromo-succinimide, drip and finish, insulated and stirred 1 hour, reaction is finished, and adds 10% sodium sulfite solution (10 mL), reaction solution dichloromethane extraction, merge organic phase, saturated sodium bicarbonate solution washs, anhydrous sodium sulfate drying, concentrated, obtain pale yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) acetic acid first tert-butyl ester.
By this oily matter and acetone, (20 g) put in reaction flask, camphorating, (1.50 g), stirs 24 hours in 35 DEG C, and reaction is finished for sulfonic acid, add saturated sodium bicarbonate solution (10 mL), concentrating under reduced pressure acetone, residual solution is extracted with ethyl acetate, and merges organic phase, use 10% sodium sulfite solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, obtain yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) tert.-butyl acetate (1.14 g, 71%).
Embodiment 4
By 3-((carbobenzoxy) the oxygen)-5-hexenoic acid tert-butyl ester, (1.60 g) are dissolved in toluene (20 mL), and (1.38 g), and (2 g) to drip bromine under stirring in-60 DEG C to add salt of wormwood, drip and finish, insulated and stirred 1.5 hours, reaction is finished, and adds 10% sodium sulfite solution (10 mL), reaction solution toluene extracts, merge organic phase, saturated sodium bicarbonate solution washs, anhydrous sodium sulfate drying, concentrated, obtain pale yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) acetic acid first tert-butyl ester.
By this oily matter and acetone, (20 g) put in reaction flask, (0.50 g) to add tosic acid monohydrate, stir 48 hours in 25 DEG C, reaction is finished, and adds saturated sodium bicarbonate solution (10 mL), concentrating under reduced pressure acetone, residual solution is extracted with ethyl acetate, and merges organic phase, uses 10% sodium sulfite solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, obtains yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) tert.-butyl acetate (1.02 g, 63%).
Embodiment 5
By 3-((tertiary fourth oxygen formyl) oxygen)-5-hexenoic acid methyl ester, (1.22 g) are dissolved in tetrahydrofuran (THF) (20 mL), and (1.38 g), and (1.6 g) to drip bromine under stirring in-40 DEG C to add salt of wormwood, drip and finish, insulated and stirred 45 minutes, reaction is finished, and adds 10% sodium sulfite solution (10 mL), reaction solution dichloromethane extraction, merge organic phase, saturated sodium bicarbonate solution washs, anhydrous sodium sulfate drying, concentrated, obtain pale yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate crude product.
By this oily matter and acetone, (10 g) put in reaction flask, and (0.90 g), in 56 DEG C of return stirrings 6 hours to add tosic acid monohydrate, reaction is finished, be chilled to room temperature, add saturated sodium bicarbonate solution (10 mL), concentrating under reduced pressure acetone, residual solution is extracted with ethyl acetate, merge organic phase, use 10% sodium sulfite solution and saturated common salt water washing successively, anhydrous sodium sulfate drying,, obtain yellow oil 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) methyl acetate (1.04 g, 74%).
Claims (7)
1. a 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that concrete steps are:
(1) carry out bromo cyclization in organic solvent with brominated reagent in the presence of an inorganic base by compound (II): 3-((replacing oxygen formyl) oxygen)-5-hexene acid esters, obtain compound (III): 2-((4
r, 6
s)-6-brooethyl-2-oxo-1,3-dioxane-4-base) acetic ester (III);
(2) compound (III) carries out ketal reaction with ketalization reagent under the existence of protonic acid, obtains target compound (I): 2-((4
r, 6
s)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester; Its reaction formula is:
R, R in formula ' be identical or different C
1-C
8alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl;
Concrete preparation condition is:
(1), when preparing compound (III) by compound (II), mineral alkali used is the oxyhydroxide of basic metal or alkaline-earth metal, carbonate, phosphoric acid salt or C
1-C
4alcoxyl salt;
(2) when preparing compound (III) by compound (II), brominated reagent used be bromine,
n-bromo acetamide,
n-bromo-succinimide, 1,3-bis-bromo-5,5-dimethyl hydantion,
n,N-dibromo-benzene sulphonamide;
(3) when preparing compound (III) by compound (II), the organic solvent used is halo or alkyl polyhalides hydrocarbon, the mixed solvent of monosubstituted or polysubstituted aromatic hydrocarbons, symmetry or asymmetric ether or cyclic ethers, acetonitrile or above-mentioned solvent composition;
(4), when preparing compound (I) by compound (III), the protonic acid used is hydrogenchloride, sulfuric acid, C
1-C
6alkylsulphonic acid, monosubstituted or polysubstituted aryl sulfonic acid or camphorsulfonic acid;
(5), when preparing compound (I) by compound (III), ketalization reagent used is acetone, 2,2-dimethoxypropane, or the mixture of both arbitrary proportions.
2. preparation method as claimed in claim 1, is characterized in that: step is in (one), and the mol ratio of compound (II), mineral alkali and brominated reagent is 1: (1 ~ 5): (1 ~ 5), and temperature of reaction is-80 ~ 0 DEG C, and the reaction times is 10 ~ 120 minutes.
3. preparation method as claimed in claim 1, is characterized in that: step is in (one), and the mineral alkali used is salt of wormwood; Brominated reagent is bromine; Solvent is methylene dichloride.
4. preparation method as claimed in claim 2, it is characterized in that: step is in (one), the mol ratio of compound (II), mineral alkali and brominated reagent is 1:(1.5 ~ 2.5): (1.5 ~ 2.5), temperature of reaction is-40 ~-20 DEG C, and the reaction times is 30 ~ 60 minutes.
5. preparation method as claimed in claim 1, is characterized in that: step is in (two), and the mol ratio of compound (III), protonic acid and ketalization reagent is 1:(0.01 ~ 1): (5 ~ 500), temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 6 ~ 72 hours.
6. preparation method as claimed in claim 1, is characterized in that: step is in (two), and the protonic acid used is tosic acid or methanesulfonic; The ketalization reagent used is acetone.
7. preparation method as claimed in claim 3, is characterized in that: step is in (two), and the mol ratio of compound (III), protonic acid and ketalization reagent is 1:(0.5 ~ 1): (20 ~ 50), temperature of reaction is 25 ~ 35 DEG C, and the reaction times is 24 ~ 48 hours.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410633271.0A CN104356109B (en) | 2014-11-12 | 2014-11-12 | A kind of preparation method of 2-((4R, 6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic acid esters |
| PCT/CN2014/095502 WO2016074324A1 (en) | 2014-11-12 | 2014-12-30 | Preparation method of 2-((4r, 6s)-6-bromomethyl-2, 2-dimethyl-1, 3-dioxane-4-yl)acetate |
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|---|---|---|---|
| CN201410633271.0A CN104356109B (en) | 2014-11-12 | 2014-11-12 | A kind of preparation method of 2-((4R, 6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic acid esters |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496182A (en) * | 2016-09-09 | 2017-03-15 | 复旦大学 | A kind of preparation method of atorvastatin surveyor's chain intermediate |
| CN106588865A (en) * | 2017-01-17 | 2017-04-26 | 复旦大学 | Preparation method for (4S,6R)-4-bromomethyl-6-substituted methyl-2-oxo-1,3-dioxane |
| CN107188880A (en) * | 2017-05-25 | 2017-09-22 | 复旦大学 | The preparation method of 2 (base of 2 oxo of (4R, 6S) 6 bromomethyl, 1,3 dioxane 4) acetic acid esters |
| CN112159403A (en) * | 2020-09-30 | 2021-01-01 | 复旦大学 | Preparation method of key intermediate for synthesizing statins |
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|---|---|---|---|---|
| CN107119081B (en) | 2017-05-26 | 2021-01-26 | 复旦大学 | Method for preparing (R) -3-hydroxy-5-hexenoic acid ester |
| CN112375801A (en) | 2020-10-22 | 2021-02-19 | 复旦大学 | Micro-reaction system and method for continuously preparing (R) -3-hydroxy-5-hexenoic acid ester by using same |
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|---|---|---|---|---|
| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
| WO2003053950A1 (en) * | 2001-12-20 | 2003-07-03 | Choongwae Pharma Corporation | New process for the preparation of optically active 2-[6-(substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN101735272A (en) * | 2009-12-11 | 2010-06-16 | 重庆博腾精细化工有限公司 | Method for preparing rosuvastatin calcium midbody |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
-
2014
- 2014-11-12 CN CN201410633271.0A patent/CN104356109B/en active Active
- 2014-12-30 WO PCT/CN2014/095502 patent/WO2016074324A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
| WO2003053950A1 (en) * | 2001-12-20 | 2003-07-03 | Choongwae Pharma Corporation | New process for the preparation of optically active 2-[6-(substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN101735272A (en) * | 2009-12-11 | 2010-06-16 | 重庆博腾精细化工有限公司 | Method for preparing rosuvastatin calcium midbody |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496182A (en) * | 2016-09-09 | 2017-03-15 | 复旦大学 | A kind of preparation method of atorvastatin surveyor's chain intermediate |
| CN106496182B (en) * | 2016-09-09 | 2019-07-05 | 复旦大学 | A kind of preparation method of Atorvastatin surveyor's chain intermediate |
| CN106588865A (en) * | 2017-01-17 | 2017-04-26 | 复旦大学 | Preparation method for (4S,6R)-4-bromomethyl-6-substituted methyl-2-oxo-1,3-dioxane |
| CN106588865B (en) * | 2017-01-17 | 2020-09-25 | 复旦大学 | Preparation method of (4S,6R) -4-bromomethyl-6-substituted methyl-2-oxo-1, 3-dioxane |
| CN107188880A (en) * | 2017-05-25 | 2017-09-22 | 复旦大学 | The preparation method of 2 (base of 2 oxo of (4R, 6S) 6 bromomethyl, 1,3 dioxane 4) acetic acid esters |
| CN107188880B (en) * | 2017-05-25 | 2020-10-30 | 复旦大学 | Preparation method of 2- ((4R,6S)6 bromomethyl 2 oxo-1, 3-dioxane-4-yl) acetate |
| CN112159403A (en) * | 2020-09-30 | 2021-01-01 | 复旦大学 | Preparation method of key intermediate for synthesizing statins |
| CN112159403B (en) * | 2020-09-30 | 2022-04-15 | 复旦大学 | Preparation method of key intermediate for synthesizing statins |
| US11708363B2 (en) | 2020-09-30 | 2023-07-25 | Fudan University | Method for preparing a key intermediate for the synthesis of statins |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104356109B (en) | 2016-08-24 |
| WO2016074324A1 (en) | 2016-05-19 |
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Effective date of registration: 20170322 Address after: 344000 Fuzhou hi tech Industrial Park, Jiangxi, weft Road, six Patentee after: Jiangxi Boya Xin Pharmaceutical Co. Ltd. Address before: 200433 Handan Road, Shanghai, No. 220, No. Patentee before: Fudan University |
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