CN110698467B - Synthesis method of englitjing - Google Patents
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Abstract
The invention provides a novel process for synthesizing englitjing. The process utilizes borate to perform halogen pulling action, and combines specific reaction conditions, so that the method can prepare the englitazone with high yield and simple operation. The method for synthesizing the englitz is mild in reaction condition, high in total yield, less in side reaction and convenient to operate, thereby being beneficial to industrial production and cost control.
Description
Technical Field
The invention belongs to the fields of medicine and fine chemical industry. In particular, the invention relates to a novel synthesis method of englitazone and a novel intermediate for synthesizing englitazone.
Background
Engliflozin (Empagliflozin) is a selective oral SGLT-2 inhibitor developed by Boringer Ghansey, and is a novel oral hypoglycemic agent. First to market in europe in 5 months of 2014, in the united states and japan in 8 months and 12 months of 2014, and in china in 9 months of 2017, respectively. Engliflozin can selectively inhibit the reabsorption of filtered glucose by the glomerular proximal tubule, so that excessive glucose is discharged from urine, and directly reduces blood sugar, and is used for treating type II diabetes.
The Engliclazide purification academic name is: (1S) -1, 5-anhydro-1-C- (4-chloro-3- ((4- ((((3S) -tetrahydro-3-furanyl) oxy) phenyl) methyl) phenyl) -D-glucitol the structure of enggliflozin is as follows:
with respect to the synthesis of engagliflozin, there are several documents reported in the prior art. For example, WO2006120208 discloses a preparation method of englitazone, and the specific synthetic process is as follows: halogen-metal exchanging (S) -4-bromo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene with tert-butyllithium in anhydrous diethyl ether at-78 ℃; then adding 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone for addition reaction; after the reaction is finished, adding a methanol solution and a methanesulfonic acid solution to continuously react to generate 1-chloro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofuran-3-yloxy-benzyl) -benzene; finally, the englitazone is obtained by reduction under the action of triethylsilane and boron trifluoride diethyl etherate.
The method is carried out at low temperature (-78 ℃), the operation is complicated, the generated lithium salt and the protected glucolactone do not completely react to generate the impurity of the formula 10 and the ring-opening impurity formula 11 shown below, and the 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone is unstable and easy to hydrolyze. Therefore, the total yield of the route is very low, only about 12%, and the process operation cost is high.
One method of preparing engagliflozin is reported by Label Compd. Radiopharm 2014, volume 57, page 687. Wherein fluorobenzene is reacted with (S) -3-hydroxy-tetrahydrofuran, followed by Friedel-crafts reaction with an acid chlorinating reagent, followed by Et3SiH/BF 3 Reducing Et2O system, extracting halogen with n-butyllithium to form lithium salt, nucleophilic adding reaction with glucose ester, methyl etherification with methanol, final Et 3 SiH/BF 3 Reduction of the Et2O system gives englitazone.
The method needs a reagent which is easy to self-ignite, namely n-butyllithium, and the reaction temperature is also harsh (-78 ℃). In addition, this method also involves side reactions (the reaction of the resulting lithium salt with protected glucolactone is not complete with the formula 10 impurity and ring opening impurity formula 11), and 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone is unstable and is easily hydrolyzed. Thus, the overall yield of the process remains low, only around 13.5%, resulting in still high costs for the route.
Therefore, there is an urgent need in the art for a method for synthesizing englitz, which has the advantages of high yield, low cost, convenient operation, suitability for large-scale industrial production, and the like.
Disclosure of Invention
The invention aims to provide a synthetic method of the enggliflozin, which can prepare the enggliflozin with high yield and low cost, and has the advantages of convenient operation, suitability for large-scale industrial production and the like.
In a first aspect, the present invention provides a method for synthesizing englitjing as shown below, comprising the steps of:
1) Coupling of (S) -4-halo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 5) with pinacol biborate (compound of formula 6) in the presence of a base and a catalyst to give (S) -2- (4-chloro-3- (4- ((tetrahydrofuran-3-yl) methyl) benzyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (compound of formula 7);
2) Coupling (S) -2- (4-chloro-3- (4- ((tetrahydrofuran-3-yl) methyl) benzyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (compound of formula 7) with acetyl bromo- α -D-glucose (compound of formula 8) in the presence of a base and a catalyst to give 1-chloro-4- (2, 3,4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 9); and
3) Deprotection of 1-chloro-4- (2, 3,4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofurane-3-yloxy-benzyl) -benzene (compound of formula 9) gives enggliflozin.
In specific embodiments, step 1) is performed in a single solvent or in a combined solvent; including but not limited to toluene/toluene aqueous two-phase solution, tetrahydrofuran/tetrahydrofuran aqueous solution, acetonitrile/acetonitrile aqueous solution, dioxane/dioxane aqueous solution, N-Dimethylformamide (DMF)/DMF ethanol mixed solution/DMF methanol solution, N-dimethylacetamide (DMAc), DMSO/DMSO aqueous solution, methylpyrrolidone (NMP), preferably dioxane aqueous solution combined solvent.
In a specific embodiment, the base in step 1) is an organic base or an inorganic base; wherein the organic base includes but is not limited to triethylamine, N-diisopropylethylamine, sodium (potassium) methoxide, sodium (potassium) ethoxide, sodium (potassium) tert-butoxide, sodium (potassium) acetate; inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, preferably potassium acetate.
In a specific embodiment, the molar ratio of the amount of base used in step 1) to the compound of formula 5 is: 2eq-5eq, preferably 3eq-3.5eq.
In a specific embodiment, the catalyst in step 1) is a palladium or nickel compound; the nickel compounds include, but are not limited to, nickel chloride, nickel bromide, 1' -bis-diphenylphosphino ferrocene nickel dichloride (dppfNiCl) 2 ) Bis (triphenylphosphine) nickel chloride NiCl 2 (PPh 3 ) 2 Preferably dppfNiCl 2 The method comprises the steps of carrying out a first treatment on the surface of the Palladium compounds include, but are not limited to, palladium chloride, palladium acetate, tetraphenylphosphine palladium, 1' -bis-diphenylphosphine ferrocene palladium dichloride (dppfppdcl) 2 ) Bis (triphenylphosphine) palladium chloride PdCl 2 (PPh 3 ) 2 、pd(dba) 2 Preferably dppfPdCl 2 。
In a specific embodiment, the catalyst is used in step 1) in an amount of: 0.5mol% to 10mol%, preferably 2mol% to 5mol%.
In a specific embodiment, the temperature in step 1) is 80-140 ℃, preferably 95-100 ℃.
In a specific embodiment, the base in step 2) is an organic base or an inorganic base; the organic base includes, but is not limited to, triethylamine, N-diisopropylethylamine, sodium (potassium) methoxide, sodium (potassium) ethoxide, sodium (potassium) tert-butoxide, sodium (potassium) acetate; the inorganic base includes, but is not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, preferably potassium phosphate.
In a specific embodiment, the amount of base used in step 2) is: 2eq-6eq, preferably 3eq-4eq.
In a specific embodiment, the catalyst in step 2) is a palladium or nickel compound; the nickel compound is nickel chloride, nickel bromide, tetraphenyl phosphine nickel, 1' -bis-diphenyl phosphine ferrocene nickel dichloride (dppfNiCl) 2 ) Bis (triphenylphosphine) nickel chloride [ NiCl ] 2 (PPh 3 ) 2 )]Nickel tetraphenylphosphine is preferred; the palladium compound is palladium chloride, palladium acetate, tetraphenylphosphine palladium, 1' -bis-diphenylphosphine ferrocene palladium dichloride (dppfppdcl) 2 ) Bis (triphenylphosphine) palladium chloride PdCl 2 (PPh 3 ) 2 、pd(dba) 2 Tetraphenylphosphine palladium is preferred.
In a specific embodiment, the catalyst is used in step 2) in an amount of: 0.01mol% to 5mol%, preferably 1mol% to 2mol%.
In specific embodiments, step 2) is performed in a single solvent or in a combined solvent; including but not limited to toluene/aqueous two-phase solution, tetrahydrofuran/tetrahydrofuran aqueous solution, acetonitrile/acetonitrile aqueous solution, dioxane/dioxane aqueous solution, N-Dimethylformamide (DMF)/DMF ethanol mixed solution/DMF methanol solution, N-dimethylacetamide (DMAc), DMSO/DMSO aqueous solution, methylpyrrolidone (NMP), preferably toluene aqueous two-phase solution.
In a specific embodiment, the temperature in step 2) is 70-140 ℃, preferably 100-110 ℃.
In a preferred embodiment, the yield of the process for the synthesis of englitz is 20% or more, preferably 25% or more. More preferably 30% or more.
In a second aspect, the present invention provides a compound of formula 7,
in a third aspect, the present invention provides a process for the preparation of a compound of formula 7, as depicted in the following reaction scheme:
coupling of (S) -4-halo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 5) with pinacol biborate (compound of formula 6) in the presence of a base and a catalyst gives (S) -2- (4-chloro-3- (4- ((tetrahydrofuran-3-yl) methyl) benzyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (compound of formula 7).
In a preferred embodiment, the illustrated process is carried out in a single solvent or in a combined solvent; including but not limited to toluene/toluene aqueous two-phase solution, tetrahydrofuran/tetrahydrofuran aqueous solution, acetonitrile/acetonitrile aqueous solution, dioxane/dioxane aqueous solution, N-Dimethylformamide (DMF)/DMF ethanol mixed solution/DMF methanol solution, N-dimethylacetamide (DMAc), DMSO/DMSO aqueous solution, methylpyrrolidone (NMP), preferably dioxane aqueous solution combined solvent.
In a preferred embodiment, the base in the illustrated process is an organic base or an inorganic base; organic bases include, but are not limited to, triethylamine, N-diisopropylethylamine, sodium (potassium) methoxide, sodium (potassium) ethoxide, sodium (potassium) tert-butoxide, sodium (potassium) acetate; inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, preferably potassium acetate.
In a preferred embodiment, the amount of base used in the process shown is: 2eq-5eq, preferably 3eq-3.5eq.
In a preferred embodiment, the catalyst in the illustrated process is a palladium or nickel compound; the nickel compounds include, but are not limited to, nickel chloride, nickel bromide, 1' -bis-diphenylphosphino ferrocene nickel dichloride (dppfNiCl) 2 ) Bis (triphenylphosphine) nickel chloride NiCl 2 (PPh 3 ) 2 Preferably dppfNiCl 2 The method comprises the steps of carrying out a first treatment on the surface of the Palladium compounds include, but are not limited to, palladium chloride, palladium acetate, tetraphenylphosphine palladium, 1' -bis-diphenylphosphine ferrocene palladium dichloride (dppfppdcl) 2 ) Bis (triphenylphosphine) palladium chloride PdCl 2 (PPh 3 ) 2 、pd(dba) 2 Preferably dppfPdCl 2 。
In a preferred embodiment, the catalyst is used in the process shown in the following amounts: 0.5mol% to 10mol%, preferably 2mol% to 5mol%.
In a preferred embodiment, the temperature in the process shown is 80-140 ℃, preferably 95-100 ℃.
In a fourth aspect, the invention provides the use of a compound of formula 7 in the preparation of englitjing.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows a mass spectrum of a compound of formula 7;
FIG. 2 shows HNMR diagrams of compounds of formula 7;
FIG. 3 shows a mass spectrum of Engliflozin;
fig. 4 shows HNMR diagram of englitjing.
Detailed Description
The inventor has conducted extensive and intensive studies to unexpectedly find a novel process for synthesizing englitjing. The process utilizes borate to perform halogen pulling action, and combines specific reaction conditions, so that the method can prepare the englitazone with high yield and simple operation. The present invention has been completed on the basis of this finding.
In order to overcome the defects in the prior art, the invention provides a high-efficiency method for synthesizing the englitazone, the synthetic route of which is shown as follows (involving the following 3 reaction steps):
This process reduces the occurrence of side reactions, in contrast to the prior art processes, such as those described in WO2006120208 and J.Label Compd.radiopharm, which produce impurity 10 and impurity 11. In addition, the method has mild reaction conditions and high total yield (more than 20%, preferably more than 25%, more preferably more than 30%), thereby being beneficial to industrial production.
Those skilled in the art can know how to obtain some intermediates in the above process by means of the prior art knowledge in light of the teachings of the present invention. For example, in the process of the present invention, (S) -4-halo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene (formula 5) may be prepared by known methods, for example Wang, xiao-Jun; zhang, li; organic Letters,2014, vol.16, #16p.4090-4093 and WO2011039107, US2011237789, etc. For example, inexpensive and readily available 2-chloro-5-halobenzoic acid (formula 1) is first acylated to provide formula 2, then reacted with fluorobenzene Fu Kefan to provide formula 3, then reacted with (S) -3-hydroxy-tetrahydrofuran to provide formula 4, and finally reduced with sodium borohydride/aluminum trichloride to provide (S) -4-halo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene (formula 5).
However, in further studies, the inventors have found that the specific reactants and process parameters employed in steps 1 and 2 above also have a considerable effect on the yields of intermediate compounds of formula 7 and formula 9 and ultimately engagliflozin.
For example, in step 1, it is preferable to conduct the reaction using a single solvent or a combination of solvents; such as toluene/toluene aqueous two-phase solution, tetrahydrofuran/tetrahydrofuran aqueous solution, acetonitrile/acetonitrile aqueous solution, dioxane/dioxane aqueous solution, N-Dimethylformamide (DMF)/DMF ethanol mixed solution/DMF methanol solution, N-dimethylacetamide (DMAc), DMSO/DMSO aqueous solution, methylpyrrolidone (NMP), preferably dioxane aqueous solution combined solvent. The base to be used is preferably an organic base or an inorganic base, for example, an organic base such as triethylamine, N-diisopropylethylamine, sodium (potassium) methoxide, sodium (potassium) ethoxide, sodium (potassium) t-butoxide, sodium (potassium) acetate and the like; or inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and potassium hydroxide; potassium acetate is preferred. The amount of base used is preferably in a molar ratio relative to the compound of formula 5: 2eq-5eq, preferably 3eq-3.5eq. The catalyst is preferably palladium or a nickel compound, such as nickel chloride, nickel bromide, 1' -bis-diphenylphosphino ferrocene nickel dichloride (dppfNiCl) 2 ) Bis (triphenylphosphine) nickel chloride NiCl 2 (PPh 3 ) 2 Preferably dppfNiCl 2 The method comprises the steps of carrying out a first treatment on the surface of the Or palladium chloride, palladium acetate, tetraphenylphosphine palladium, 1' -bis-diphenylphosphine ferrocene palladium dichloride (dppfppdcl) 2 ) Bis (triphenylphosphine) palladium chloride PdCl 2 (PPh 3 ) 2 、pd(dba) 2 Preferably dppfPdCl 2 The method comprises the steps of carrying out a first treatment on the surface of the While promotingThe dosage of the chemical agent can be as follows: 0.5mol% to 10mol%, preferably 2mol% to 5mol%; the reaction of step 1 is preferably carried out at a temperature of from 80 to 140℃and preferably from 95 to 100 ℃.
In another specific embodiment, in step 2, the base is preferably an organic base such as triethylamine, N-diisopropylethylamine, sodium (potassium) methoxide, sodium (potassium) ethoxide, sodium (potassium) tert-butoxide, sodium (potassium) acetate or an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide or potassium hydroxide, preferably potassium phosphate. The amount of the base to be used is preferably 2eq to 6eq, more preferably 3eq to 4eq. The catalyst is preferably palladium or nickel compounds; the nickel compound is nickel chloride, nickel bromide, tetraphenyl phosphine nickel, 1' -bis-diphenyl phosphine ferrocene nickel dichloride (dppfNiCl) 2 ) Bis (triphenylphosphine) nickel chloride [ NiCl ] 2 (PPh 3 ) 2 )]Nickel tetraphenylphosphine is preferred; the palladium compound is palladium chloride, palladium acetate, tetraphenylphosphine palladium, 1' -bis-diphenylphosphine ferrocene palladium dichloride (dppfppdcl) 2 ) Bis (triphenylphosphine) palladium chloride PdCl 2 (PPh 3 ) 2 、pd(dba) 2 Tetraphenylphosphine palladium is preferred. The catalyst is preferably used in an amount of 0.01mol% to 5mol%, preferably 1mol% to 2mol%. The reaction of step 2 is preferably carried out in a single solvent or in a combination of solvents; such as toluene/aqueous toluene two-phase solution, tetrahydrofuran/tetrahydrofuran aqueous solution, acetonitrile/acetonitrile aqueous solution, dioxane/dioxane aqueous solution, N-Dimethylformamide (DMF)/DMF ethanol mixed solution/DMF methanol solution, N-dimethylacetamide (DMAc), DMSO/DMSO aqueous solution, methylpyrrolidone (NMP), preferably toluene aqueous two-phase solution. The reaction of step 2 is preferably carried out at a temperature of from 70 to 140℃and preferably from 100 to 110 ℃.
The main advantages of the invention include:
1. the method for synthesizing the englitazone has mild reaction conditions;
2. the total yield of the Engliflozin synthesized by the method is high;
3. the method has less side reaction for synthesizing the enggliflozin, so that impurities are not easy to generate;
4. the method for synthesizing the enggliflozin is convenient to operate, thereby being beneficial to industrial production and cost control.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
EXAMPLE 1 Synthesis of ((2-chloro-5-bromophenyl) (4-fluorophenyl) methanone) (formula 3)
Synthetic formula 2: 235.5g of formula 1 was added to the reaction flask; 1L of dichloromethane; 10 ml of DMF. Cooling to internal temperature below 10deg.C. 140g of oxalyl chloride are added dropwise. After the completion of the dropwise addition, the reaction was carried out at a temperature of 20℃or lower for 120min, followed by TLC detection. Concentration to remove the reaction solvent dichloromethane and excess oxalyl chloride gave 252.8g of white solid form 2.
Synthetic formula 3: 1L of methylene chloride was added to the reaction flask, and 190g of fluorobenzene was added. And cooling the ice water to below 0 ℃. 185g of anhydrous aluminum trichloride are added at controlled temperature. After the addition was completed, formula 2 (252.8 g of methylene chloride dissolved in 1L) was added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature for 5 hours, and the reaction was complete by TLC. The reaction was poured into ice water. The mixture was washed twice with saturated sodium chloride to neutrality, dried over anhydrous magnesium sulfate, and the solid obtained by filtration and concentration was purified with ethyl acetate to obtain 272.6g of a white solid. The yield thereof was found to be 86.9%.
EXAMPLE 2 Synthesis of [4- [ [ (3S) -tetrahydro-3-furanyloxy ] phenyl ] - (5-bromo-2-chlorophenyl) methanone (formula 4)
250g of the compound of formula 3 are introduced into a reaction flask, and then 750ml of tetrahydrofuran are added for dissolution, and 78g of (S) -3-hydroxytetrahydrofuran are added. And cooling the ice water to below 0 ℃. Wen Jiaru Potassium tert-butoxide solution (122 g of potassium tert-butoxide in 1L of tetrahydrofuran) was prepared. After the addition was completed, the reaction was allowed to proceed below 10℃for 2 hours, and the completion of the reaction was detected by TLC. The reaction solution was poured into ice water, and isopropyl ether was added thereto with stirring to extract. Washing twice with saturated sodium chloride to neutrality, drying over anhydrous magnesium sulfate, filtering and concentrating to obtain residue, and refining with acetone to obtain 259.7g white solid compound of formula 4, yield 85.3%.
EXAMPLE 3 Synthesis of (S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) tetrahydrofuran (formula 5)
247g of the compound of formula 4, 2L of tetrahydrofuran are introduced into the reaction flask. Cooling to below 20deg.C. 159g of potassium borohydride was added at controlled temperature. 193g of anhydrous aluminum trichloride is added in batches under the temperature of 20 ℃ after the addition. After the addition was completed, the reaction was refluxed for 6 hours, and the reaction was complete by TLC. The reaction solution was poured into ice water. Dilute hydrochloric acid is added dropwise. Ethyl acetate, drying and concentration gave a residue which was purified with ethanol to give 193.5g of a white compound of formula 5 in 81.8% yield.
EXAMPLE 4 Synthesis of (S) -2- [ 4-chloro-3- (4- ((tetrahydro-3-furanyl) oxy) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (formula 7) Compound
36.6g of the compound of formula 5, 350 ml of dioxane, 38g of bisboronic acid pinacol ester (formula 6), 30g of potassium acetate, 1.47g of dppfPdCl, and an oil bath heated to 100 ℃ under nitrogen filling are added into a reaction bottle for reaction for 8 hours, the reaction is cooled to room temperature after the reaction is finished, the reaction bottle is filtered, and a yellow solid obtained by concentrating the filtrate after washing with water is purified by adding ethanol to obtain a white solid (formula 7) of which 26.1g. The yield thereof was found to be 71.3%. HPLC 98.6%.
ESI-MS m/z:437.32[M+Na] + ： 1 H-NMR(400MHz,CDCl 3 )δ：1.25～127(t,12H)，2.03-2.09(m,2H)，3.13(s,1H)，3.78～3.99(m,4H)，3.97(s,2H)，6.67～6.69(d,2H)，7.27～7.29(d,1H)，7.51～7.53(d,1H)，7.61(s,1H)。
EXAMPLE 5 Synthesis of 1-chloro-4- (2, 3,4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofurane-3-yloxy-benzyl) -benzene (formula 9)
Synthesis of compounds of formula 8: to the reaction flask was added 40g of glucose followed by 200ml of acetic anhydride. After the addition, the temperature is raised until the mixture is dissolved. 10g of sodium acetate is added at a controlled temperature. After the addition was completed, the reaction was completed by TLC for 2 hours at 140℃or below. The reaction solution was poured into ice water, stirred, filtered and washed to obtain a crude product, which was purified with ethanol to obtain 80g of beta-D-glucose pentaacetate as a white solid.
80g of the above-obtained beta-D-glucose pentaacetate was added to 400 ml of acetic anhydride and 120ml of phosphorus tribromide. Cooling to below 0deg.C. 175g of water is added dropwise at controlled temperature, the reaction is carried out for 60min at the temperature of 0 ℃ after the completion of the dropwise addition, and the TLC detection reaction is carried out. The reaction solution was poured into ice water. Dichloromethane extraction, organic layer water washing, sodium bicarbonate solution washing, saturated saline water washing, drying and concentration to obtain a white solid compound of formula 8, which is obtained by refining the residue with isopropyl ether, 72.5g.
Synthesis of compounds of formula 9: 55g (formula 7) of toluene (500 ml), 72.5g of compound of formula 8, 85g of potassium phosphate, 5g of tetraphenylphosphine palladium (5 g) are added into a reaction bottle, the temperature is raised to 105 ℃ for reaction for 12 hours in an oil bath, the reaction is cooled to room temperature after the reaction is finished, the reaction is filtered, the filtrate is washed twice with 250 ml of multiplied by 2 water, the organic layer is concentrated to obtain a raffinate, and the raffinate is refined by ethyl acetate to obtain 63.5g of compound of formula 9, the yield is 77.4%, and the HPLC is 99.4%.
ESI-MS m/z：641.11[M+Na] + 。
1 H-NMR(400MHz,CDCl 3 )δ：2.49～2.51(m,9H)，3.32(s,18H)。
EXAMPLE 6 Synthesis of Engliflozin
31g of the compound of formula 9 and 50ml of methanol are added into a reaction bottle, 50g of 20% sodium hydroxide solution is dropwise added below 20 ℃ after stirring and dissolution, the reaction liquid reacts for 60 minutes below 20 ℃ after the dropwise addition, the pH value of the reaction liquid is regulated to be 7 by dilute hydrochloric acid after the HPLC detection, the methanol is concentrated, the residual liquid is extracted twice by methylene dichloride, the organic layers are combined and concentrated, the residual liquid is added into ethyl acetate and water to obtain 20.7g, and the yield of the step is 91.7%, and the HPLC value is 99.1%.
ESI-MS m/z：473.21.[M+Na] + 。
1 H-NMR(400MHz,CDCl 3 )δ： l H NMR(DMS0-d6)б:7.37(d,J＝8.2Hz,1H),7.33(d,J＝1.9Hz,1H),7.23(dd,J＝8.3,2.1Hz,1H),7.10(d,J＝8.6Hz,2H),6.82(d,J＝8.7Hz,2H),4.94(m,3H),4.82(d,J＝5.8Hz,1H),4.43(t,J＝5.8Hz,1H),4.04(m,3H),3.84(m,2H),3.75(m,3H),3.43(m,1H),3.30(m,3H),2.21(m,1H),1.95(m,1H)。
Example 7: synthesis of Compound 7
Comparative studies of different catalysts C1: referring to the experimental procedure in example 4, only the kind of catalyst in the feeding parameters was changed, and the remaining parameters were subjected to feeding, reaction, treatment, and purification to obtain the purity and yield of the compound of formula 7 as shown in table 1.
TABLE 1
Example 8: synthesis of Compound 7
Comparison of catalyst usage study: synthetic experimental group referring to the experimental procedure in example 4, only the amount of catalyst (molar ratio of raw material relative to formula 5) in the feeding parameters was changed, and the remaining parameters were unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in table 2.
TABLE 2
Example 9: synthesis of Compound 7
Comparative study of different solvents S1: synthetic experimental group referring to the experimental procedure in example 4, only the S1 solvent type in the feed parameters was changed, and the remaining parameters were unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in table 3.
TABLE 3 Table 3
Example 10: synthesis of Compound 7
Comparative study of different bases B1: synthetic experimental group referring to the experimental procedure in example 4, only the B1 base type in the feed parameters was changed, and the remaining parameters were unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 4.
TABLE 4 Table 4
Example 11: synthesis of Compound 7
Comparative study of different alkali usage: synthetic experimental group referring to the experimental operation in example 4, only the amount of B1 alkali (potassium acetate) used (molar ratio of raw materials relative to formula 5) in the feed parameters was changed, and the remaining parameters were unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in table 5.
TABLE 5
Example 11: synthesis of Compound 7
Comparative studies of the different solvent amounts: synthetic experimental group referring to the experimental operation in example 4, only the amount of S1 solvent (dioxane) in the feed parameters (mass ratio relative to formula 5) was changed, and the remaining feed parameters and reaction parameters were unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 6.
TABLE 6
Example 12: synthesis of Compound 7
Comparative study of different temperatures T1: synthetic experimental group referring to the experimental procedure in example 4 (reaction solvent DMF), only T1 of the T1 temperature parameters of the reaction process was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 7 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 7.
TABLE 7
Example 13: synthesis of Compound 9
Comparison of different catalysts C2: synthetic experimental groups referring to experimental operation of the compound of formula 9 in example 5, only the C2 catalyst of the feed process was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 8.
TABLE 8
Example 14: synthesis of Compound 9
Comparison of catalyst usage study: synthetic experimental group referring to experimental operation of the compound of formula 9 in example 5, only the amount of the C2 catalyst (tetraphenylphosphine palladium) used in the feeding process (molar ratio with respect to the starting material of formula 7) was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in table 9.
TABLE 9
Example 15: synthesis of Compound 9
Comparative study of different solvents S2: synthetic experimental groups referring to experimental operation of the compound of formula 9 in example 5, only the type of S2 solvent for the feeding process was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 10.
Table 10
Example 16: synthesis of Compound 9
Comparative study of different bases B2: synthetic experimental groups referring to experimental operation of the compound of formula 9 in example 5, only the type of B2 base during the feeding process was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 11.
TABLE 11
Example 17: synthesis of Compound 9
Comparative study of different alkali usage: synthetic experimental group referring to the experimental operation of the compound of formula 9 in example 5, only the amount of B2 base (potassium phosphate) used in the feeding process (molar ratio with respect to the starting material of formula 7) was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 12.
Table 12
Example 18: synthesis of Compound 9
Comparative studies of the different solvent amounts: synthetic experimental group referring to experimental operation of the compound of formula 9 in example 5, only the amount of S2 solvent (toluene) used in the feeding process (relative to the amount of raw material fed in formula 7) was changed. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the compound of formula 9 obtained by the steps of feeding, reacting, treating, refining and purifying are shown in Table 13.
TABLE 13
Example 19: synthesis of Compound 7
Comparative study of different temperatures T2: synthetic experimental group referring to the experimental procedure (solvent DMSO) of the compound of formula 9 in example 5, only the T2 temperature parameter of the reaction solution was changed during the reaction. The rest of the feeding parameters and the reaction parameters are unchanged. The purity and yield of the purified compound of formula 9 are shown in Table 14 after the addition, reaction, treatment and purification.
TABLE 14
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (1)
1. The method for synthesizing the englitjing comprises the following steps of:
1) Coupling of (S) -4-halo-1-chloro-2- (4-tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 5) with pinacol biborate (compound of formula 6) in the presence of a base and a catalyst to give (S) -2- (4-chloro-3- (4- ((tetrahydrofuran-3-yl) methyl) benzyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (compound of formula 7), the halo being iodo or bromo;
2) Coupling (S) -2- (4-chloro-3- (4- ((tetrahydrofuran-3-yl) methyl) benzyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (compound of formula 7) with acetyl bromo- α -D-glucose (compound of formula 8) in the presence of a base and a catalyst to give 1-chloro-4- (2, 3,4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 9); and
3) Deprotection of 1-chloro-4- (2, 3,4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4- (S) -tetrahydrofuran-3-yloxy-benzyl) -benzene (compound of formula 9) to give enggliflozin;
characterized in that step 1) is carried out in a dioxane aqueous solution combined solvent;
the alkali in the step 1) is potassium acetate;
the molar ratio of the base used in step 1) to the compound of formula 5 is 3eq to 3.5eq;
the catalyst in step 1) is dppfppdcl 2 ；
The catalyst dosage in the step 1) is 2mol percent to 5mol percent;
the temperature in step 1) is 95-100 ℃;
the alkali in the step 2) is potassium phosphate;
the amount of alkali used in step 2) is 3eq-4eq;
the catalyst in the step 2) is tetraphenylphosphine palladium;
the catalyst dosage in the step 2) is 1mol percent to 2mol percent;
step 2) is carried out in toluene-water two-phase solution;
the temperature in step 2) is 100-110 ℃.
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