CN109553609B - Preparation method of canagliflozin - Google Patents
Preparation method of canagliflozin Download PDFInfo
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- CN109553609B CN109553609B CN201710884648.3A CN201710884648A CN109553609B CN 109553609 B CN109553609 B CN 109553609B CN 201710884648 A CN201710884648 A CN 201710884648A CN 109553609 B CN109553609 B CN 109553609B
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention relates to a preparation method of canagliflozin, which is characterized by comprising the following steps: 1) reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone at low temperature, and then carrying out methylation and deprotection reactions with a methanol solution of methanesulfonic acid to generate an intermediate 1; 2) under the low temperature condition, the intermediate 1 reacts with triethylsilane and boron trifluoride ethyl ether, and then is subjected to post-treatment to obtain an intermediate 2; 3) under the condition of low temperature, the intermediate 2 reacts with organic alkali, DMAP and acetic anhydride, and is purified to obtain an intermediate 3; 4) and reacting the intermediate 3 with an alkaline aqueous solution, and purifying to obtain the canagliflozin. The invention has mild condition, safe operation and simple post-treatment; the product has high purity, no alpha-isomer is detected, and the product is safer.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to an industrial preparation method of canagliflozin.
Background
Canagliflozin (Canagliflozin) is the first approved drug in sodium-glucose co-transporter 2(SGLT2) inhibitors for the glycemia of adult patients with type 2 diabetes. It acts on the SGLT2 protein in the kidney to help reabsorb glucose, removing more sugar from the patient's urine, and lowering blood glucose levels. The medicine is jointly developed by Mitsubishi corporation and Johnson corporation in Japan, and approved by FDA to be sold in the market in 3 months in 2013. Chemical name of canagliflozin: (1S) -1, 5-dehydro-1- [3- [ [5- (4-fluorophenyl) -2-thienyl ] group]Methyl radical]-4-methylphenyl radical]-D-glucose hemihydrate of formula C24H25FO5S.1/2H2O, molecular weight 453.5, structural formula as follows:
at present, the preparation method disclosed by the canagliflozin comprises the following steps: the preparation methods disclosed by Chinese patent CN102264714A, WO2016128995 and CN10544002A, CN10180137A and CN201510981375A, etc. are summarized as follows:
in the route, 2- (4-fluorophenyl) -5- [ (5-halo-2-methylphenyl) methyl ] thiophene and protected D-gluconolactone are used as starting materials, and are subjected to coupling reaction, reduction reaction and deprotection reaction to obtain canagliflozin. In the preparation process, the second step mostly uses triethylsilane and boron trifluoride diethyl etherate to carry out reduction reaction, and the glycosidic bond has two configurations of alpha-and beta-in which the beta-configuration is a dominant configuration and the alpha-configuration is an isomer impurity.
The disadvantages of the above route in the published literature are as follows: firstly, as in patent CN105440025, the temperature needs to be reduced to-78 ℃ in the first step of reaction, the requirement on equipment is high, and the temperature control is strict; secondly, alpha-configurational isomer impurities are generated in the reduction reaction in the second step, and the disclosed information has no effective purification method, so that the alpha-configurational isomer impurities are completely removed, which may influence the safety of the medicine; the post-treatment operation is complex and is not beneficial to industrial production; the intermediate 1 in patents CN10180137 and CN105541815 has poor stability and is not beneficial to long-term storage.
(2) The preparation methods disclosed in patents CN1829729A, CN102264714A, WO2016016852, US20160228375, WO2016142950 and US20130237487, CN103694230A, CN103936727A are summarized as follows:
in the above route, 2- (4-fluorophenyl) -5- [ (5-halo-2-methylphenyl) methyl ] thiophene, activated with lithium metal, is coupled, methylated and hydrolyzed with 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone to give intermediate 1; reducing by triethylsilane and boron trifluoride diethyl etherate to obtain a coarse product of canagliflozin; and (3) obtaining an intermediate 3 through acetylation, purifying the intermediate 3, then performing deprotection to obtain the canagliflozin with higher purity or the canagliflozin crude product and L-proline to form eutectic substance for purification, and then decomposing to obtain the canagliflozin with higher purity. In the preparation route, the second step of reduction reaction generates glycosidic bonds with alpha-configuration and beta-configuration, wherein the beta-configuration is a dominant configuration, and the alpha-configuration is an isomer impurity.
In the literature currently published, the above routes have the following disadvantages: firstly, as in patents CN200480022007, WO2016016852 and WO2016142950, n-butyllithium is used as an activating reagent, the temperature needs to be reduced to below-70 ℃, the requirement on equipment is high, the temperature control is strict and strict, and the requirement on operation safety is high; secondly, isomer impurities with alpha-configuration are generated in the reduction reaction, an intermediate 3-1 is obtained through acetylation, and the intermediate 3-1 is not purified to completely remove the isomer impurities with alpha-configuration; ③ impurities are easy to remain, for example, in patents US20130237487, CN103694230, and CN103936727, it is mentioned that canagliflozin and amino acid form eutectic compound for purification, and then amino acid impurities are easy to remain in the canagliflozin obtained by decomposition and extraction;
(3) the synthetic route mentioned in US20140128595 is as follows:
the above route mainly has the defects that the starting raw material 1, 6-diether-2, 4-OTBDPS-beta-D-glucopyranose is not easy to obtain, formatting reaction and n-butyl lithium are used in the reaction, the requirement on operation safety is high, the synthesis yield is low and the like, and the route is not suitable for industrial production.
Similarly, patent CN105481915 has the problems that L-gulono-gamma-lactone as a starting material is not easily available and expensive, and thus it is difficult to industrially produce.
(4) Patents CN103596944A, CN103980263A and US20110087017 mention the following direct chiral synthesis methods:
in the route, 2,3,4, 6-O-tet pivaloyl-alpha-D-bromo glucopyranose is expensive, high in production cost and long in reaction time, and the single isomer of the intermediate 1 is obtained through column chromatography, so that the method is not suitable for industrial production.
(5) The synthetic route mentioned in WO2015181692 is as follows:
in the synthetic route, (5-iodine-2-methylphenyl) - (5- (4-fluorophenyl) -2-thienyl) ketone is used as an initial raw material, and the reaction is carried out for 3 steps to obtain a crude product of canagliflozin, and the crude product of canagliflozin is crystallized by ethyl acetate, methyl tert-butyl ether and water to obtain the canagliflozin. The synthesis route has the advantages that the temperature required by the reaction of 2 steps is-70 ℃, and the requirement on equipment is high; in addition, n-butyl lithium is used in the second step, so that the operation safety requirement is high; the crystallization and purification steps of the crude product of canagliflozin have the defects of low yield and the like.
Disclosure of Invention
Based on the background technology, the invention aims to provide an industrial preparation method of high-purity canagliflozin; in particular to an industrial preparation method for preparing high-purity canagliflozin intermediate 3. The method comprises the following steps:
1) reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone at low temperature, and then carrying out methylation and deprotection reactions with a methanol solution containing methanesulfonic acid to generate an intermediate 1;
2) reacting the intermediate 1 with triethylsilane and boron trifluoride diethyl etherate to generate an intermediate 2;
3) the intermediate 2 reacts with organic alkali, DMAP and acetic anhydride to generate an intermediate 3;
4) reacting the intermediate 3 with an alkaline aqueous solution to generate the canagliflozin
Base in the step 1) refers to an alkaline reagent; Acid/MeOH is methanesulfonic Acid methanol solution; et in step 2)3SiH refers to triethylsilane; BF (BF) generator3.Et2O is boron trifluoride diethyl etherate; ac in step 3)2O is acetic anhydride.
Wherein, the preparation of the intermediate 1 specifically comprises the following steps: reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone at low temperature, and then carrying out methylation and deprotection reaction on the obtained product and a methanol solution containing methanesulfonic acid to obtain the compound.
The invention further provides that the method comprises the following steps:
1) in an inert environment, reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone at the temperature of-30 to-15 ℃, heating to room temperature, reacting with a methanol solution containing methanesulfonic acid, and purifying to obtain an intermediate 1;
2) dissolving the intermediate 1 prepared in the step 1) in an organic solvent at the temperature of-30 to-15 ℃, reacting with triethylsilane and boron trifluoride diethyl etherate, and performing post-treatment to obtain an intermediate 2;
3) adding organic base and DMAP into the intermediate 2 prepared in the step 2) at the temperature of-5 ℃, uniformly mixing, adding acetic anhydride for reaction, and purifying to obtain an intermediate 3;
4) dissolving the intermediate 3 prepared in the step 3) in an organic solvent, dropwise adding an alkaline aqueous solution, reacting, and purifying to obtain the canagliflozin.
The invention further provides that the alkaline reagent in the step 1) is selected from one or more of isopropyl magnesium chloride lithium chloride, sec-butyl magnesium chloride lithium chloride, isopropyl magnesium chloride, tert-butyl magnesium chloride or cyclohexyl magnesium chloride; preferred are isopropylmagnesium chloride lithium chloride and sec-butylmagnesium chloride lithium chloride.
In the step 1), the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the alkaline reagent is 1: 1-2, preferably 1: 1.3-1.5;
the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is 1: 1-2, and preferably 1: 1.3-1.6.
The invention further provides that the step 1) is specifically as follows: tetrahydrofuran is used as a solvent, 2- (4-fluorophenyl) -5- [ (5-iodine-2-methylphenyl) methyl ] thiophene reacts with an alkaline reagent at the temperature of-25 to-20 ℃, and then 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is added dropwise for reaction; .
The reaction in the step 1) has the best effect at the temperature of minus 25 ℃ to minus 20 ℃, but the reaction is very slow and even basically not reacted when the temperature is lower than minus 35 ℃ or higher than minus 15 ℃.
And 1) after the early-stage reaction, adding methanesulfonic acid and methanol, wherein the methanesulfonic acid not only plays a role in catalyzing the methylation reaction, but also can hydrolyze the TMS protective group of the hydroxyl.
The molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the methanesulfonic acid in the step 1) is 1: 2-2.7, preferably 1: 2.1-2.3;
the amount of methanol added is 2 to 5L per mole of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene.
In the step 1), 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene reacts with an alkaline reagent for 0.8-1.2 hours, and then 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is added to react for 1-3 hours; adding a methanol solution containing methanesulfonic acid, naturally heating, stirring, and reacting for 12-18 hours.
The invention further provides that the first purification in the step 1) is specifically as follows: adjusting the pH value of the reaction liquid to 7-8 at the temperature of-5 ℃; heating to 30-40 ℃, carrying out reduced pressure rotary removal on the solvent, extracting the organic solvent, drying, filtering, further carrying out reduced pressure rotary removal on the solvent, and then carrying out recrystallization to obtain an intermediate 1;
the first purification further comprises: cooling the reaction liquid to-5 ℃, dripping a sodium bicarbonate aqueous solution into the reaction liquid to quench the reaction, and adjusting the pH value of the reaction liquid to 7-8; performing reduced pressure rotary removal on the organic solvent at the temperature of 30-40 ℃, extracting by using the organic solvent, drying by using anhydrous sodium sulfate, and further performing reduced pressure rotary removal on the organic solvent after filtering to obtain a crude product; and recrystallizing the crude product to obtain the intermediate 1-methyl-1-C- (3- ((5- (4-fluorophenyl) -2-thienyl) methyl) -4-benzyl) -D-glucopyranoside.
The invention further provides that in the step 2), the molar ratio of the intermediate 1 to the triethylsilane is 1: 2-6, preferably 1: 3; the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 2-6, preferably 1: 3.
In the step 2), the intermediate 1 is dissolved in an organic solvent dichloromethane, and the usage amount of the dichloromethane is 6-10 ml/g of the intermediate 1, preferably 7-8 ml/g of the intermediate 1.
In the step 2), triethylsilane is added into the organic solvent containing the intermediate 1, and then boron trifluoride ethyl ether is added dropwise. Carrying out reaction at the temperature of-25 to-5 ℃;
preferably, the reaction is carried out at a temperature of-25 to-10 ℃.
In the step 2), the intermediate 1 is added into a dichloromethane solution, stirred and fully dissolved, and then reacted for 2-4 hours in triethylsilane and boron trifluoride diethyl etherate.
The invention further provides that the post-treatment in the step 2) is specifically as follows: at the temperature of not higher than-10 ℃, dripping saturated sodium bicarbonate solution, quenching reaction, standing for phase splitting, taking an organic phase, drying and filtering to obtain an intermediate 2 organic solution;
the drying is carried out by using anhydrous sodium sulfate.
The invention further provides that in the step 3), the organic base is selected from one or more of N-methylmorpholine, triethylamine and diisopropylethylamine;
preferably, the molar ratio of the intermediate 2 to the organic base is 1: 4-8; the molar ratio of the intermediate 2 to acetic anhydride is 1: 4-8; the molar ratio of the intermediate 2 to the DMAP is 1: 0.08-0.12;
more preferably, the molar ratio of the intermediate 2 to the organic base is 1: 5-6; the molar ratio of the intermediate 2 to acetic anhydride is 1: 5-6; the molar ratio of the intermediate 2 to the DMAP was 1: 0.1.
In the step 3), after adding organic base and DMAP into the intermediate 2, slowly dropwise adding acetic anhydride, after dropwise adding, heating to room temperature, and reacting for 4-6 hours.
The organic base is used for neutralizing the generated acid to provide an alkaline environment for the reaction system; DMAP is a highly efficient acylation catalyst.
The invention further provides that the second purification in the step 3) is specifically as follows: adding water into the reaction solution, removing the solvent by rotary removal under reduced pressure, filtering to obtain a white solid, adding the white solid into alcohol, fully stirring, heating to reflux, cooling to room temperature, filtering, and drying under reduced pressure to obtain the white solid.
And the second purification further comprises the steps of adding the white solid into the organic solvent C, heating until the white solid is completely dissolved, dripping the organic solvent D, naturally cooling to room temperature, and stirring overnight. Filtration and washing with organic solvent D gave intermediate 3 as a white solid.
The alcohol is selected from one or more of methanol, ethanol and isopropanol, preferably ethanol and methanol;
the organic solvent C is selected from one or more of methyl tert-butyl ether, methyl n-butyl ether, methyl sec-butyl ether, methyl tert-amyl ether and ethyl acetate, and preferably methyl tert-butyl ether, methyl n-butyl ether and ethyl acetate;
the organic solvent D is selected from one or more of petroleum ether, n-hexane and n-heptane, preferably n-hexane and n-heptane.
The invention further provides that, in the step 4), the alkali in the alkaline aqueous solution is selected from one or more of sodium methoxide, lithium hydroxide, sodium hydroxide and potassium hydroxide;
preferably, the molar ratio of the intermediate 3 to the base is 1: 2-5, and more preferably 1: 3-4.
In the step 4), tetrahydrofuran is used as an organic solvent for the intermediate 3, the intermediate 3 is added into the tetrahydrofuran and then mixed with methanol, after stirring, a sodium methoxide water solution is dripped into the mixture, and the mixture is stirred for 2 to 4 hours at normal temperature;
the invention further provides that the third purification in the step 4) is specifically as follows: after the reaction is finished, adding water into the reaction solution, decompressing and rotatably removing the organic solvent, filtering, washing with pure water, and drying to obtain a white solid; dissolving the white solid in alcohol completely, adding water, stirring to obtain white suspension, filtering, washing, and drying to obtain canagliflozin.
The third purification further comprises: after the reaction is finished, adding pure water, decompressing, rotatably removing the organic solvent, filtering, washing with pure water, and drying to obtain a white solid; adding the white solid into alcohol, adding activated carbon, heating to reflux for 30 minutes, filtering, adding pure water for the second time, stirring at room temperature for more than 12 hours to obtain a white suspension, filtering, and washing with pure water to obtain the high-purity canagliflozin.
The alcohol is selected from one or more of methanol, ethanol or isopropanol, preferably ethanol and methanol;
the using amount of the alcohol is 5-6 ml/g of white solid, and preferably 5.5ml/g of white solid; the using amount of the added pure water is 5-4 ml/g of white solid, and 4.5ml/g of white solid is preferable;
the total amount of the alcohol and the pure water added for the second time is 10ml/g of white solid.
As a preferred aspect of the present invention, there is provided a method for preparing canagliflozin, comprising the steps of:
1) in an inert environment, tetrahydrofuran is used as a solvent, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene and an alkaline reagent are added according to a molar ratio of 1: 1.3-1.5 at a temperature of-25 ℃ to-20 ℃, and after reaction, 1.3-1.6 mol of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is added dropwise into each mol of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene for reaction;
maintaining the temperature, adding a methanol solution containing methanesulfonic acid according to the molar ratio of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to methanesulfonic acid of 1: 2.1-2.3, and continuing the reaction; cooling the reaction liquid to-5 ℃, quenching, and adjusting the pH value to 7-8; heating to 30-40 ℃, and purifying to obtain an intermediate 1;
wherein 2-5L of methanol solution is added to each mole of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene;
2) dissolving the intermediate 1 prepared in the step 1) in an organic solvent at the temperature of-25 to-10 ℃, adding triethylsilane and boron trifluoride diethyl etherate according to the molar ratio of 1:3:3, and reacting; quenching at a temperature of not higher than-10 ℃ to obtain an intermediate 2;
3) adding N-methylmorpholine or triethylamine and DMAP into the intermediate 2 prepared in the step 2) at the temperature of-5 ℃, uniformly mixing, then dripping acetic anhydride, heating to room temperature, reacting, and purifying to obtain an intermediate 3;
wherein the molar ratio of the intermediate 2 to the organic base is 1: 5-6; the molar ratio of the intermediate 2 to acetic anhydride is 1: 5-6; the molar ratio of the intermediate 2 to the DMAP is 1: 0.1;
4) dissolving the intermediate 3 prepared in the step 3) in an organic solvent, dropwise adding a sodium methoxide or lithium hydroxide aqueous solution, wherein the molar ratio of the intermediate 3 to the sodium methoxide or lithium hydroxide is 1: 3-4, reacting, and purifying to obtain the canagliflozin.
The invention at least comprises the following beneficial effects:
1. the used starting raw materials are easy to obtain and low in price, and the production cost is favorably reduced;
2. the alkali metal reagent used in the step 1) has high relative safety, the coupling temperature is-25 to-20 ℃, the equipment temperature requirement is low, the operation is safer, and the equipment volume requirement is small;
3. in the step 2), after quenching reaction with sodium bicarbonate aqueous solution, separating to obtain an organic phase, and drying the organic phase for direct use in the next reaction. The operations such as distillation, extraction and the like are avoided, the operation is simplified, and the using amount of the solvent is reduced;
4. in the step 3), the obtained intermediate 3 crude product is purified twice by using alcohol, an organic solvent C and an organic solvent D to obtain the high-purity canagliflozin intermediate 3 with a single isomer, the purity of the intermediate 3 is over 99.8%, and the high-purity canagliflozin intermediate 3 with the single isomer is obtained by further reacting to obtain the high-purity canagliflozin with the single isomer, and the purity of the intermediate is over 99.95%.
The method has the advantages of mild reaction conditions, safer operation, simple post-treatment, high purity of the obtained canagliflozin product, less residual impurity types, low content, no alpha-isomer detection and safer product.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The methods used in the following examples are conventional methods unless otherwise specified.
Example 1
The embodiment is a preparation method of canagliflozin, which comprises the following steps:
1. preparation of intermediate 1:
taking a 3L three-mouth bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; adding 300ml of anhydrous tetrahydrofuran, adding 100g (0.245mol) of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene, and stirring to dissolve; under the protection of nitrogen, cooling to-25-20 ℃, dropping 263.8mL (0.343mol) of sec-butyl magnesium chloride, lithium chloride/THF solution, and continuing to react for 1 hour after dropping;
and maintaining the temperature, and dropwise adding 171.6g (0.368mol) of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone which is pre-cooled to-25 to-20 ℃ into the reaction solution, wherein the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is dissolved in 200mL of anhydrous tetrahydrofuran solution. After the dropwise addition is finished, the reaction is continued for 2 hours;
then, 51.8g (0.539mol) of methanesulfonic acid was added dropwise, wherein the methanesulfonic acid was dissolved in 1L of an anhydrous methanol solution; the reaction was allowed to proceed at room temperature for 18 hours.
Cooling the reaction liquid to-5 ℃, slowly dripping the sodium bicarbonate aqueous solution into the reaction liquid, and monitoring the pH to be 7-8 after dripping is finished; removing solvent under reduced pressure to obtain aqueous solution, extracting with methyl n-butyl ether (600ml × 300ml) for 2 times, mixing organic phases, drying with anhydrous sodium sulfate for several hours, filtering, and removing solvent under reduced pressure to obtain yellow viscous solid; at room temperature, 300ml of methyl n-butyl ether was added and dissolved with stirring, and the solution was dropped into 600ml of n-heptane, followed by stirring, removal of the solvent and vacuum drying to obtain 1108.9 g of a pale yellow solid intermediate, yield 93.7%, HPLC 85.2%.
2. Preparation of intermediate 2:
taking a 2L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; adding 700ml of dichloromethane, adding 100g (0.211mol) of the intermediate 1, and stirring to dissolve; cooling to-25-10 deg.C, adding 73.5g (0.632mol) triethylsilane; maintaining the temperature, slowly adding 89.7g (0.632mol) of boron trifluoride diethyl etherate dropwise; after the completion of the dropwise addition, the reaction was continued for 2 hours.
Adjusting the temperature to be lower than minus 10 ℃, dropping 800ml of sodium bicarbonate aqueous solution, stopping stirring after dropping, standing for phase separation, separating an organic phase, drying for a plurality of hours by using anhydrous sodium sulfate, and filtering to obtain about 850ml of dichloromethane solution of the intermediate 2. And according to HPLC detection, 81.36% of beta-isomer and 3.22% of alpha-isomer are obtained. The yield was calculated as 100%.
3. Preparation of intermediate 3:
taking a 2L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; adding 850ml of dichloromethane solution of the intermediate 2 into a reaction bottle, cooling to-5 ℃, adding 162g (1.27mol) of N-methylmorpholine and 2.58g (0.0211mol) of DMAP under the stirring condition; maintaining the temperature, slowly adding 129.3g (1.27mol) of acetic anhydride dropwise; after the completion of the dropwise addition, the reaction was continued for 4 hours.
After the reaction, 425ml of pure water was added dropwise thereto, and the mixture was stirred for 30 minutes. The organic solvent was removed under reduced pressure and filtered to give a white solid. The white solid was added to 1.3L of ethanol, heated to reflux, stirred for 30 minutes, cooled to room temperature, filtered, and dried to give 94.0g of white solid. Adding the white solid into 752ml of methyl tert-butyl ether, heating to reflux to obtain a clear solution, slowly adding 564ml of n-heptane, continuously heating to reflux to obtain a clear solution, slowly cooling to room temperature, and stirring overnight; the solution was filtered and the filter cake was washed with 50ml x 2 n-heptane to give 89.9g of a white solid with a yield of 69.5%. The purity of intermediate 3 was 99.81% by HPLC, and no tetraacetyl alpha-isomer was detected.
4. Preparation of canagliflozin:
taking a 2L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; 89g (0.145mol) of intermediate 3 was added to a mixed solvent of 445ml of methanol and 445ml of tetrahydrofuran, and stirred to obtain a slurry solution. A pure aqueous solution (100ml) of 31.3g (0.58mol) of sodium methoxide was slowly added dropwise thereto at room temperature. After the completion of the dropwise addition, the reaction was continued for 4 hours. After the reaction, 425ml of purified water was added, the organic solvent was removed under reduced pressure, filtered under reduced pressure, washed with 50ml of 2-fold purified water, and dried to obtain 64g of a white solid. The resulting solid was added to 352ml methanol, dissolved with stirring, activated carbon (3.2g, 5%) was added, heated to reflux for 30 minutes, filtered to remove the activated carbon, purified water (288ml) was added, heated to reflux to give a clear solution, slowly cooled to room temperature, stirred for more than 12 hours, filtered, and dried to give 59.8g of a white solid, yield 93.5%, HPLC purity 99.93%, no alpha-isomer impurity detected.
Example 2
The embodiment is another preparation method of canagliflozin, which comprises the following steps:
1. preparation of intermediate 1:
taking a 2L three-mouth bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; 150ml of anhydrous tetrahydrofuran was added, 50g (0.122mol) of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene was added, and stirring was carried out until dissolved; under the protection of nitrogen, cooling to-25-20 ℃, dropping 122.5mL (0.159mol) of isopropyl magnesium chloride, lithium chloride/THF solution, and continuing to react for 1 hour after dropping;
maintaining the temperature, and dropwise adding 74.3g (0.159mol) of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone which is pre-cooled to-25 to-20 ℃ into the reaction solution, wherein the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is dissolved in 100mL of anhydrous tetrahydrofuran solution. After the dropwise addition is finished, the reaction is continued for 2 hours;
then 25.8g (0.268mol) of methanesulfonic acid is added dropwise, wherein the methanesulfonic acid is dissolved in 350ml of anhydrous methanol solution; the reaction was allowed to proceed at room temperature for 18 hours.
Cooling the reaction liquid to-5 ℃, slowly dripping the sodium bicarbonate aqueous solution into the reaction liquid, and monitoring the pH to be 7-8 after dripping is finished; removing solvent under reduced pressure to obtain water solution, extracting with ethyl acetate (300ml × 150ml) for 2 times, mixing organic phases, drying with anhydrous sodium sulfate for several hours, filtering, and removing solvent under reduced pressure to obtain yellow viscous solid; at room temperature, 150ml of ethyl acetate was added and dissolved with stirring, and the solution was dropped into 300ml of n-hexane, stirred, removed of the solvent, and dried under vacuum to obtain 150.9g of a pale yellow solid intermediate, yield 87.7%, HPLC 86.7%.
2. Preparation of intermediate 2:
taking a 1L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; adding 400ml of dichloromethane, adding 50g (0.105mol) of intermediate 1, and stirring to dissolve; cooling to-25-10 deg.C, adding 36.8g (0.316mol) triethylsilane; maintaining the temperature, slowly adding 44.8g (0.316mol) of boron trifluoride diethyl etherate dropwise; after the completion of the dropwise addition, the reaction was continued for 2 hours.
Adjusting the temperature to be lower than minus 20 ℃, dripping 800ml of sodium bicarbonate aqueous solution, controlling the temperature to be not more than minus 10 ℃, stopping stirring after finishing dripping, standing for phase separation, separating out an organic phase, drying anhydrous sodium sulfate for a plurality of hours, and filtering to obtain about 480ml of dichloromethane solution of the intermediate 2. HPLC detection shows that the beta-isomer is 80.51 percent, and the alpha-isomer is 4.72 percent. The yield was calculated as 100%.
3. Preparation of intermediate 3:
taking a 1L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; adding 480ml of dichloromethane solution of the intermediate 2 into a reaction bottle, cooling to-5 ℃, adding 53.6g (0.53mol) of triethylamine under the stirring condition, and adding 1.28g (0.011mol) of DMAP; maintaining the temperature, slowly and dropwise adding 54.1g (0.53mol) of acetic anhydride; after the completion of the dropwise addition, the reaction was continued for 4 hours.
After the reaction, 215ml of pure water was added dropwise thereto, and the mixture was stirred for 30 minutes. Maintaining the temperature at 30-40 ℃, removing the organic solvent by rotary removal under reduced pressure, and filtering to obtain a white solid. The white solid was added to 650ml of methanol, heated to reflux, stirred for 30 minutes, cooled to room temperature, filtered and dried to give 45.5g of a white solid. Adding the white solid into 423ml ethyl acetate, heating to reflux to obtain a clear solution, slowly adding 280ml n-hexane, slowly cooling to room temperature, and stirring overnight; the solution was filtered and the filter cake was washed with 25ml x 2 n-hexane to give 41.1g of a white solid with a yield of 63.9%. The purity of intermediate 3 was 99.79% by HPLC, and no tetraacetyl alpha-isomer was detected.
4. Preparation of canagliflozin:
taking a 1L reaction bottle, and installing a mechanical stirring device, a thermometer and a constant-pressure low-liquid funnel; 40g (0.065mol) of intermediate 3 was added to a mixed solvent of 200ml of methanol and 200ml of tetrahydrofuran, and stirred to obtain a slurry solution. A pure aqueous solution (90ml) of 8.1g (0.196mol) of lithium hydroxide was slowly added dropwise at room temperature. After the dropwise addition, the reaction was carried out for about 1 hour, the reaction solution became clear, and the reaction was continued for 4 hours. After the reaction, 200ml of purified water was added, the organic solvent was removed under reduced pressure, and a solid was precipitated, filtered under reduced pressure, washed with 30ml of 2ml of purified water, and dried to obtain 27.6g of a white solid. The resulting solid was added to 152ml methanol, dissolved with stirring, activated carbon (1.4g, 5%) was added, heated to reflux for 30 minutes, filtered to remove the activated carbon, purified water (125ml) was added, heated to reflux to give a clear solution, slowly cooled to room temperature, stirred for more than 12 hours, filtered, and dried to give 25.9g of a white solid with a yield of 89.8%. HPLC purity 99.95%, no alpha-isomer impurity detected, single impurity less than 0.02%.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (26)
1. A preparation method of canagliflozin is characterized by comprising the following steps:
1) reacting 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent at the temperature of-25 to-20 ℃ by taking tetrahydrofuran as a solvent, dropwise adding a tetrahydrofuran solution of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone for reaction, then heating to room temperature, reacting with a methanol solution containing methanesulfonic acid, and purifying to obtain an intermediate 1;
wherein the alkaline reagent is isopropyl magnesium chloride lithium chloride or sec-butyl magnesium chloride lithium chloride;
2) dissolving the intermediate 1 prepared in the step 1) in an organic solvent at the temperature of-25 to-10 ℃, adding triethylsilane into the organic solvent containing the intermediate 1, dropwise adding boron trifluoride diethyl etherate, reacting at the temperature of-25 to-10 ℃, and performing post-treatment to obtain an intermediate 2;
3) adding organic base and DMAP into the intermediate 2 prepared in the step 2) at the temperature of-5 ℃, uniformly mixing, adding acetic anhydride for reaction, and purifying to obtain an intermediate 3;
wherein the purification specifically comprises: adding water into the reaction solution, removing the solvent by rotary removal under reduced pressure, filtering to obtain a white solid, adding the white solid into alcohol, fully stirring, heating to reflux, cooling to room temperature, filtering, and drying under reduced pressure to obtain a white solid; adding the white solid into an organic solvent C, heating until the white solid is completely dissolved, dripping the organic solvent D, naturally cooling to room temperature, stirring overnight, filtering, and washing by using the organic solvent D to obtain a white solid intermediate 3;
in the purification, the alcohol is ethanol and/or methanol; the organic solvent C is selected from one or more of methyl tert-butyl ether, methyl n-butyl ether and ethyl acetate; the organic solvent D is n-hexane and/or n-heptane;
4) dissolving the intermediate 3 prepared in the step 3) in an organic solvent, dropwise adding an alkaline aqueous solution, reacting, and purifying to obtain canagliflozin;
2. the method according to claim 1, wherein the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the basic agent in step 1) is 1:1 to 2; the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is 1: 1-2.
3. The method according to claim 2, wherein the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the basic agent in step 1) is 1:1.3 to 1.5; the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is 1: 1.3-1.6.
4. The production method according to any one of claims 1 to 3, wherein the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the methanesulfonic acid in step 1) is 1:2 to 2.7;
the amount of methanol added is 2 to 5L per mole of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene.
5. The method according to claim 4, wherein the molar ratio of the 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to the methanesulfonic acid in the step 1) is 1:2.1 to 2.3.
6. The production method according to any one of claims 1 to 3 and 5, wherein in the step 2), the molar ratio of the intermediate 1 to the triethylsilane is 1:2 to 6; the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 2-6.
7. The preparation method according to claim 4, wherein in the step 2), the molar ratio of the intermediate 1 to the triethylsilane is 1: 2-6; the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 2-6.
8. The method according to claim 6, wherein in step 2), the molar ratio of the intermediate 1 to the triethylsilane is 1: 3; the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 3.
9. The method according to claim 7, wherein in step 2), the molar ratio of the intermediate 1 to the triethylsilane is 1: 3; the molar ratio of the intermediate 1 to the boron trifluoride diethyl etherate is 1: 3.
10. The preparation method according to any one of claims 1 to 3, 5 and 7 to 9, wherein in the step 3), the organic base is selected from one or more of N-methylmorpholine, triethylamine and diisopropylethylamine.
11. The preparation method according to claim 4, wherein in the step 3), the organic base is selected from one or more of N-methylmorpholine, triethylamine and diisopropylethylamine.
12. The preparation method according to claim 6, wherein in the step 3), the organic base is selected from one or more of N-methylmorpholine, triethylamine and diisopropylethylamine.
13. The preparation method according to claim 10, wherein in the step 3), the molar ratio of the intermediate 2 to the organic base is 1: 4-8; the molar ratio of the intermediate 2 to acetic anhydride is 1: 4-8; the molar ratio of the intermediate 2 to the DMAP is 1: 0.08-0.12.
14. The preparation method according to claim 11 or 12, wherein in the step 3), the molar ratio of the intermediate 2 to the organic base is 1: 4-8; the molar ratio of the intermediate 2 to acetic anhydride is 1: 4-8; the molar ratio of the intermediate 2 to the DMAP is 1: 0.08-0.12.
15. The preparation method according to claim 13, wherein in the step 3), the molar ratio of the intermediate 2 to the organic base is 1: 5-6; the molar ratio of the intermediate 2 to acetic anhydride is 1: 5-6; the molar ratio of the intermediate 2 to the DMAP was 1: 0.1.
16. The preparation method according to claim 14, wherein in the step 3), the molar ratio of the intermediate 2 to the organic base is 1: 5-6; the molar ratio of the intermediate 2 to acetic anhydride is 1: 5-6; the molar ratio of the intermediate 2 to the DMAP was 1: 0.1.
17. The method according to any one of claims 1 to 3, 5, 7 to 9, 11 to 13, and 15 to 16, wherein in the step 4), the alkali in the alkaline aqueous solution is one or more selected from sodium methoxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide.
18. The method according to claim 4, wherein the alkali in the basic aqueous solution in step 4) is one or more selected from sodium methoxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide.
19. The method according to claim 6, wherein in step 4), the alkali in the basic aqueous solution is selected from one or more of sodium methoxide, lithium hydroxide, sodium hydroxide and potassium hydroxide.
20. The method according to claim 10, wherein in step 4), the alkali in the basic aqueous solution is selected from one or more of sodium methoxide, lithium hydroxide, sodium hydroxide and potassium hydroxide.
21. The method according to claim 14, wherein in step 4), the alkali in the basic aqueous solution is selected from one or more of sodium methoxide, lithium hydroxide, sodium hydroxide and potassium hydroxide.
22. The preparation method according to claim 17, wherein in the step 4), the molar ratio of the intermediate 3 to the base is 1: 2-5.
23. The method according to any one of claims 18 to 21, wherein the molar ratio of the intermediate 3 to the base in step 4) is 1:2 to 5.
24. The preparation method according to claim 22, wherein in the step 4), the molar ratio of the intermediate 3 to the base is 1: 3-4.
25. The preparation method according to claim 23, wherein in the step 4), the molar ratio of the intermediate 3 to the base is 1: 3-4.
26. The method of claim 1, comprising the steps of:
1) in an inert environment, tetrahydrofuran is used as a solvent, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene and an alkaline reagent are added according to a molar ratio of 1: 1.3-1.5 at a temperature of-25 ℃ to-20 ℃, and after reaction, 1.3-1.6 mol of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-gluconolactone is added dropwise into each mol of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene for reaction;
maintaining the temperature, adding a methanol solution containing methanesulfonic acid according to the molar ratio of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene to methanesulfonic acid of 1: 2.1-2.3, and continuing the reaction; cooling the reaction liquid to-5 ℃, quenching, and adjusting the pH value to 7-8; heating to 30-40 ℃, and purifying to obtain an intermediate 1;
wherein 2-5L of methanol solution is added to each mole of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene;
2) dissolving the intermediate 1 prepared in the step 1) in an organic solvent at the temperature of-25 to-10 ℃, adding triethylsilane and boron trifluoride diethyl etherate according to the molar ratio of 1:3:3, and reacting; quenching at a temperature of not higher than-10 ℃ to obtain an intermediate 2;
3) adding N-methylmorpholine or triethylamine and DMAP into the intermediate 2 prepared in the step 2) at the temperature of-5 ℃, uniformly mixing, then dripping acetic anhydride, heating to room temperature, reacting, and purifying to obtain an intermediate 3;
wherein the molar ratio of the intermediate 2 to the organic base is 1: 5-6; the molar ratio of the intermediate 2 to acetic anhydride is 1: 5-6; the molar ratio of the intermediate 2 to the DMAP is 1: 0.1;
4) dissolving the intermediate 3 prepared in the step 3) in an organic solvent, dropwise adding a sodium methoxide or lithium hydroxide aqueous solution, wherein the molar ratio of the intermediate 3 to the sodium methoxide or lithium hydroxide is 1: 3-4, reacting, and purifying to obtain the canagliflozin.
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