CN113200860B - Preparation method of SGLT2 inhibitor intermediate - Google Patents
Preparation method of SGLT2 inhibitor intermediate Download PDFInfo
- Publication number
- CN113200860B CN113200860B CN202110489088.8A CN202110489088A CN113200860B CN 113200860 B CN113200860 B CN 113200860B CN 202110489088 A CN202110489088 A CN 202110489088A CN 113200860 B CN113200860 B CN 113200860B
- Authority
- CN
- China
- Prior art keywords
- reaction
- continuous flow
- sglt2 inhibitor
- metering pump
- reactor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 239000002994 raw material Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 39
- 239000012295 chemical reaction liquid Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 239000005662 Paraffin oil Substances 0.000 claims description 7
- 238000006462 rearrangement reaction Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 2
- 230000001351 cycling effect Effects 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 238000005821 Claisen rearrangement reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000005336 allyloxy group Chemical group 0.000 description 11
- 238000010907 mechanical stirring Methods 0.000 description 10
- 230000006641 stabilisation Effects 0.000 description 10
- 238000011105 stabilization Methods 0.000 description 10
- 230000000087 stabilizing effect Effects 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940054021 anxiolytics diphenylmethane derivative Drugs 0.000 description 3
- HQMRIBYCTLBDAK-UHFFFAOYSA-M bis(2-methylpropyl)alumanylium;chloride Chemical compound CC(C)C[Al](Cl)CC(C)C HQMRIBYCTLBDAK-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical class C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 238000004939 coking Methods 0.000 description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 2
- 238000005111 flow chemistry technique Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000004407 iron oxides and hydroxides Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229940083037 simethicone Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KORCWPOBTZTAFI-YVTYUBGGSA-N (2s,3r,4r,5s,6r)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC(CC=2C=CC(=CC=2)C2CC2)=C(Cl)C2=C1CCO2 KORCWPOBTZTAFI-YVTYUBGGSA-N 0.000 description 1
- 101000716682 Homo sapiens Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 1
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- -1 allyl ethers Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007275 deallylation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 102000052543 human SLC5A2 Human genes 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005648 named reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing an SGLT2 inhibitor intermediate through continuous flow reaction. 4-allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester is taken as a raw material to react for 5 to 20 minutes at 180 to 250 ℃ in a continuous flow tubular reactor I to carry out Claisen rearrangement reaction, and then the intermediate of the SGLT2 inhibitor shown in the formula II is obtained through cooling, crystallization and filtration. The method for synthesizing the key intermediate of the SGLT2 inhibitor by continuous flow reaction has the advantages of stable and feasible process, low cost, high yield, high reaction rate, simple and convenient operation, safety, environmental friendliness and great practical value in the aspect of improving the production efficiency.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an SGLT2 inhibitor intermediate.
Background
Methods for preparing diphenylmethane derivatives which are effective as sodium-dependent glucose cotransporter (SGLT 2) inhibitors for preventing or treating metabolic diseases, particularly diabetes, are reported in patents CN109311861a and CN103596564B by the green cross of the k.a. And the korean bear pharmacy.
Among 243 diphenylmethane derivatives reported, the E172 compound: (2S, 3R,4R,5S, 6R) -2- (7-chloro-6- (4-cyclopropylbenzyl) -2, 3-dihydrobenzofuran-4-yl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, IC50 is only 0.463nM in the test of inhibiting human SGLT2 activity, with good specificity. Compared with other diphenyl methane derivatives with the same efficacy, such as E110, E098, E113, E114 and the like, has no stimulating functional group, has the characteristics of simple structure and low preparation cost, and is a medicament with very high potential application value.
4-Allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester:
Is a key intermediate for preparing E172, and the specification 0395 of patent CN109311861A discloses a compound of methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (compound c31, structure is ) Is prepared by the following steps: the rearrangement reaction was carried out using 2.4 equivalents of diisobutylaluminum chloride to catalyze the reaction of methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate at room temperature for 12 hours, followed by quenching with dilute hydrochloric acid at 0 ℃, extraction with ethyl acetate, drying, filtration, and concentration. However, the method has complicated operation steps, the diisobutyl aluminum chloride reagent is dangerous, expensive and not environment-friendly, and the product is directly subjected to the next reaction without purification, so that the method does not actually disclose how to obtain the 4-allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester with high yield and high purity.
More importantly, the mechanism of the rearrangement reaction is a typical Claisen rearrangement, which is a classical name reaction in which allyl ethers of allyl alcohols or phenols undergo intramolecular rearrangement under heating to produce gamma, delta-unsaturated aldehydes (ketones) or ortho (para) allylphenols. The reaction requires conditions of high temperature, typically 200 ℃. In the above patent, the reaction is carried out at room temperature for 12 hours, which results in excessively long reaction time, and is not suitable for industrial application and production. If the Claisen rearrangement reaction is carried out under high temperature conditions, however, the following disadvantages are also present: the temperature in the reaction kettle is increased to 200 ℃ from room temperature, generally 1-2 hours are needed, and more time is needed for cooling. The materials are easy to generate side reactions such as coking, carbonization, oxidation and the like under the condition of long-time treatment and high temperature, about 15-20% of deallylation byproducts are generated in the reaction, the post-treatment is difficult, and the yield is reduced.
Continuous flow chemistry, also known as flow chemistry, refers to the technique of transporting materials through a pump and performing chemical reactions in a continuous flow mode. The mass transfer and heat transfer are rapid due to the continuous flow reaction (1); (2) The parameter control is accurate, the reaction selectivity is good, and the method is particularly suitable for inhibiting series side reactions; (3) continuous operation, high space-time efficiency; (4) easy automation; (5) Safety and the like, continuous flow reactions have received increasing attention in recent years.
However, although the continuous flow reaction has advantages of small volume, large specific surface area, large heat exchange efficiency, easy precise control of reaction temperature and material proportion, etc., compared with the traditional kettle reaction, not all reactions can be optimized by continuous flow, the continuous flow reaction needs precise control, and various factors such as material quantity, reaction temperature, time, etc. can influence the reaction result, so that the conventional kettle reaction still has difficulties when being applied to the continuous flow reaction. At present, claisen rearrangement by using a continuous flow reaction technology has not been reported yet.
In order to reduce the generation of byproducts in the synthesis process of the 4-allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester, improve the conversion rate and the yield, shorten the reaction time and realize safe production, the process for synthesizing the 4-allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester by continuous flow reaction is provided with great significance.
Disclosure of Invention
The invention aims to provide a key intermediate for synthesizing an SGLT2 inhibitor through continuous flow reaction, which has the advantages of high yield, high purity, safe reaction and short time and is suitable for industrial large-scale production: a method for synthesizing 4-allyl-5-bromo-2-chloro-3-hydroxybenzoic acid methyl ester.
The invention provides a method for preparing an SGLT2 inhibitor intermediate through continuous flow reaction, which comprises the following steps:
(1) The compound shown in the formula I is directly used as raw material liquid or is dissolved in a solvent with the boiling point higher than 180 ℃ to prepare raw material liquid;
(2) Feeding the raw material liquid into a continuous flow tubular reactor I through a metering pump P1, and reacting for 5-20 minutes at 180-250 ℃ to obtain a rearrangement reaction liquid;
(3) Inputting the rearrangement reaction liquid into a continuous flow tubular reactor II, and cooling to obtain reaction liquid containing an SGLT2 inhibitor intermediate shown in the formula II;
the reaction formula is:
further, the solvent in the step (1) is selected from diphenyl ether, N, N-dimethylaniline, simethicone or paraffin oil; preferably diphenyl ether or paraffin oil, more preferably paraffin oil.
Further, the flow rate of the metering pump P1 in the step (2) is 10 mL/min-500 mL/min, preferably 50-200 mL/min.
Further, the temperature of the reaction in the step (2) is 200-220 ℃ and the reaction time is 10-15 minutes.
Further, the cycle temperature of the cooling in the step (3) is 30 to 80 ℃, preferably 40 to 50 ℃.
Further, the cooling time is 5 to 10 minutes.
Further, the above synthesis method further comprises the following steps: and (3) inputting the reaction liquid obtained in the step (3) into a collecting kettle with crystallization solvent, cooling and crystallizing, and filtering to obtain the SGLT2 inhibitor intermediate shown in the formula II.
Further, the crystallization solvent is petroleum ether, n-heptane or n-hexane, preferably n-heptane; and/or the weight ratio of the crystallization solvent to the reaction solution is (1-10): 1, preferably (2-3): 1.
Further, the temperature of the cooling crystallization is 5-10 ℃.
The invention provides a method for preparing a key intermediate of an SGLT2 inhibitor by using a continuous flow technology, which has the following advantages: 1. the use of dangerous, expensive and non-environment-friendly reagent diisobutyl aluminum chloride catalyst is avoided, and the cost is reduced; 2. the continuous flow reaction process is simple and easy to control, has no coking, carbonization and other side reactions, and has high yield and purity; 3. the reaction post-treatment is simple, the solvent is easy to recycle, the emission is zero, and the environment is protected and pollution is avoided. The method is safe and controllable, economical, environment-friendly and has extremely high industrial application potential and value.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a reaction scheme of the invention.
Detailed Description
The metering pump used in the following examples is any one of a constant flow pump, peristaltic pump, gear pump, etc. The reagents are all of industrial grade and are obtained by purchasing commercial products.
Example 1
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of diphenyl ether are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 220 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the collection vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 475g of target product, the yield is 95 percent, and the HPLC is 98 percent.
Example 2
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of simethicone are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 220 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the receiving vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 465g of target product, the yield is 93 percent, and the HPLC is 98 percent.
Example 3
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of paraffin oil are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 220 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the receiving vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 480g of target product, the yield is 96 percent and the HPLC is 98 percent.
Example 4
1) Preparing raw material liquid: 500g (1.636 mol) of methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate was connected to a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 220 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the receiving vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 440g of target product, the yield is 88%, and the HPLC is 98%.
Example 5
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of paraffin oil are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 210 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the receiving vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 475g of target product, the yield is 95 percent, and the HPLC is 98 percent.
Example 6
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of paraffin oil are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 220 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the receiving vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 100.0ml/min, the metering pump P1 was started, the reaction was conducted for 5 minutes in the reactor I, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 480g of target product, the yield is 96 percent and the HPLC is 98 percent.
Comparative example 1
1) Preparing raw material liquid: 500g (1.636 mol) of methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate and 250g of methylene chloride are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 140 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the collection vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 275g of target product, the yield is 55%, and the HPLC is 97%.
Comparative example 2
1) Preparing raw material liquid: 500g (1.636 mol) of 3- (allyloxy) -5-bromo-2-chlorobenzoic acid methyl ester and 250g of diphenyl ether are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 160 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the collection vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw materials are pumped, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 310g of target product, the yield is 62 percent and the HPLC is 97 percent.
Comparative example 3
1) Preparing raw material liquid: 500g (1.636 mol) of methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate and 250g of methylene chloride are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 100 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the collection vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and no target product exists.
Comparative example 4
1) Preparing raw material liquid: 500g (1.636 mol) of methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate and 250g of methylene chloride are stirred and mixed uniformly, and connected with a metering pump P1;
2) Setting a continuous flow reactor I, wherein the circulation temperature is 200 ℃, and stabilizing; the continuous flow reactor II was set at 40 ℃ for circulation and stabilization was achieved.
3) 1500G of n-heptane was added to the collection vessel and a mechanical stirring device was mounted.
4) The flow rate of the metering pump P1 was set to 50.0ml/min, the metering pump P1 was started, the reaction was run in the reactor I for 5 minutes, and after 10 minutes in the reactor II, the reaction solution was collected.
5) After all the raw material pumps are completed, the collected reaction liquid is cooled to 5 ℃, stirred for 1 hour, filtered and dried to obtain 65g of target product, the yield is 13 percent, and the HPLC is 90 percent.
Specific comparisons of the examples of the present invention with the comparative examples are shown in the following table:
It can be seen that if the tank reaction solvent methylene chloride of prior art patent application CN109311861a is used, the solvent is rapidly gasified in the continuous flow reactor, which makes the reaction difficult to proceed, and the final yield is very low or even the product is not obtained. Meanwhile, the reaction temperature also has a great influence on the reaction, and when the temperature is lower than 180 ℃, the yield is obviously reduced. In addition, the flow rate of a metering pump and the selection of a solvent can influence the yield and purity of a product prepared by the continuous flow reaction, and the SGLT2 inhibitor intermediate with high yield and purity can be finally obtained under the specific conditions of the solvent, the temperature, the reaction time and the flow rate and the specific post-treatment method.
Experimental results show that the method for synthesizing the key intermediate of the SGLT2 inhibitor through continuous flow reaction has the advantages of stable and feasible process, low cost, high yield, high reaction rate, simple and safe operation, environmental friendliness and great practical value in the aspect of improving production efficiency.
Claims (7)
1. A method for preparing an SGLT2 inhibitor intermediate by a continuous flow reaction, comprising the steps of:
(1) The compound shown in the formula I is dissolved in a solvent with the boiling point higher than 180 ℃ to prepare raw material liquid; the solvent is paraffin oil;
(2) Feeding the raw material liquid into a continuous flow tubular reactor I through a metering pump P1, and reacting for 10 minutes at 220 ℃ to obtain a rearrangement reaction liquid; the flow rate input by the metering pump P1 is 50-200 mL/min;
(3) Inputting the rearrangement reaction liquid into a continuous flow tubular reactor II, and cooling to obtain reaction liquid containing an SGLT2 inhibitor intermediate shown in the formula II; inputting the obtained reaction liquid into a collecting kettle with crystallization solvent, cooling and crystallizing, and filtering to obtain an SGLT2 inhibitor intermediate shown in a formula II; the crystallization solvent is n-heptane;
the reaction formula is:
2. the method of claim 1, wherein the cooling cycle temperature in step (3) is 30-80 ℃.
3. The method of claim 2, wherein the chilled cycling temperature is 40-50 ℃.
4. The method of claim 2, wherein the cool down time is between 5 and 10 minutes.
5. The method according to claim 1, wherein the weight ratio of the crystallization solvent to the reaction solution is (1-10): 1.
6. The method according to claim 5, wherein the weight ratio of the crystallization solvent to the reaction solution is (2-3): 1.
7. The method according to any one of claims 1 to 6, wherein the temperature of the reduced crystallization is 5 to 10 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110489088.8A CN113200860B (en) | 2021-04-29 | 2021-04-29 | Preparation method of SGLT2 inhibitor intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110489088.8A CN113200860B (en) | 2021-04-29 | 2021-04-29 | Preparation method of SGLT2 inhibitor intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113200860A CN113200860A (en) | 2021-08-03 |
| CN113200860B true CN113200860B (en) | 2024-07-30 |
Family
ID=77030289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110489088.8A Active CN113200860B (en) | 2021-04-29 | 2021-04-29 | Preparation method of SGLT2 inhibitor intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113200860B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109311861A (en) * | 2016-06-17 | 2019-02-05 | 株式会社大熊制药 | The method for being used to prepare diphenylmethane derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880717B (en) * | 2014-03-21 | 2015-11-04 | 江苏傲伦达科技实业股份有限公司 | The preparation method of two (3-allyl group-4-hydroxy phenyl) sulfones and derivative thereof |
-
2021
- 2021-04-29 CN CN202110489088.8A patent/CN113200860B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109311861A (en) * | 2016-06-17 | 2019-02-05 | 株式会社大熊制药 | The method for being used to prepare diphenylmethane derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Efficient Claisen rearrangement of allyl para-substituted phenyl ethers using microreactors;Lingjie Kong, et al.;Green Chemistry;第11卷;第1108-1111页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113200860A (en) | 2021-08-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112851493B (en) | Preparation method of 2,4, 5-trifluoro phenylacetic acid | |
| CN113200860B (en) | Preparation method of SGLT2 inhibitor intermediate | |
| CN106589017A (en) | Preparing method of 3',4',7'-troxerutin | |
| CN111170837B (en) | Synthesis method of methyl ketone compound | |
| CN106748752B (en) | A kind of preparation method of 2,3- naphthalenedicarboxylic acid | |
| CN113717039B (en) | Preparation of chlorofluoroether bacteria Process for azole intermediates | |
| CN102351677A (en) | A kind of method for chemically synthesizing vitamin K2 | |
| CN105504305B (en) | One kind contains 3（4 pyridines）Coordination polymer of pyrazoles propionic acid and preparation method thereof, purposes | |
| US10385087B1 (en) | Xylose derivatives and process for preparation thereof | |
| CN111333504A (en) | A method for synthesizing 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate using a microchannel reactor | |
| CN115368217B (en) | Synthesis method of 3,4, 5-trimethoxytoluene | |
| CN111892572B (en) | Synthesis process of watermelon ketone precursor | |
| Liang et al. | Basic ionic liquid: A reusable catalyst for Knoevenagel Condensation in aqueous media | |
| CN108675925B (en) | Production process of cyclopentanecarboxylic acid | |
| CN115073364B (en) | Preparation method of 6-nitropyridin-3-ol | |
| RU2838317C1 (en) | Method of producing cyclohexanone | |
| CN114380713B (en) | O-methyl benzoyl cyanide synthesis method | |
| RU2797603C1 (en) | Method of obtaining 1-bromomethyl-4-chloromethylbenzene | |
| CN116903454B (en) | A method for preparing 3,4,7-trimethyl-1-indanone by one-step conversion of 2,5-hexanedione | |
| CN116332882B (en) | A synthetic process for a key intermediate of empagliflozin | |
| CN118530155B (en) | Method for preparing 7-methylindole under normal temperature condition | |
| CN112441997B (en) | Method for synthesizing alpha- (2-tetrahydrofuryl) -acetophenone compound | |
| CN119100933A (en) | A method for co-producing nitro-containing aromatic aldehydes and aromatic acids | |
| CN117683003A (en) | New process for synthesizing englitjing intermediate | |
| CN108752260B (en) | A kind of preparation method of mitiglinide calcium intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |