CN114394993B - Preparation method of dapagliflozin intermediate - Google Patents
Preparation method of dapagliflozin intermediate Download PDFInfo
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- CN114394993B CN114394993B CN202111673316.3A CN202111673316A CN114394993B CN 114394993 B CN114394993 B CN 114394993B CN 202111673316 A CN202111673316 A CN 202111673316A CN 114394993 B CN114394993 B CN 114394993B
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 23
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 116
- 238000006243 chemical reaction Methods 0.000 claims abstract description 101
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- ZUNCHZBITMUSRD-UHFFFAOYSA-N 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene Chemical compound C1=CC(OCC)=CC=C1CC1=CC(Br)=CC=C1Cl ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 claims abstract description 13
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 238000005086 pumping Methods 0.000 claims abstract description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- -1 glucose lactone Chemical class 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 7
- 238000010924 continuous production Methods 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 2
- 108091052347 Glucose transporter family Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- TYNKHEKALKCUBV-OOJXKGFFSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxy-1-trimethylsilylhexan-1-one Chemical compound C[Si](C)(C)C(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO TYNKHEKALKCUBV-OOJXKGFFSA-N 0.000 description 1
- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 206010052341 Impaired insulin secretion Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 108091006269 SLC5A2 Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 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
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Abstract
The invention discloses a method for preparing dapagliflozin intermediate by adopting a microreactor, and belongs to the field of preparation of medical intermediate. The invention comprises the following steps: (1) Pre-cooling a tetrahydrofuran solution of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane and an n-butyllithium solution at a temperature of between 78 ℃ below zero and 20 ℃ below zero respectively, and then pumping the tetrahydrofuran solution and the n-butyllithium solution into a first reaction unit of a microreactor respectively, mixing and reacting, wherein the mole ratio of the 5-bromo-2-chloro-4' -ethoxydiphenylmethane to the n-butyllithium in the first reaction unit is 1 (0.85 to 1.5), and the flow rate of the n-butyllithium solution is not lower than 20ml/min; and (3) pumping the reaction solution obtained in the step (1) and the glucolactone protected by the trimethylsilyl group into a second reaction unit respectively, mixing and reacting. The invention has the advantages of continuous production, no dangerous process, simple operation, less environmental pollution, safety, high efficiency and the like, and has higher industrialized application prospect.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing dapagliflozin intermediates by utilizing a microreactor.
Technical Field
Dapagliflozin (Dapagliflozin) is a sodium-dependent glucose transporter SGLT2 inhibitor for use in the treatment of type 2 diabetes and may be an important choice in the treatment of diabetes. About 1 million people worldwide suffer from type II diabetes (NIDDM-non-insulin dependent diabetes mellitus) characterized by hyperglycemia due to hepatic glucose overproduction and peripheral insulin resistance, but the root cause thereof is not clear. Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion that occurs in late NIDDM. It is expected that normalization of blood glucose in NIDDM patients will improve insulin action and counteract the development of diabetic complications. Inhibitors of sodium-dependent glucose transporter SGLT2 in the kidney are expected to help normalize plasma glucose levels, and perhaps body weight, by excretion of glucose.
Dapagliflozin (dapagliflozin), chemical name (2 s,3r,4r,5s,6 r) -2- [3- (4-ethoxybenzyl) -4-chlorophenyl ] -6-hydroxymethyltetrahydro-2H-pyran-3, 4, 5-triol, developed jointly by Bai-me-schirku and aslican, is the first approved sodium-glucose cotransporter 2 (SGLT 2) inhibitor for the treatment of type 2 diabetes. The trade name is Farxigao.
The traditional stirring preparation method of dapagliflozin mainly comprises two steps, wherein 5-bromo-2-chlorobenzoic acid is used as a starting material, and dapagliflozin is prepared by acyl chlorination, friedel-crafts acylation, reduction, condensation with 2,3,4, 6-tetraoxo-trimethylsilyl-D-glucopyranose-1, 5-lactone, formylation and reduction demethoxy. Such as the patent: PCT Int.Appl.,2010022313,PCT Int.Appl, 2009026537; documents Journal of Medicinal Chemistry,51 (5), 1145-1149;2008, the specific synthetic route is as follows:
another synthesis scheme is to prepare dapagliflozin by taking o-methylaniline as a starting material, carrying out bromination, diazotizing chlorination, NCS chlorination and alkylation reaction, and then condensing with 2,3,4, 6-tetra-oxo-trimethylsilyl-D-glucopyranose-1, 5-lactone, formylating and reducing demethoxy, wherein the specific synthesis route is as follows:
these two methods are considered to be the simplest and most economical synthetic routes at present, and are the main methods in industrial production. However, the traditional synthesis process in the stirred tank has poor mixing, uneven reaction in the system, larger impurities, lower yield of dapagliflozin, waste of reaction materials, more impurities generated by side reaction and more impurities generated by side reaction in the sugar condensation reaction process, can directly influence the safety and effectiveness of the product, and increase the cost for purifying and removing the impurities; the existing stirring reaction has low mass transfer efficiency, butyl lithium is firstly added dropwise, then sugar is added, the traditional stirring effect is added with longer subsequent stirring time, and the production efficiency is low.
The invention discloses a preparation method of dapagliflozin intermediate microreactor, and the prior patent CN109400561A discloses a synthesis method for preparing dapagliflozin by the microreactor. Wherein the optimal molar ratio of the 5-bromo-2-chloro-4-ethoxydiphenylmethane to the toluene/tetrahydrofuran mixed solvent is 1:1.2, the optimal flow rate of the tetrahydrofuran solution of the 5-bromo-2-chloro-4-ethoxydiphenylmethane is 12-15ml/min, and the optimal flow rate of the butyllithium is 2-3mi/min; the reaction residence time of the first reaction unit is optimally 27-30S; the second reaction unit is to mix the solution at the liquid outlet of the first unit with trimethylsilyl glucose for the second stage condensation reaction. The preparation method has milder reaction conditions and efficient reaction progress, but has the defects of low flow rate of the first secondary reaction unit, low utilization rate of equipment, low productivity and low flow rate of the n-butyl lithium solution, and is easy to deposit in a pipeline and block the pipeline; secondly, because of the particularity of the n-butyllithium, the pipeline between the pipeline feed inlet and the sample mixing front adopts room temperature, and the high risk and unsafe factors are provided; and finally, the equivalent weight of the n-butyllithium in the patent is 1.2eq, which is far greater than the dosage of theoretical butyllithium, and the residual n-butyllithium is easy to condense with the compound 3 sugar compound in the second reaction unit to generate side reaction, so that the yield is reduced.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of providing a method for preparing dapagliflozin intermediates by adopting a micro-reactor, so as to solve the problems of low preparation efficiency and serious raw material waste of the dapagliflozin intermediates in the prior art.
The technical scheme is as follows: in order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of dapagliflozin intermediate comprises the following reaction routes:
the specific preparation method of the invention comprises the following steps:
(1) Pre-cooling a tetrahydrofuran solution of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane and an n-butyllithium solution at a temperature of between 78 ℃ below zero and 20 ℃ below zero respectively, and then pumping the pre-cooled tetrahydrofuran solution and the n-butyllithium solution into a first reaction unit of a microreactor respectively, mixing and reacting, wherein the mol ratio of the 5-bromo-2-chloro-4' -ethoxydiphenylmethane to the n-butyllithium in the first reaction unit is 1: (0.85-1.5), and preferably 1:0.95;
(2) Pumping the reaction solution obtained in the step (1) and the glucolactone protected by the trimethylsilyl group into a second reaction unit respectively, mixing and reacting.
In the step (1), the concentration of the 5-bromo-2-chloro-4 '-ethoxydiphenylmethane in the tetrahydrofuran solution of the 5-bromo-2-chloro-4' -ethoxydiphenylmethane is 0.8mol/L to 1.6mol/L.
In the step (1), the concentration of the n-butyllithium solution is 1.6-2.5mol/L, preferably 1.6mol/L.
In the step (1), the flow rate of the tetrahydrofuran solution of the 5-bromo-2-chloro-4 '-ethoxydiphenylmethane and the flow rate of the n-butyllithium solution are not lower than 20ml/min, the flow rate of the tetrahydrofuran solution of the 5-bromo-2-chloro-4' -ethoxydiphenylmethane is preferably 36.4-49.5ml/min, and the flow rate of the n-butyllithium solution is preferably 20.0-27.2ml/min.
In step (1), the reaction temperature of the first reaction unit is-20 ℃ to-40 ℃, preferably-20 ℃; the reaction time in the first reaction unit is 5 to 20S, preferably 5 to 12S.
In the step (2), the flow rates of the reaction solution and the glucolactone solution obtained in the step (1) are 40-74mL/min and 12.3-21.6mL/min respectively, the flow rate of the reaction solution is preferably 74mL/min, and the flow rate of the glucolactone solution is preferably 21.6mL/min.
In the step (2), the ratio of the reaction solution obtained in the step (1) to the glucolactone solution in the second reaction unit is (0.9-1.0) to (1.2-2.0), preferably 0.95:1.2.
In step (2), the reaction temperature of the second reaction unit is 10 ℃ to-30 ℃, preferably-20 ℃, and the reaction time of the second reaction unit is 8-50S, preferably 8S.
In the step (2), the glucolactone solution is a tetrahydrofuran solution of the glucolactone protected by trimethylsilyl.
In step (2), the concentration of the glucolactone is 2.0 to 2.3mol/L, preferably 2.2mol/L.
The beneficial effects are that:
according to the invention, the mixed toluene/tetrahydrofuran mixed solvent is replaced by the single solvent tetrahydrofuran, the single tetrahydrofuran is used as the solvent, the solvent can be better recovered in the later stage of production amplification, the mixed solvent recovery efficiency is low, and the cost is higher. The molar ratio of the n-butyl lithium is optimized, and the molar ratio of the compound 1 to the n-butyl lithium is reduced to 1:0.95, so that the generation of byproducts is reduced; the n-butyl lithium solution adopts 1.6mol/L solution which is easy to purchase in the market, the flow rate of the n-butyl lithium solution is not lower than 20ml/min, and the problem of low-speed easy deposition of the n-butyl lithium is solved; the pre-cooling of the reaction pipeline is added before the first reaction unit, the problem of serious heat release of the reaction is solved, the effect is beneficial to shortening the reaction unit time, and the reaction time of the two units is 13S to 20S, so that the reaction is more efficient compared with the reaction time of 45S to 53S in the prior art.
Drawings
FIG. 1 is a schematic diagram of the synthesis of dapagliflozin intermediates using a microreactor in accordance with the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: determination of the influence of the flow rate of n-butyllithium on the valve and the tubing of a microreactor device
The n-butyl lithium solution is a hexane solution with the concentration of 1.6mol/L, in the test process, the n-butyl lithium solution is directly connected into the n-butyl lithium solution by adopting a filter head, the whole operation of the n-butyl lithium is required to be performed without oxygen and water, the operation is performed under the protection of nitrogen, and the pump head and the one-way valve of the microreactor are considered to be very easy to be blocked, so that whether different butyl lithium flow rates are consistent with actual metering is set, the weight of the n-butyl lithium is weighed by recording different time points through video recording, whether the weight reduced at a constant speed is consistent with the weight at different time points is recorded, and the reasonable butyl lithium flow rate is metered.
TABLE 1 influence of flow Rate of n-butyllithium on valves and tubing of microreactor devices
Results: from the statistical record value, the flow rate of n-butyl lithium is low, the flow rate and the residence time in a pipeline are long, solids are easy to separate out, a check valve of a micro-reactor is blocked, and the equipment is blocked within 20 seconds from the beginning of the running of the equipment at 5 mL/min; the flow rate of 10mL/min is between the running time of the device and 1min, and the device is still running, but the weight of the scale in the video is not changed any more, which indicates that the check valve of the micro-reactor is blocked; when the flow rate is increased to 20mL/min, the system is prolonged along with the time, and the weight reduction of the balance shows a uniform change trend; in summary, the flow rate of the n-butyllithium solution should be not less than 20mL/min, otherwise, the problem that the n-butyllithium pump is blocked and not operated or the flow rate is reduced easily occurs, and the test fails.
Example 2: effect of different flow rates on the progress of the reaction.
A method for synthesizing a compound 2 by utilizing a microreactor, wherein the equivalent ratio of the compound 1 to the n-butyllithium is 1:1.1 according to the fact that the flow rate of the n-butyllithium is not less than 20mL/min; and designing the influence of different flow rates on the reaction progress, and optimizing the reaction flow rate.
And (3) a component A: c (C) Compound 1 =0.8 moL/L (preparation method: 30g of compound 1 is weighed and dissolved in 116mL of tetrahydrofuran, and the solution is prepared for later use);
and the component B comprises the following components: c (C) N-butyllithium =1.6 moL/L (commercially available), tetrafluoro tubing;
first, the influence of A, B component flow rate on the reaction progress was examined:
the flow rate of the component B was set to 20.0ml/min, 23.5ml/min, and 27.2ml/min in this order, and the test results are shown in the following table.
TABLE 2 influence of different flow rates on the progress of the reaction
Results: from experimental data, the flow rate of the experiment I, the experiment II and the experiment III has almost no influence on the reaction progress, the product accounts for about 78-79%, the substrate flow rate is judged to be not a main influence factor on the product, the larger the flow rate is, the larger the flux is, the higher the efficiency is, and therefore the flow rate of the experiment III is preferably selected. Meanwhile, according to test data analysis, the temperature of a liquid outlet of a micro-reactor pipeline is higher, the traditional glass bottle is stirred, the external temperature is adopted for cooling, a reaction unit of the micro-reactor is cooled, different components collide in the micro-reactor reaction pipeline, the temperature of the micro-reactor pipeline is rapidly increased, heat is released greatly, and the temperature is increased and uncontrollable. From the analysis of the microreactor device itself, it is considered that a section of pipeline is added to cool down before the mixing collision of the reaction units.
Example 3: the effect of different pre-cooling temperatures on the reaction was examined.
And (3) a component A: c (C) Compound 1 ＝0.8moL/L，V A ＝49.5mL/min
And the component B comprises the following components: c (C) N-butyllithium ＝1.6moL/L，V B ＝27.2mL/min
Results: the length of the reaction unit of the micro-reactor pipeline is 13m, and the residence time of the reaction unit is controlled to be 18s, so that the pre-cooling temperature is determined to be minus 20 ℃. From the data analysis of the table, the lower the pre-cooling temperature is, the slower the reaction process is, the lower the content of main products is, and the raw material residues are more; the temperature is low, and the process of converting the intermediate possibly existing in other unknown peaks into the product is slow due to the low temperature, so that the pre-cooling temperature of minus 20 ℃ is obviously increased, the other unknown peaks are obviously reduced, and meanwhile, the pre-cooling temperature of minus 20 ℃ is easier to control in production, so that the pre-cooling temperature of minus 20 ℃ is selected.
Example 4: investigation of the temperature of the mixing of the microreactor tube reaction units
Pre-cooling temperature-20 ℃ before mixing the reaction units;
and (3) a component A: c (C) Compound 1 ＝0.8moL/L，V A ＝49.5mL/min
And the component B comprises the following components: c (C) N-butyllithium ＝1.6moL/L，V B ＝27.2mL/min
Results: after the pre-cooling temperature of minus 20 ℃ is determined, the mixed reaction temperature of the first reaction unit is examined in the group of tests, the reaction temperatures of the minus 30 ℃ and minus 40 ℃ reaction units are lower in analysis from the data results of the table, the reaction speed is reduced, the product content is reduced, and the raw material residue is obviously increased; the raw material residue at-20 ℃ is less than 1%, other unknown peaks are less than 1%, and the product content is optimal, so that the optimal reaction temperature is preferably-20 ℃.
Example 5: the number of molar equivalents of n-butyllithium was examined.
The traditional synthesis process in the stirred tank has poor mixing, uneven reaction in the system, larger impurities, lower yield of dapagliflozin and waste of reaction materials, so that the molar equivalent number of n-butyllithium is further examined.
And (3) a component A: c (C) Compound 1 =0.8 moL/L, B component: c (C) N-butyllithium =1.6 moL/L, set V A =49.5 mL/min, pre-cooling temperature of-20 ℃, reaction temperature of-20 ℃, different molar equivalents of n-butyllithium were designed, and the results are shown in the following table:
results: from the data analysis of the above table, when the amount of n-butyllithium is greater than 0.95eq, the conversion rate of the product is greater than 99%, so the amount of n-butyllithium of the first unit in the data analysis of this example is 0.95 to 1.2eq.
Example 6: effect of different n-butyllithium equivalent numbers of the first unit on the progress of the second reaction unit
And (3) a component A: c (C) Compound 1 ＝0.8moL/L
And the component B comprises the following components: c (C) N-butyllithium ＝1.6moL/L，
C pump group: c (C) Compound 3 ＝2.2mol/L。
Set V A =49.5 mL/min, the pre-cooling temperature of the first unit was-20 ℃, the reaction temperature was-20 ℃, the reaction progress of the second reaction unit was examined according to the optimal n-butyllithium molar amount of example 5, and the reaction results were counted as follows:
results: after the second reaction unit is connected, the result shows that the second unit product obtained by adopting different equivalents of n-butyllithium by the first reaction unit has large difference, further analysis and verification prove that the residual n-butyllithium of the first unit can be condensed with sugar of the second unit to generate byproducts, and the byproducts compete with the main reaction in the step, so that the conversion rate of the product is reduced, the impurity is increased, the dosage of the n-butyllithium is preferably less than 1.0eq, and the conversion rate of the first reaction unit is ensured, and the raw material waste and the impurity generation of the second reaction unit can be reduced by selecting 0.95eq of n-butyllithium.
In the comprehensive analysis of the embodiment 5 and the embodiment 6, the product of the first reaction unit is connected to the second reaction unit, the conversion rate theory of the reaction process should reach 99%, the conversion rate is reduced after passing through the second reaction unit, and in the experimental process, the temperature of the liquid outlet of the second reaction unit is 26.4 ℃, so that the influence of the reaction temperature of the second reaction unit on the conversion rate can be studied in the next step.
Example 7: influence of the reaction temperature of the second reaction unit on the reaction progress
A pump assembly: c (C) Compound 1 =0.8 moL/L; b pump components: c (C) N-butyllithium =1.6 moL/L; c pump group: c (C) Compound 3 ＝2.2mol/L。
Setting: first reaction unit V A ＝49.5mL/min；V B =23.5 mL/min, V was determined by calculation as equivalent ratio compound 1:n-butyllithium:compound 2=1:0.95:1.2 eq C Let 21.6mL/min, examine the reaction temperature of the second reaction unit examine the effect of the reaction progress of the team:
results: and (3) flowing the outlet of the micro-reactor into water under stirring, adding ethyl acetate for extraction, layering, combining organic phases, washing with saturated saline, layering, drying, concentrating to dryness to obtain a crude product, purifying and separating by column chromatography, and then drying in vacuum to obtain oily liquid. When the reaction temperature of the micro-reactor pipeline of the compound 2 and the compound 3 is-20 ℃, the conversion rate and the yield of the reaction are optimal, and the final yield of the compound 4 is 97.9%.
Claims (5)
1. The preparation method of the dapagliflozin intermediate is characterized by comprising the following steps:
(1) Pre-cooling tetrahydrofuran solution of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane and n-butyllithium solution at the temperature of minus 20 ℃ respectively, then pumping into a first reaction unit of a microreactor respectively, mixing, reacting, wherein the mole ratio of 5-bromo-2-chloro-4' -ethoxydiphenylmethane to n-butyllithium in the first reaction unit is 1:0.95, and the flow rate of the n-butyllithium solution is not lower than 20ml/min;
(2) Pumping the reaction solution obtained in the step (1) and the glucose lactone protected by the trimethylsilyl group into a second reaction unit respectively, mixing and reacting;
in the step (1), the concentration of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane in the tetrahydrofuran solution of 5-bromo-2-chloro-4' -ethoxydiphenylmethane is 0.8mol/L to 1.6mol/L;
in the step (1), the concentration of the n-butyl lithium solution is 1.6-2.5 mol/L;
in the step (1), the flow rate of the tetrahydrofuran solution of the 5-bromo-2-chloro-4' -ethoxydiphenylmethane is 36.4-49.5 mL/L;
in the step (1), the reaction temperature of the first reaction unit is-20 ℃, and the reaction time in the first reaction unit is 8S;
in the step (2), the reaction temperature of the second reaction unit is 10 ℃ to-30 ℃.
2. The method for preparing dapagliflozin intermediate according to claim 1, wherein in the step (2), the flow rate of the reaction solution obtained in the step (1) is 40-74mL/min and the flow rate of the glucolactone solution is 12.3-21.6 mL/min.
3. The process for preparing dapagliflozin intermediate according to claim 1, wherein in step (2), the molar ratio of the reaction solution obtained in step (1) to the glucolactone solution in the second reaction unit is (0.9-1.0): 1.2-2.0.
4. The method of claim 1, wherein in step (2), the glucolactone solution is a tetrahydrofuran solution of a trimethylsilyl protected glucolactone.
5. The method for producing dapagliflozin intermediate according to claim 4, wherein in the step (2), the concentration of the glucolactone solution is 2.0mol/L to 2.3mol/L.
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| CN113549042A (en) * | 2021-07-23 | 2021-10-26 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
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| CN104250272A (en) * | 2013-06-27 | 2014-12-31 | 上海方楠生物科技有限公司 | Method for preparing Invokana medicine intermediate by using micro-reactor |
| CN109400561A (en) * | 2018-12-21 | 2019-03-01 | 山东豪迈化工技术有限公司 | The synthetic method of Dapagliflozin |
| CN113549042A (en) * | 2021-07-23 | 2021-10-26 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
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