CN105132477A - Preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester - Google Patents
Preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester Download PDFInfo
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Abstract
The invention discloses a preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester. The preparation method has the advantages that chloroacetaldehyde and acetaldehyde serve as reaction substrates to complete a condensation reaction under the action of aldolase, an open-loop esterification reaction between an oxidative obtained product and isopropanol is achieved in the presence of a catalyst, and ester exchange between the product and 2, 2-dimethoxy propane is completed to obtain a target product, so that synthetic route is short, highly toxic products are not used in the whole reaction process, and raw materials are low in cost.
Description
Technical field
The present invention relates to biological pharmacy technical field, particularly relate to the preparation method of one (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate.
Background technology
(4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate (formula I) is the crucial chiral intermediate (WO0049014 of synthesis blood lipid-lowering medicine ZD-4522 (Rosuvastatincalcium), WO2010077062, and WO2011132172 etc.).
At present, the synthetic route about ZD-4522 side chain (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-acetic ester reports mainly chemical method.This type of method steps is long, and reaction conditions is all harsher.
Such as: the route that US Patent No. 5399722 is reported is as follows:
This method needs six-step process just can complete, and has two-step reaction to need high-pressure hydrogenation, and cost compare is high.
It is raw material with monochloroacetaldehyde that the people such as FenerChen (Tetrahedron70 (2014) 5794-5799) report a kind of, generates target compound through the following steps.
This method has used highly toxic product sodium cyanide and tin class, and first two steps reaction all needs metal catalytic, and cost compare is high.
The route of patent WO2014/203045A1 report is as follows:
This method also needs to use highly toxic product sodium cyanide, and there is the shortcomings such as the route of reaction is long and cis-selectivity is not high.
Also aldolase catalyzes is utilized to be obtained by reacting compound (4R)-6-(chloromethyl) tetrahydrochysene-2H-pyrans-2 at present, 4-glycol, as document PNAS, 2004, the report of 101 (16): 5788 – 5793, and adopt hypochlorite oxidation to obtain compound (4R)-6-(chloromethyl)-4-hydroxy tetrahydro-2H-pyran-2-one.But the reaction scheme of open loop after the process employs first itrile group, is applied to poor effect in statin synthesis.
Patent WO2013068917 discloses and utilizes zymohexase to synthesize target product (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, the method of the analogue of 3-dioxane-4-isopropyl acetate, the method needs with enzyme catalysis (4R)-6-(chloromethyl) tetrahydrochysene-2H-pyrans-2, 4-glycol generates (4R)-6-(chloromethyl)-4-hydroxy tetrahydro-2H-pyran-2-one, enzyme dosage is 10% of substrate, cost is higher, aftertreatment is complicated, the product needed obtained just can obtain (4R-cis)-6-chloromethyl-2 through transesterification reaction, 2-dimethyl-1, 3-dioxane-4-isopropyl acetate, complex steps.
In sum, there is no the method report synthesizing (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate easily at present, also there is the problem being difficult to industrial applications in the synthesis of its analogue.
Summary of the invention
The object of this invention is to provide the preparation method of one (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, the method synthetic route is short, in whole reaction process, all do not use highly toxic product, reaction safety.
For achieving the above object, the technical solution used in the present invention is: a kind of preparation method of (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, its reaction scheme and concrete steps as follows:
1) under zymohexase exists, in the reaction system of pH5 ~ 8, compound II and compound III generation condensation reaction generate compound IV;
2), in the presence of an oxidizer, in the reaction system of pH < 7, the oxidation of compound IV is obtained compound V;
3) in the presence of a catalyst, described compound V and Virahol carry out open loop, esterification successively, after reacting completely, then in system, add 2,2-dimethoxypropane carry out transesterify, be obtained by reacting target product compound I.
Preferably, described step 1) in zymohexase be the zymohexase of EW069 purchased from the trade mark of Suzhou Chinese biotechnology of enzymes company limited.
Further preferably, described step 1) in, the quality that feeds intake of described zymohexase is that compound II and compound III feed intake 1% ~ 10% of quality summation.
Preferably, described step 1) in, compound II and compound III join in reaction system by the mode adopting stream to add.Adopt which to carry out adding compound II and compound III, effectively can avoid the deactivation to zymohexase.
As a kind of concrete embodiment, described step 1) concrete operations are as follows: under zymohexase exists, in the reaction system of pH5 ~ 8, the mode adopting stream to add adds compound II and compound III, make compound II and compound III carry out condensation reaction, products therefrom after filtration, extract, merge organic phase, revolve steaming and obtain compound IV.
Preferably, in order to improve the transformation efficiency of reactant, described step 1) temperature of reaction control at 15 DEG C ~ 30 DEG C.
Preferably, described step 2) described in oxygenant be the mixture of chlorine bleach liquor or bromine and barium carbonate.
As a kind of concrete embodiment, described step 2) concrete operations are as follows: reaction system compound IV being joined pH < 7, in the presence of an oxidizer, compound IV is oxidized, to stopped reaction during the GC content < 3% of compound IV, obtain compound V.Here, step 2) in temperature of reaction control 0 DEG C ~ room temperature.
Preferably, step 2) in the pH of reaction system be preferably 1 ~ 4.
Preferably, described step 3) in catalyzer be methylsulfonic acid.
Further preferably, described step 3) in temperature of reaction control at 10 ~ 40 DEG C.In step 3) obtain target product after, cancellation reaction, extraction, merging organic phase, dry concentrated operation are carried out successively, to obtain the sterling of compound I to compound I.
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages: (4R-cis) of the present invention-6-chloromethyl-2, 2-dimethyl-1, the preparation method of 3-dioxane-4-isopropyl acetate, with monochloroacetaldehyde, acetaldehyde is reaction starting raw material, compound IV is obtained through condensation reaction, then be oxidized and generated compound V, react through esterification by ring opening again, with 2 after reacting completely, 2-Propanal dimethyl acetal carries out transesterify and obtains target product compound I, highly toxic product are not used in whole reaction process, reaction safety, and reaction scheme is short, three steps are only needed to complete 4R-cis)-6-chloromethyl-2, 2-dimethyl-1, the preparation of 3-dioxane-4-isopropyl acetate, the total recovery of three steps can reach more than 40%, enantioselectivity > 99%.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further elaborated.
Embodiment 1
The 0.1MPBS buffered soln of the pH6.5 of 140ml is added in the reactor of 500ml, at 25 DEG C, add DERA enzyme (purchases from Suzhou Chinese enzyme, the trade mark is EW069, lower same) 2.55g, the mode then adopting stream to add adds the monochloroacetaldehyde 49.1g that massfraction is 24%, massfraction is the acetaldehyde 13.7g of 99.6%, add deionized water 100ml to provide reaction environment to DERA simultaneously, control to dropwise in 3h, in whole reaction process, pH controls between 6.5 ~ 6.7, after dropwising, continue stirring reaction 1h to reacting completely, and add acetone in backward system to remove zymohexase, again through diatomite filtration, extraction into ethyl acetate three times, dry after merging organic phase, revolve the pale yellow oily liquid body steaming and obtain 14g, be compound IV ((4R)-6-(chloromethyl) tetrahydrochysene-2H-pyrans-2, 4-glycol), its GC purity is 77%, the molar yield of single step gained is 56%.
Embodiment 2
At 25 DEG C of temperature, adding DERA enzyme in the reactor (purchases from Suzhou Chinese enzyme, the trade mark is EW069) 2.55g, 140ml deionized water, stir, the mode adopting stream to add adds the monochloroacetaldehyde 75g that massfraction is 24%, massfraction is the acetaldehyde 13.7g of 99.6%, in whole reaction process, pH controls between 6.5 ~ 6.7, after dropwising, continue stirring reaction 1h to reacting completely, and add acetone in backward system to remove zymohexase, again through diatomite filtration, extraction into ethyl acetate three times, dry after merging organic phase, revolve the pale yellow oily liquid body iv steaming and obtain 15.8g, GC purity is 70%, the molar yield of single step gained is 61.2%.
Embodiment 3
At 25 DEG C of temperature, add DERA enzyme 2.55g in the reactor, 140ml deionized water, stir, the mode adopting stream to add adds the monochloroacetaldehyde 49.1g that massfraction is 24%, massfraction is the acetaldehyde 20g of 99.6%, in whole reaction process, pH controls between 6.5 ~ 6.7, after dropwising, continue stirring reaction 1h to reacting completely, and add acetone in backward system to remove zymohexase, again through diatomite filtration, extraction into ethyl acetate three times, dry after merging organic phase, revolve the pale yellow oily liquid body iv steaming and obtain 14.5g, GC purity is 70%, the molar yield of single step gained is 58%.
Embodiment 4
Add DERA enzyme 2.55g, 140ml deionized water in the reactor, stir, respectively under 15 DEG C, 20 DEG C, 25 DEG C, 30 DEG C temperature condition, adopt the mode that adds of stream add massfraction be 24% monochloroacetaldehyde 49.1g, massfraction be 99.6% acetaldehyde 13.7g, in whole reaction process, pH controls between 6.5 ~ 6.7, after dropwising, continue stirring reaction 3h, under adopting GC detector to detect differential responses temperature condition, the transformation efficiency of reactant monochloroacetaldehyde, as table one.
Table one
| Temperature of reaction DEG C | 15 | 20 | 25 | 30 |
| Transformation efficiency % | 47.8 | 53.0 | 70.9 | 55.1 |
As can be seen from Table I, at 25 DEG C, the transformation efficiency of reactant is the highest.
Embodiment 5
By compound IV ((4R)-6-(chloromethyl) tetrahydrochysene-2H-pyrans-2 of 14g obtained in embodiment 1,4-glycol) join in reactor, add 100mL Glacial acetic acid, stir, at ambient temperature, slow dropping chlorine bleach liquor 50ml, compound IV is oxidized, after dropwising, continue to stir, by high resolution gas chromatography monitoring reaction, the stopped reaction as the GC content < 3% of compound IV, obtains compound V ((4R)-6-(chloromethyl)-4-hydroxy tetrahydro-2H-pyran-2-one).And after acetic acid unnecessary in underpressure distillation removal system, add saturated sodium bicarbonate aqueous solution and regulate pH to 7.0, carry out the extraction of ethyl acetate, the dry concentrated crude product obtaining compound V, then obtain the sterling of 11.2g compound V again through column chromatography purification (PE:PA=1:1), the molar yield of single step gained is 81%.
Embodiment 6
Methylsulfonic acid 0.048g is added in 50ml reaction flask, Virahol 5ml, add the compound V 1.65g obtained by preparation method adopted in embodiment 5 under 25 DEG C of conditions in batches, stirring reaction is to generating intermediate product (its structural formula is as follows), in system, 2 are added again after reacting completely, 2-Propanal dimethyl acetal 1.52g, with intermediate product generation transesterify, stirring reaction is to generating target product compound I, then carry out cancellation reaction with saturated sodium bicarbonate aqueous solution 10ml successively, the extraction into ethyl acetate of 30ml three times, merge organic phase, the dry concentrated sterling 2.39g obtaining compound I, GC purity is 99%, the molar yield of single step gained is 90%.
Intermediate product structural formula is:
Above-described embodiment is only for illustrating technical conceive of the present invention and feature; its object is to person skilled in the art can be understood content of the present invention and be implemented; can not limit the scope of the invention with this; all equivalences done according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (9)
1. the preparation method of (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, is characterized in that, its reaction scheme and concrete steps as follows:
1) under zymohexase exists, in the reaction system of pH5 ~ 8, compound II and compound III generation condensation reaction generate compound IV;
2), in the presence of an oxidizer, in the reaction system of pH < 7, the oxidation of compound IV is obtained compound V;
3) in the presence of a catalyst, described compound V and Virahol carry out esterification by ring opening reaction, after reacting completely, then in system, add 2,2-dimethoxypropane carry out transesterify, be obtained by reacting target product compound I.
2. (4R-cis)-6-chloromethyl-2 according to claim 1,2-dimethyl-1, the preparation method of 3-dioxane-4-isopropyl acetate, is characterized in that: described step 1) in zymohexase be the zymohexase of EW069 purchased from the trade mark of Suzhou Chinese biotechnology of enzymes company limited.
3. (4R-cis)-6-chloromethyl-2 according to claim 1 and 2,2-dimethyl-1, the preparation method of 3-dioxane-4-isopropyl acetate, it is characterized in that: described step 1) in, the quality that feeds intake of described zymohexase is that compound II and compound III feed intake 1% ~ 10% of quality summation.
4. (4R-cis)-6-chloromethyl-2 according to claim 1, the preparation method of 2-dimethyl-1,3-dioxane-4-isopropyl acetate, is characterized in that, described step 1) in, compound II and compound III join in reaction system by the mode adopting stream to add.
5. the preparation method of (4R-cis)-6-chloromethyl-2, the 2-dimethyl-1,3-dioxane-4-isopropyl acetate according to claim 1 or 4, is characterized in that, described step 1) temperature of reaction control at 15 DEG C ~ 30 DEG C.
6. (4R-cis)-6-chloromethyl-2 according to claim 1,2-dimethyl-1, the preparation method of 3-dioxane-4-isopropyl acetate, is characterized in that, described step 2) described in oxygenant be the mixture of chlorine bleach liquor or bromine and barium carbonate.
7. the preparation method of (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate according to claim 1, is characterized in that, step 2) in the pH of reaction system be preferably 1 ~ 4.
8. 4R-cis according to claim 1) preparation method of-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, it is characterized in that: described step 3) in catalyzer be methylsulfonic acid.
9. the 4R-cis according to claim 1 or 8) preparation method of-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, it is characterized in that: described step 3) in temperature of reaction control at 10 ~ 40 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590733A (en) * | 2019-09-29 | 2019-12-20 | 江西开元生物医药科技有限公司 | Synthesis method of 1,4-dioxane-2,5-diol |
| CN111454216A (en) * | 2019-10-21 | 2020-07-28 | 山东理工职业学院 | Process for the preparation of HMG-CoA reductase inhibitors and intermediates thereof |
Citations (1)
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| WO2013068917A1 (en) * | 2011-11-07 | 2013-05-16 | Dr. Reddy's Laboratories Limited | Processes for the production of a lactone statin intermediate by enzymatic oxidation |
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- 2015-08-06 CN CN201510475282.5A patent/CN105132477A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013068917A1 (en) * | 2011-11-07 | 2013-05-16 | Dr. Reddy's Laboratories Limited | Processes for the production of a lactone statin intermediate by enzymatic oxidation |
Non-Patent Citations (1)
| Title |
|---|
| 赵杰: "DERA酶原原核表达及阿托伐他汀钙手性中间体的生物合成", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590733A (en) * | 2019-09-29 | 2019-12-20 | 江西开元生物医药科技有限公司 | Synthesis method of 1,4-dioxane-2,5-diol |
| CN111454216A (en) * | 2019-10-21 | 2020-07-28 | 山东理工职业学院 | Process for the preparation of HMG-CoA reductase inhibitors and intermediates thereof |
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Effective date of registration: 20180524 Address after: American California Applicant after: Codexis, Inc. Address before: 215600 No. 603, Gangcheng Road, Zhangjiagang, Suzhou, Jiangsu Applicant before: Suzhou EnzymeWorks, Inc. |
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Application publication date: 20151209 |