CN113831295A - Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor - Google Patents
Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- -1 rosuvastatin ester Chemical class 0.000 title claims abstract description 15
- 229960000672 rosuvastatin Drugs 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000000463 material Substances 0.000 claims abstract description 37
- 230000035484 reaction time Effects 0.000 claims abstract description 18
- 229940125904 compound 1 Drugs 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 238000005086 pumping Methods 0.000 claims abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 238000005260 corrosion Methods 0.000 claims description 4
- 230000007797 corrosion Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910045601 alloy Inorganic materials 0.000 claims description 2
- 239000000956 alloy Substances 0.000 claims description 2
- 239000000919 ceramic Substances 0.000 claims description 2
- 229910021421 monocrystalline silicon Inorganic materials 0.000 claims description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 24
- 239000006227 byproduct Substances 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 8
- IJHZGLLGELSZAF-OKLSWEBGSA-N tert-butyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C IJHZGLLGELSZAF-OKLSWEBGSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 4
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 3
- MSHKEMUMXTZIIT-MCBHFWOFSA-N ethyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CCOC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 MSHKEMUMXTZIIT-MCBHFWOFSA-N 0.000 description 3
- SUTPUCLJAVPJRS-NDZBKKTDSA-N methyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 SUTPUCLJAVPJRS-NDZBKKTDSA-N 0.000 description 3
- 229960004796 rosuvastatin calcium Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
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- 230000007613 environmental effect Effects 0.000 description 2
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- 239000003921 oil Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- MMTXSCWTVRMIIY-PHDIDXHHSA-N (3r,5s)-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)C=C MMTXSCWTVRMIIY-PHDIDXHHSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing rosuvastatin ester by using a continuous flow tubular reactor, which comprises the following steps: (1) mixing the compound 1 with a solvent to obtain a material A; (2) preparing 0.01-0.05 mol/L sulfuric acid solution to obtain a material B; (3) respectively pumping the material A and the material B into a first tubular reactor for chemical reaction, wherein the reaction temperature is 35-45 ℃, and the reaction time is 40-80 s; after the reaction is finished, adjusting the pH of the obtained reaction liquid to 6.5-7.5, separating liquid, concentrating under reduced pressure, recrystallizing, centrifuging, and drying to obtain a target product, wherein the specific synthetic route is as follows. By adopting the method, the time required by the whole reaction process is extremely short, the reaction condition is mild, and the by-products generated by overlong reaction time or overhigh reaction temperature are effectively avoided, so that the yield of the target product is high, the yield reaches more than 97 percent, the purity is high, and the purity reaches more than 99 percent.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing rosuvastatin ester by using a continuous flow tubular reactor.
Background
Rosuvastatin calcium, chemically known as bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2:1) and CAS number 147098-20-2, is a selective HMG-CoA reductase inhibitor developed and developed by the company asikang and marketed in various countries and regions of the united states, japan, europe, china, etc. The structural formula is as follows:
rosuvastatin calcium can be used for treating hyperlipidemia. Rosuvastatin ester is an important intermediate for synthesizing rosuvastatin calcium. Chinese patent CN103724278B discloses a process route for preparing rosuvastatin ester, and the synthetic route is shown as follows. Under the action of alcohol compounds, the compound shown in the formula II is subjected to ring opening and is converted into rosuvastatin ester.
Another Chinese patent CN103420919B also discloses a preparation method of rosuvastatin tert-butyl ester, and the synthetic route is shown as follows. The lowest temperature is required to be-80 ℃ in the whole reaction process, the yield is 84%, and the requirements on operating equipment and environment are high.
The preparation methods disclosed in the two patents are all carried out in the existing kettle type reaction bottle, the feeding mode is mostly multi-time step-by-step feeding, the reaction time is several hours, isomer impurities are generated, the post-treatment process is complex, and the product yield is not high.
Disclosure of Invention
The invention aims to provide a method for synthesizing rosuvastatin ester by using a continuous flow tubular reactor based on the prior art, which has the advantages of mild reaction conditions, extremely short time required in the whole reaction process, high yield, high purity, low cost and environmental friendliness, and effectively avoids byproducts generated by overlong reaction time or overhigh reaction temperature.
The technical scheme of the invention is as follows:
a method for synthesizing rosuvastatin ester by using a continuous flow tubular reactor, comprising the steps of:
(1) mixing the compound 1 with a solvent, and uniformly stirring to obtain a material A;
(2) preparing 0.01-0.05 mol/L sulfuric acid solution to obtain a material B;
(3) respectively pumping the material A and the material B into a tubular reactor for chemical reaction, wherein the reaction temperature is 35-45 ℃, and the reaction time is 40-80 s; after the reaction is finished, adjusting the pH of the obtained reaction liquid to 6.5-7.5, separating liquid, concentrating under reduced pressure, recrystallizing, centrifuging, and drying to obtain a target product, wherein the specific synthetic route is as follows:
wherein R represents methyl, ethyl or tert-butyl, preferably tert-butyl.
For the present invention, the solvent in step (1) is one or more of acetone, DCM or DMF, preferably DCM (dichloromethane), which can improve the yield and purity of the target product, whereas THF, acetonitrile and water are used as solvents, which under the same reaction conditions, the yield and purity of the target product decrease.
In the step (3), the molar ratio of the compound 1 to the sulfuric acid is controlled by strictly controlling the flow rates of the material A and the material B, so that better yield can be obtained, the generation of byproducts is reduced, and an intermediate product with higher purity and yield is obtained. For the present invention, the molar ratio of compound 1 to sulfuric acid is 1:0.02 to 0.06, but not limited to 1:0.02, 1:0.03, 1:0.04, 1:0.05 or 1:0.06, and for better effect, the molar ratio of compound 1 to sulfuric acid is 1: 0.03.
Further, in the present invention, the material a is a dilute sulfuric acid solution, and the concentration of sulfuric acid in the sulfuric acid solution in the material B also needs to be controlled during the reaction in the tubular reactor, so as to improve the yield and purity of the target product. In the step (2), the concentration of the sulfuric acid in the sulfuric acid solution is 0.01-0.05 mol/L, but not limited to 0.01mol/L, 0.02mol/L, 0.03mol/L, 0.04mol/L or 0.05mol/L, and in order to obtain better effects, the concentration of the sulfuric acid in the sulfuric acid solution is 0.02 mol/L.
In the invention, when the rosuvastatin ester is synthesized by adopting a continuous flow tubular reactor, the reaction temperature and the reaction time need to be controlled to improve the yield and the purity of the target product. In the step (4), when the target product is prepared by performing a chemical reaction in the tubular reactor, the reaction temperature is 35 to 45 ℃, and may be, but is not limited to, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃ or 45 ℃, and for better effects, the reaction temperature is 35 to 40 ℃, and more preferably 38 ℃. The reaction time is 40 to 80 seconds, but is not limited to 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 70 seconds or 80 seconds, and in order to obtain a preferable effect, the reaction time is 45 to 60 seconds, and more preferably 50 seconds.
In the step (1), the compound 1 and a solvent are mixed and stirred until the mixture is dissolved to be clear, so as to obtain a material A, wherein in the solution of the material A, the percentage content of the compound 1 is 4-15%, and can be but not limited to 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12% or 15%, and in order to obtain a better effect, the percentage content of the compound 1 is 8%.
For the present invention, the continuous flow tubular reactor comprises a preheater I and a preheater II, wherein the preheater I and the preheater II are connected to the feed inlet of the first tubular reactor, respectively; the material A is placed in a raw material tank A, and a metering pump I is arranged on a pipeline between the raw material tank A and the preheater I; the material B is placed in the raw material tank B, and a metering pump II is arranged on a pipeline between the raw material tank B and the preheater II.
Further preferably, the raw material tank a and the continuous flow tube reactor are both in a light-shielding state, and the whole reaction is carried out under a nitrogen protection state.
In the present invention, the reactants are pumped into the continuous flow tubular reactor by a metering pump. The reactor was precisely adjusted for the temperature required for the reaction by means of an external heat exchanger, while the actual temperature of the reaction was measured by means of a thermocouple. During the reaction process, the feeding molar ratio of the reaction materials is controlled by adjusting the flow rate of the counting pump.
For the continuous flow tubular reactor of the present invention, the reaction temperature is controlled by an external heat exchanger; the heat exchange medium is heat conducting oil or water. In the invention, the tubular reactor is of a spiral tubular structure, which is beneficial to increasing the contact area between reactants so as to ensure more complete reaction; the length of the tubular reactor is determined by the reaction time.
In a preferred embodiment, the material of the first tubular reactor is monocrystalline silicon, ceramic, corrosion-resistant stainless steel, corrosion-resistant alloy or polytetrafluoroethylene.
By adopting the technical scheme of the invention, the advantages are as follows:
the method utilizes the continuous flow tube reactor to synthesize the target product rosuvastatin ester, strictly controls the consumption of reaction materials and the reaction temperature and time in the reaction process, has extremely short time required in the whole reaction process and mild reaction conditions, effectively avoids byproducts generated by overlong reaction time or overhigh reaction temperature, and has the advantages of high yield of the target product, high purity of over 97 percent, over 99 percent, low cost, resource saving, simple post-treatment of the product and environmental friendliness.
Drawings
FIG. 1 is a schematic diagram of the structure of a continuous flow tubular reactor according to the present invention;
wherein, 1-raw material tank A, 2-raw material tank B, 4-metering pump I, 5-metering pump II, 7-preheater I, 8-preheater II, 10-heat exchange medium, and 11-tubular reactor.
Detailed Description
The process for synthesizing rosuvastatin ester using a continuous flow tubular reactor according to the present invention will be further illustrated by the following examples in conjunction with the accompanying drawings, which are not intended to limit the present invention in any way.
EXAMPLE 1 preparation of rosuvastatin tert-butyl ester (2a)
The length of the tubular reactor is determined according to the reaction time, and the heat exchange medium is heat conduction oil.
Preparation of Material A: adding the compound 1a (1.2kg, 2.08mol) into dichloromethane (13.7 kg) in a dark state, stirring to uniformly mix to obtain a material A, and placing the material A in a raw material tank A;
preparing a material B: preparing a sulfuric acid solution (0.02mol/L) and placing the sulfuric acid solution in a stock tank B;
respectively introducing the material A, B into a preheater I and a preheater II for preheating under a light-shielding state, wherein the set temperature is 38 ℃;
respectively controlling the flow rates of the material A and the material B by a metering pump I and a metering pump II to ensure that the feeding molar ratio of the compound 1a to the sulfuric acid is 1: 0.03; simultaneously conveying the material A, B into the tubular reactor, mixing and reacting for 50s, wherein the material flowing out of the discharge port of the tubular reactor is a reaction product;
dropwise adding a sodium bicarbonate solution into the reaction product to adjust the pH value to 6.5-7.5, separating liquid, and removing impurity black salt; concentrating under reduced pressure at 45 deg.C; cooling to obtain a rosuvastatin tert-butyl ester wet product; and adding toluene into the obtained wet product for recrystallization, centrifuging and drying to obtain a finished product of rosuvastatin tert-butyl ester, wherein the yield of the finished product is 99.2 percent, and the purity is 99.8 percent.
EXAMPLE 2 preparation of rosuvastatin methyl ester (2b)
Other parameters and preparation method only changing R to methyl referring to example 1, the feeding molar ratio of the compound 1b and sulfuric acid is controlled to be 1:0.03, the temperature is set to be 38 ℃, the reaction time is 50s, and the rosuvastatin methyl ester finished product is obtained with the yield of 97.2% and the purity of 99.4%.
EXAMPLE 3 preparation of rosuvastatin Ethyl ester (2c)
Other parameters and preparation method only changing R to ethyl referring to example 1, the feeding molar ratio of the compound 1c and sulfuric acid is controlled to be 1:0.03, the temperature is set to be 38 ℃, the reaction time is 50s, and the rosuvastatin ethyl ester finished product is obtained with the yield of 96.4% and the purity of 99.2%.
The following examples and comparative examples were carried out with only changes in the charge ratio, reaction temperature and reaction time, and the embodied data are shown in Table 1, wherein the reaction parameters of the blank in each example are the same as those disclosed in example 1.
TABLE 1 reaction parameters and Experimental results in examples and comparative examples
As can be seen from table 1, in the reaction process, the target product with high yield and high purity can be obtained only by strictly controlling the addition ratio of the materials, the solvent, the reaction temperature and the reaction time in the reaction process, otherwise, the reaction conditions are not well controlled, and the target product with high yield and purity cannot be obtained even by using the continuous flow tubular reactor.
Comparative example 12
Pumping 660g of acetonitrile into the batch reactor under the protection of nitrogen and in a dark state, and adding 120g of compound 1 a; heating to 38 ℃, dropwise adding 228mL of 0.02M hydrochloric acid, and keeping the temperature at 38 ℃; after the dropwise addition, reacting at 38 ℃ for 4 hours, detecting that the compound 1a basically disappears by TLC, and stopping the reaction; dropwise adding a sodium bicarbonate solution into the reacted materials to adjust the pH value to 6.5-7.5, separating the solution, wherein the lower layer contains impurity black salt; concentrating under reduced pressure at 45 deg.C; cooling, centrifuging, and leaching with 60 deg.C hot water to remove the impurity black salt to obtain rosuvastatin tert-butyl ester wet product; and adding toluene into the obtained wet product for recrystallization, centrifuging and drying to obtain a finished product of rosuvastatin tert-butyl ester, wherein the yield of the finished product is 80.5%, and the purity is 95.3%.
Compared with the example 1 in the table 1, in the comparative example 12, under the condition of the same reaction conditions, the reaction time is shortened to 40-80 seconds from 4 hours by adopting the continuous flow tubular reactor, and the reaction yield is improved to 99.2% from 80.5%, so that the excellent technical effect is achieved.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for synthesizing rosuvastatin ester by using a continuous flow tubular reactor, which is characterized by comprising the following steps:
(1) mixing the compound 1 with a solvent, and uniformly stirring to obtain a material A;
(2) preparing 0.01-0.05 mol/L sulfuric acid solution to obtain a material B;
(3) respectively pumping the material A and the material B into a tubular reactor for chemical reaction, wherein the reaction temperature is 35-45 ℃, and the reaction time is 40-80 s; after the reaction is finished, adjusting the pH of the obtained reaction liquid to 6.5-7.5, separating liquid, concentrating under reduced pressure, recrystallizing, centrifuging, and drying to obtain a target product, wherein the specific synthetic route is as follows:
wherein the content of the first and second substances,
r represents methyl, ethyl or tert-butyl;
in the step (1), the solvent is one or more of acetone, DCM or DMF;
in the step (3), the molar ratio of the compound 1 to the sulfuric acid is 1: 0.02-0.06.
2. The method according to claim 1, wherein in the step (3), the molar ratio of the compound 1 to the sulfuric acid is 1:0.02 to 0.04.
3. The process according to claim 2, wherein in step (3), the molar ratio of compound 1 to sulfuric acid is 1: 0.03.
4. The method according to claim 1, wherein the reaction temperature in the step (3) is 35 to 40 ℃.
5. The method according to claim 4, wherein, in the step (3), the reaction temperature is 38 ℃.
6. The process according to claim 1, wherein in step (3), the reaction time is 45 to 60s, preferably 50 s.
7. The process according to claim 1, wherein in step (1), the solvent is DCM; the percentage content of the compound 1 in the material A is 4-15%, and the preferable percentage content is 8%.
8. The method according to claim 1, wherein in the step (2), the concentration of the sulfuric acid in the sulfuric acid solution is 0.02 mol/L.
9. The method of claim 1, wherein the continuous flow tubular reactor comprises a preheater I and a preheater II, wherein the preheater I and the preheater II are respectively connected to the feed inlet of the tubular reactor; the material A is placed in a raw material tank A, and a metering pump I is arranged on a pipeline between the raw material tank A and the preheater I; the material B is placed in the raw material tank B, and a metering pump II is arranged on a pipeline between the raw material tank B and the preheater II.
10. The method of claim 9, wherein the first tubular reactor is comprised of single crystal silicon, ceramic, corrosion resistant stainless steel, corrosion resistant alloy, or polytetrafluoroethylene.
Priority Applications (1)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| CN102219749A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin calcium |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
| CN103483269A (en) * | 2012-06-13 | 2014-01-01 | 上海迪赛诺药业有限公司 | Preparation methods for rosuvastatin calcium and intermediates thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| CN102219749A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin calcium |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
| CN103483269A (en) * | 2012-06-13 | 2014-01-01 | 上海迪赛诺药业有限公司 | Preparation methods for rosuvastatin calcium and intermediates thereof |
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