CN107540685B - Preparation method and intermediate of Sotagliflozin - Google Patents
Preparation method and intermediate of Sotagliflozin Download PDFInfo
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- CN107540685B CN107540685B CN201710786892.6A CN201710786892A CN107540685B CN 107540685 B CN107540685 B CN 107540685B CN 201710786892 A CN201710786892 A CN 201710786892A CN 107540685 B CN107540685 B CN 107540685B
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Abstract
The preparation method of the Sotagliflozin provided by the invention is to improve the structure of the L-xylose derivative 1, and the hydroxyl is protected by benzyl or PMB groupThe compound 2 or the compound 2 obtained by carrying out series derivatization reaction on the L-xylose derivative 1A, and the Grignard docking reaction conditions of the compound and the 4-halogeno-1-chloro-2- (4-ethoxybenzyl) benzene compound 3 are optimized, so that the reaction yield is improved to over 85 percent, the use of excessive Grignard reagents or lithium reagents is avoided, the material consumption is reduced, and the route efficiency is improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a novel method for preparing Sotagliflozin. Specifically, the invention discloses a preparation method of a SGLT1/2 dual inhibitor medicine Sotagliflozin for treating diabetes and an intermediate thereof.
Background
Diabetes is clinically classified into two types: insulin-dependent diabetes mellitus (i.e., type I diabetes) and non-insulin-dependent diabetes mellitus (i.e., type II diabetes), the international diabetes association (IDF) predicts that the number of diabetic patients will reach 59 billion worldwide by 2035 years, with nearly 90% of them being type II diabetes patients. The Sotagliflozin is a novel oral dual inhibitor for sodium-glucose cotransporters 1 and 2(SGLT-1 and SGLT-2), and clinical researches show that the Sotagliflozin can reduce postprandial blood sugar, increase GLP-1 and promote urine sugar excretion by dual inhibiting effects of SGLT1 and SGLT 2.
The chemical name of Sotagliflozin is: (2S,3R,4R,5S,6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol having the following structural formula:
PCT patent WO2008109591A reports the synthesis of Sotagliflozin as follows:
the synthesis method of the Sotagliflozin has low total yield and difficult process amplification. Wherein, the oxidation of the L-xylose derived alcohol intermediate needs Swern reaction and low temperature reaction at-70 ℃, the amplification production has higher requirements on reaction equipment and operation, the process cost is higher, in addition, the reaction produces byproduct dimethyl sulfide, and the waste gas treatment is more troublesome; in the route, the addition reaction of the lithium reagent formed by the 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene under the action of butyllithium and the aldehyde derived from L-xylose is easy to carry out, but the reaction still needs low temperature of-70 ℃, the experimental condition requirement is higher, the reaction selectivity is poorer, the reaction yield is lower, and the process amplification has greater difficulty.
PCT patent WO2009014970A improves the synthesis method of Sotagliflozin, wherein Weinreb amide prepared from an L-xylose derivative reacts with 4-iodo-1-chloro-2- (4-ethoxybenzyl) benzene to form a lithium reagent, and the obtained intermediate carbonyl is reduced with sodium borohydride, so that although the selectivity of the reaction is improved by chiral-induced reduction, the reaction yield is improved, the exposed hydroxyl group of the Weinreb amide substrate requires the consumption of an additional lithium reagent, and thus, an excessive amount of 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene and n-butyllithium are required, and the synthesis route is as follows:
therefore, the method for synthesizing the Sotagliflozin, which has the advantages of simple process route, higher yield and low cost and is suitable for industrial production, still needs to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a new in synthesis method of Sotaglifloz and a key intermediate thereof, and the synthesis method has the advantages of simple process route, low cost and suitability for industrial production.
The invention provides a key intermediate compound 2 for synthesizing Sotagliflozin and two synthesis methods thereof, wherein the intermediate compound 2 has the following structural formula:
wherein Pg is a protecting group, including but not limited to benzyl, 4-methoxybenzyl (PMB), and the like.
The invention relates to a synthesis method of a key intermediate compound 2 of Sotagliflozin, which comprises the steps of protecting hydroxyl of an L-xylose derivative compound 1 by using benzyl or PMB groups to obtain an L-xylose derivative compound 2;
preferably, the protecting group is formed by halogenating benzyl or 4-methoxybenzyl, and the base used in the reaction is selected from inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, lithium tert-butoxide, potassium tert-butoxide or sodium tert-butoxide; the used reaction solvent is dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone and the like; the reaction temperature is generally-10 to 110 ℃.
The invention relates to another synthesis method of a key intermediate compound 2 of Sotagliflozin, which comprises the following steps:
(1) protecting the L-xylose derivative compound 1A with TBSCl under proper conditions to obtain a compound 1B;
(2) protecting hydroxyl of the compound 1B with benzyl or PMB group to obtain a compound 1C;
(3) deprotecting the compound 1C under the action of TBAF and completing cyclization reaction to obtain a compound 1D;
(4) carrying out oxidation reaction on the compound 1D to obtain a compound 1E;
(5) carrying out condensation reaction on the compound shown in the formula 1E and morpholine to obtain an intermediate compound 2;
preferably, the base used in the step (1) reaction is selected from organic bases such as pyridine, triethylamine, diisopropylethylamine, DBU or DABCO; DMAP is selected as a catalyst or not used; the used reaction solvent is dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone and the like; the reaction temperature is generally-20 to 110 ℃.
Preferably, the protecting group in step (2) is formed by halogenating benzyl or 4-methoxybenzyl, and the base used is selected from inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, lithium tert-butoxide, potassium tert-butoxide or sodium tert-butoxide; the used reaction solvent is dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone and the like; the reaction temperature is generally-10 to 110 ℃.
Preferably, the reaction solvent of step (3) is selected from dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene, acetone, or the like. The reaction temperature is generally-10 to 110 ℃.
Preferably, in the oxidation reaction of the step (4), an oxidant can be directly selected for direct oxidation, the oxidant can be selected from IBX, PDC or PCC reagents and the like, and can also be oxidized by a TEMPO catalytic oxidation method, and the oxidant is selected from NCS, DMDMH, sodium hypochlorite, sodium chlorite, TCCA and the like; the reaction solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene, ethyl acetate or methyl tertiary butyl ether, etc.; the reaction temperature is-78-120 ℃.
Preferably, the condensation reaction in step (5) is performed by using 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC), N, N ' -Diisopropylcarbodiimide (DIC), isopropyl chloroformate, etc.; the base is selected from diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylenediamine or N-methylmorpholine, etc.; the reaction solvent is selected from dimethylformamide, dimethylacetamide, dichloromethane, acetonitrile or 1, 4-dioxane, etc.; the reaction temperature is-15 to 30 ℃.
The invention also provides a Sotagliflozin key intermediate compound 4 and a synthesis method thereof, wherein the intermediate compound 4 has the following structural formula:
wherein Pg is a protecting group, including benzyl or 4-methoxybenzyl.
The invention relates to a synthesis method of a key intermediate compound 4 of Sotagliflozin, which comprises the steps of reacting a compound formula 3 with an intermediate compound 2 after undergoing a Grignard exchange reaction to obtain an intermediate compound 4;
wherein, X represents halogen Br or I.
Preferably, the Grignard exchange reaction is performed with compound 3 using isopropyl magnesium chloride, cyclohexyl magnesium chloride, n-butyl magnesium chloride, or a complex thereof with lithium chloride, or a reagent in which a halogen is directly extracted with butyl lithium, sec-butyl lithium, or the like to obtain aryl lithium; the selected reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, trifluoromethylbenzene or dichloromethane and the like; the reaction temperature is generally-75-90 ℃;
the third object of the invention is to provide a new synthesis method of a key intermediate compound 6 of Sotagliflozin,
the method comprises the following steps:
(1) carrying out reduction reaction on the compound 4 under a proper system to reduce carbonyl to obtain an intermediate compound 5;
(2) deprotecting the compound shown in the formula 5 under the action of acid and completing cyclization reaction to obtain an intermediate compound 6;
preferably, in the reduction reaction in the step (1), the reducing agent is selected from DIBAL-H, lithium aluminum hydride, red aluminum, sodium borohydride, lithium borohydride or potassium borohydride; the additive can be selected from cerium trichloride, cerium sulfate, trifluoroethanol and the like or not selected; the reaction solvent is selected from toluene, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, etc.; the reaction temperature is-78-90 ℃. Preferably, in the deprotection reaction of step (2), when the Pg protecting group is PMB, the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol, n-butanol, tert-butanol or acetonitrile, etc.; the reaction temperature is-20 to 90 ℃; when the Pg protecting group is benzyl, the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid; the catalyst is selected from palladium carbon, palladium hydroxide, palladium oxide and the like; the reducing agent is selected from ammonium formate, hydrogen and the like; the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, isopropanol, n-butanol or tert-butanol, etc.; the reaction temperature is-20 to 90 ℃.
The fourth purpose of the invention is to provide a key intermediate compound 9 of Sotagliflozin and two synthetic methods thereof, wherein the structural formula of the intermediate compound 9 is as follows:
the synthesis method of the key intermediate compound 9 of Sotagliflozin comprises the following steps:
(1) the compound 6 and pivaloyl chloride or pivalic anhydride are subjected to esterification reaction under the alkaline condition to obtain an intermediate compound 7;
(2) reacting compound 7 with hydrobromic acid to obtain bromide intermediate compound 8
(3) Reacting the compound 8 with methyl mercaptan to obtain an intermediate compound 9
Preferably, in the esterification reaction in the step (1), the base is selected from organic bases such as pyridine, triethylamine, diisopropylethylamine, DBU or DABCO; DMAP is selected as a catalyst or not used; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane or toluene. The reaction temperature is generally-10 to 110 ℃.
Preferably, in the bromination reaction of the step (2), the brominating agent is selected from lithium bromide, sodium bromide or hydrogen bromide; the reaction solvent is selected from acetic acid, propionic acid or trifluoroacetic acid, etc. The reaction temperature is generally-10 to 110 ℃.
Preferably, in the methionation reaction in the step (3), the methanethiolate is selected from sodium methionate, potassium methionate, lithium methionate, and the like; the solvent is selected from dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane or toluene. The reaction temperature is generally-10 to 110 ℃.
Another synthesis method of Sotagliflozin key intermediate compound 9 comprises the following steps:
(1) the compound 6 and pivaloyl chloride or pivalic anhydride are subjected to esterification reaction under the alkaline condition to obtain an intermediate compound 7;
(2) the intermediate compound 7 reacts with methyl iodide under the action of alkali after trimethylsilyl trifluoromethanesulfonate and thiourea reacts, and an intermediate compound 9 is obtained in one step:
preferably, in the esterification reaction in the step (1), the base is selected from organic bases such as pyridine, triethylamine, diisopropylethylamine, DBU or DABCO; DMAP is selected as a catalyst or not used; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, 1, 4-dioxane or toluene. The reaction temperature is generally-10 to 110 ℃.
Preferably, in the methylation reaction, the base is selected from triethylamine, diisopropylethylamine, DBU, DABCO and the like; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, toluene or acetonitrile, etc.; the reaction temperature is-20 to 90 ℃;
the fifth aim of the invention also provides a synthesis method of the Sotagliflozin, which comprises the steps of deprotecting the compound shown in the formula 9 under the action of a decarboxylating agent to obtain a final product of the Sotagliflozin;
preferably, in the deprotection reaction, the decarboxylating agent can be selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonia, and the like; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol, n-butanol, tert-butanol or acetonitrile, etc.; the reaction temperature is-20 to 90 ℃.
The invention relates to a preparation method of Sotagliflozin, which improves the structure of an L-xylose derivative 1, protects hydroxyl groups by benzyl or PMB groups to obtain a compound 2 or obtains the compound 2 by carrying out series derivatization reaction on the L-xylose derivative 1A, optimizes the Grignard docking reaction conditions of the compound 2 and a 4-halo-1-chloro-2- (4-ethoxybenzyl) benzene compound 3, improves the reaction yield to over 85 percent, avoids using excessive Grignard reagents or lithium reagents, reduces the material consumption and improves the route efficiency. In subsequent multi-step reactions, due to the influence of intermediate protecting groups, reaction selectivity related to chirality is improved, and crystallization performance of products is improved, so that reaction yield is improved, and purification difficulty of each intermediate is reduced. These improvements greatly improve the route efficiency, further reduce the process cost, reduce the generation of by-products and facilitate the improvement of the purity of the final product. The method is simple to operate, the yield is high, the purity of the obtained product is high, the method is suitable for large-scale production, and the synthetic route is shown as follows.
The specific implementation mode is as follows:
the following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Adding dichloromethane (190mL) to dissolve a compound shown in formula 1A (19.02g,100 mmol), adding diisopropylethylamine (25.95g,200mmol) and DMAP (1.22g,10mmol), stirring uniformly, cooling to 0-5 ℃, dropwise adding TBSCl (16.58g,110mmol), and heating to room temperature for reaction overnight after dropwise adding. After the reaction, saturated ammonium chloride (190mL) is added, the water phase is extracted for 1 time by dichloromethane (190mL), the organic phases are combined, saturated saline solution is washed for 2 times (190mL), and the solvent is dried in a spinning mode to obtain a crude compound 1B which is directly put into the next step for reaction.
The base diisopropylethylamine can be replaced by pyridine, triethylamine, DBU or DABCO, the catalyst DMAP can be omitted, and the solvent dichloromethane can be replaced by 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene or acetone.
Example 2
A three-neck flask is charged with compound 1B (100mmol, obtained in example 1) and tetrahydrofuran (152mL), stirred uniformly, cooled to 0-5 ℃, added with lithium tert-butoxide (13.47g,120mmol), stirred at low temperature for 20-30 minutes, added with benzyl bromide (18.81g,110mmol) dropwise, and heated to room temperature for reaction at 25-30 ℃ for 6-8 hours. After the reaction, saturated ammonium chloride (152mL) was added, extraction was performed 3 times with ethyl acetate (152mL), the combined organic phases were washed with saturated brine 1 time (152mL), dried over anhydrous sodium sulfate, and concentrated to give crude 1Ca as an oil, which was directly used for the next reaction.
The lithium tert-butoxide here may be replaced by potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or sodium tert-butoxide.
Example 3
Compound 1Ca (100mmol, from example 2) and tetrahydrofuran (395mL) were added to a three-necked flask, and after stirring, TBAF (94.65g,300mmol) was added thereto, and after the addition, the temperature was raised to 25 to 30 ℃ and the reaction was carried out for 6 to 8 hours. After the reaction, saturated ammonium chloride (152mL) is added, extraction is carried out for 3 times by ethyl acetate (152mL), organic phases are combined, the organic phases are washed by saturated common salt water for 1 time (152mL), dried by anhydrous sodium sulfate, and concentrated to obtain an oily 1Da crude product which is directly put into the next reaction.
Example 4
A three-necked flask was charged with crude compound 1Da (100mmol, from example 3), ethyl acetate (280mL), stirred to dissolve, cooled in an ice bath, added with sodium bicarbonate (16.8g,200mmol), added with TEMPO (313mg,2mmol), added with TCCA (11.62g,150mmol) in portions, and reacted at room temperature for 2-3 hours. After the reaction is finished, 5% dilute hydrochloric acid is added to adjust the pH value to 3-4, most of solid is removed by filtration, liquid separation is carried out, the water phase is extracted for 1 time by ethyl acetate (140mL), organic phase saline solution (156mL) is combined and washed for 1 time, anhydrous sodium sulfate is dried, filtration and concentration are carried out, petroleum ether is added after concentration and pulping is carried out, solid is separated by filtration, and 1Ea (21.19g, 72% in three steps) is obtained by vacuum drying.
Example 5
Compound 1Ea (29.43g,100mmol) was added to a three-necked flask, methylene chloride (294mL) was added thereto and dissolved with stirring, and condensation reagents EDCI (23.00g,120mmol), HOBt (16.22g,120mmol) and morpholine (9.58g,110mmol) were added thereto. DIPEA (19.39g,150mmol) was slowly added dropwise at room temperature, and after completion of the addition, the reaction was carried out at room temperature for 6 to 8 hours. After the reaction was complete, water (294mL) was added, the layers were separated, the aqueous layer was extracted 1 time with dichloromethane (147mL), the combined organic layers were washed with water (294mL), 5% sodium bicarbonate solution (294mL), saturated brine (294mL), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with petroleum ether, the solid was isolated by filtration and dried to give compound 2a (33.43g, 92%).
1H NMR(400MHz,CDCl3)δ7.41-7.24(m,5H),6.08(d,J＝3.8Hz,1H),5.00(d,J＝3.7Hz,1H),4.68(d,J＝11.7Hz,1H),4.64(d,J＝3.8Hz,1H),4.52(d,J＝11.7Hz,1H),4.28(d,J＝3.7Hz,1H),3.87-3.16(m,8H),1.49(s,3H),1.34(s,3H).
Example 6
Adding the compound 1(27.33g,100mmol) and tetrahydrofuran (137mL) into a three-neck flask, uniformly stirring, cooling to 0-5 ℃, adding lithium tert-butoxide (13.47g,120mmol), stirring at low temperature for 20-30 minutes, dropwise adding benzyl bromide (18.81g,110mmol), heating to room temperature of 25-30 ℃ after adding, and reacting for 6-8 hours. After the reaction, saturated ammonium chloride (273mL) was added, the mixture was extracted 3 times with ethyl acetate (137mL), the combined organic phases were washed with saturated brine 1 time (137mL), dried over anhydrous sodium sulfate, concentrated, and then recrystallized from a mixed solvent column of petroleum ether and ethyl acetate, filtered, and dried to obtain compound 2a (30.89g, 85%).
Example 7
Adding the compound 1(27.33g,100mmol) and toluene (137mL) into a three-neck flask, uniformly stirring, cooling to 0-5 ℃, adding sodium tert-butoxide (13.47g,120mmol), stirring at low temperature for 20-30 minutes, dropwise adding PMBBr (22.12g,110mmol), and heating to room temperature of 25-30 ℃ for reaction for 6-8 hours. After completion of the reaction, saturated ammonium chloride (273mL) was added thereto, followed by liquid separation, extraction with ethyl acetate (137mL) 2 times, mixing of organic phases, saturated brine washing 1 time (137mL), drying over anhydrous sodium sulfate, concentration, recrystallization from a mixed solvent column of petroleum ether and ethyl acetate, filtration, and drying to obtain Compound 2b (34.23g, 87%).
MS(ESI)m/z＝394.0[M+H]+
1H NMR(400MHz,CDCl3)δ7.21(d,J＝8.5Hz,2H),6.88(d,J＝8.6Hz,2H),6.07(d,J＝3.7Hz,1H),4.98(d,J＝3.7Hz,1H),4.67-4.55(m,2H),4.45(d,J＝11.4Hz,1H),4.27(d,J＝3.7Hz,1H),3.82(d,J＝4.6Hz,3H),3.78-3.38(m,8H),1.49(s,3H),1.34(s,3H).
Example 8
Adding a compound shown in formula 3a (35.82g,110mmol) and tetrahydrofuran (182mL) into a three-neck flask, stirring and dissolving, cooling to-5-0 ℃ in an ice salt bath, dropwise adding a 2.0M isopropyl magnesium chloride tetrahydrofuran solution (120mmol, 60.0mL) under the protection of nitrogen, and reacting at-5-0 ℃ for 1 hour. Dissolving the compound 2a (36.34g, 100mmol) in tetrahydrofuran (91mL) under the protection of nitrogen, slowly dropping the solution into a reaction bottle, heating to 25-30 ℃ after dropping, reacting for 2-3 hours, slowly adding saturated ammonium chloride solution (182mL) to quench the reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (182mL) for 2 times, combining organic phases, washing with water for 2 times (182mL), drying with sodium sulfate, filtering, concentrating, and recrystallizing with ethyl acetate and petroleum ether to obtain an intermediate 4a (46.03g, 88%).
1H NMR(500MHz,CDCl3)δ7.70(dd,J＝8.3,2.1Hz,1H),7.53(d,J＝2.0Hz,1H),7.38(d,J＝8.3Hz,1H),7.21(t,J＝7.4Hz,1H),7.11(t,J＝7.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.88(d,J＝7.5Hz,2H),6.82–6.77(m,2H),6.08(d,J＝3.7Hz,1H),5.31(d,J＝3.8Hz,1H),4.62(d,J＝3.7Hz,1H),4.47(d,J＝12.2Hz,1H),4.24–4.19(m,2H),4.03–3.95(m,4H),1.48(s,3H),1.39(t,J＝7.0Hz,3H),1.34(s,3H).
Example 9
Adding a compound of formula 3b (40.99g,110mmol) and tetrahydrofuran (197mL) into a three-neck flask, stirring and dissolving, cooling to-5-0 ℃ in an ice-salt bath, dropwise adding a 2.0M isopropyl magnesium chloride tetrahydrofuran solution (120mmol, 60.0mL) under the protection of nitrogen, and reacting at-5-0 ℃ for 1 hour. Dissolving the compound 2b (39.34g, 100mmol) in tetrahydrofuran (98mL) under the protection of nitrogen, slowly dropping the solution into a reaction bottle, heating to 25-30 ℃ after dropping, reacting for 2-3 hours, slowly adding saturated ammonium chloride solution (197mL) to quench the reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (197mL) for 2 times, combining organic phases, washing with water for 2 times (197mL), drying with sodium sulfate, filtering, concentrating, and recrystallizing with ethyl acetate and petroleum ether to obtain an intermediate 4b (50.33g, 91%).
1H NMR(500MHz,CDCl3)δ7.73-7.67(m,1H),7.53-7.35(m,2H),7.25-7.09(m,3H),7.05-6.73(m,5H),6.10(d,J＝3.7Hz,1H),5.28(d,J＝3.8Hz,1H),4.67-4.40(m,2H),4.25-4.17(m,2H),4.05-3.72(m,7H),1.49(s,3H),1.38(t,J＝7.0Hz,3H),1.32(s,3H).
Example 10
Adding a compound 4a (52.30g,100mmol) and methanol (262mL) into a three-neck flask, uniformly stirring, cooling to 0-5 ℃, adding cerium trichloride heptahydrate (44.71g,120mmol), stirring at low temperature for 15-20 minutes, adding sodium borohydride (3.78g,100mmol) in batches, and keeping the temperature of 0-10 ℃ for reacting for 6-8 hours. After the reaction, water (262mL) was added to quench the reaction, a portion of methanol was removed, ethyl acetate (131mL) was added and extracted 3 times, the combined organic phases were washed with saturated brine 1 time (131mL), dried over anhydrous sodium sulfate, concentrated, recrystallized from a mixed solvent column of petroleum ether and ethyl acetate, filtered, and dried to give compound 5a (44.63g, 85%).
Example 11
30% of red aluminum toluene solution (80.86g,120mmol) is added into a three-neck flask, ice bath stirring is carried out for 15-20 minutes, trifluoroethanol (12.00g,120mmol) is slowly dropped in, and reaction is carried out for 30min at 0-5 ℃ after the completion of the addition. Dissolving the compound 4b (55.30g,100mmol) in toluene (277mL), slowly dropping into a reaction flask, and stirring at 0-5 ℃ for 3-4 hours. After the reaction, saturated potassium sodium tartrate solution (553mL) is added dropwise to quench the reaction, ethyl acetate (277mL) is added and stirred until two phases are clarified, ethyl acetate (138mL) is added after liquid separation for extraction for 1 time, organic phases are combined and washed with saturated common salt water for 2 times (138mL), anhydrous sodium sulfate is dried, the organic phases are concentrated and recrystallized by a petroleum ether ethyl acetate mixed solvent column, and the mixture is filtered and dried to obtain compound 5b (49.40g, 89%).
Example 12
The intermediate 5a (52.50g,100mmol) was added to a hydrogenation flask, tetrahydrofuran (263mL) was added to dissolve it, trifluoroacetic acid (53mL) and palladium on carbon (5%, 5.25g) were added, hydrogen was switched in vacuo three times, and the internal temperature was maintained at 40-50 ℃ under pressure with a hydrogen balloon to react for 16-24 hours. After the reaction, the palladium carbon is filtered out by cooling the diatomite, part of the solvent is removed by concentration, ethyl acetate (525mL) is added for dissolution, the solution is washed by saturated sodium bicarbonate and saturated salt water (263mL respectively), dried by anhydrous sodium sulfate, filtered and concentrated to obtain a crude product 6, and the crude product is directly put into the next reaction.
Example 13
The intermediate 5b (55.51g,100mmol) was added to a three-necked flask, and toluene (277mL) was added to dissolve it, and trifluoroacetic acid (56mL) was added thereto, followed by reflux reaction for 20 to 24 hours. After the reaction, the solution was washed with water, saturated sodium bicarbonate, and saturated brine (277mL each), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 6, which was directly subjected to the next reaction.
Example 14
Crude compound 6 (100mmol, from example 7) was dissolved in dichloromethane (395mL), diisopropylethylamine (103.78g,800mmol) and DMAP (1.22g,10mmol) were added, the mixture was stirred well, cooled to 0-5 deg.C, pivaloyl chloride (72.35g,600mmol) was added dropwise, and the mixture was allowed to warm to room temperature overnight. After the reaction, water (395mL) was added, the aqueous phase was extracted with dichloromethane (197mL) 1 time, the combined organic phases were washed with brine 2 times (197mL), part of the solvent was removed, isopropanol and petroleum ether were added, slurried, filtered, and dried to give Compound 7(61.43g, 84% over two steps).
Example 15
Crude compound 6 (100mmol, from example 8) was dissolved in dichloromethane (395mL), diisopropylethylamine (103.78g,800mmol) and DMAP (1.22g,10mmol) were added, the mixture was stirred well and cooled to 0-5 deg.C, pivalic anhydride (111.75g,600mmol) was added dropwise, and the mixture was allowed to warm to room temperature for overnight reaction. After the reaction, saturated ammonium chloride (395mL) was added, the aqueous phase was extracted with dichloromethane (197mL) 1 time, the combined organic phases were washed with saturated brine 2 times (197mL), part of the solvent was removed, isopropanol and petroleum ether were added, and the mixture was slurried, filtered, and dried to give Compound 7(64.36g, 88% over two steps).
Example 16
The intermediate 7(73.13g,100mmol) was added to a reaction flask, and a 30% acetic acid hydrogen bromide solution (220mL) was added thereto, followed by reaction at room temperature for 2 to 3 hours. After the reaction, dichloromethane (731mL) was added to the solution, and the mixture was washed with water, saturated sodium bicarbonate, and saturated brine (365mL each), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 8, which was directly used in the next reaction.
Example 17
Intermediate 8 (from example 11) was added to the reaction flask, and then ethyl acetate was addedAlcohol (730mL), ice-bath is carried out to 0-5 ℃, sodium methyl mercaptide is added, and the temperature is raised to room temperature for reaction for 3-4 hours. After completion of the reaction, methylene chloride (731mL) was added and the mixture was washed with 2% sodium hydroxide, saturated sodium bicarbonate, and saturated brine (365mL each), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with ethanol and petroleum ether, filtered, and dried to obtain Compound 9(56.21g, 83% over two steps).1HNMR(CDCl3)δ7.40-7.20(m,2H),7.15-7.00(m,2H),6.92-6.78(m,2H),5.40-5.31(m,1H),5.28-4.97(m,2H),4.58-4.30(m,2H),4.12-3.97(m,2H),1.76(s,3H),1.39(t,J＝7.2Hz,3H),1.32-1.05(m,27H)
Example 18
Adding the intermediate 7(73.13g,100mmol) into a reaction bottle, adding 1, 2-dichloroethane (730mL), stirring to dissolve, adding thiourea (15.22g,200mmol), then dropwise adding trimethylsilyl trifluoromethanesulfonate (33.34g,150mmol), and heating to reflux for 2-3 hours. Cooling the reaction solution at 25-30 ℃, dropwise adding methyl iodide (22.71g,160mmol), dropwise adding diisopropylethylamine (38.77g,300mmol), washing the solution after the reaction is finished with water and saturated saline solution (365mL respectively), drying with anhydrous sodium sulfate, filtering, concentrating and removing most of the solvent, adding isopropanol (365mL), continuously concentrating and evaporating most of the solvent, adding isopropanol (584mL), heating to 65-70 ℃ and preserving heat for 1 hour, slowly cooling for crystallization, cooling to 0-5 ℃ and preserving heat for pulping for 1-2 hours, filtering, washing a filter cake with a small amount of cold isopropanol, and drying to obtain the compound 9(60.28g, 89%).
Example 19
Adding the compound 9(86.73g,100mmol) into a three-neck flask, adding tetrahydrofuran (237mL), stirring to dissolve, adding sodium methoxide (54g,1000mmol), heating to 40-45 ℃ after adding, and reacting for 2-3 hours. After the reaction is finished, tetrahydrofuran is removed by spinning, water (237mL) is added after the reaction is cooled to room temperature, ethyl acetate (237mL) is added for extraction for 2 times, organic phases are combined, the organic phases are washed with saturated common salt water for 2 times (118mL), sodium sulfate is dried, filtration is carried out, and the organic phases are concentrated and then separated by ethyl acetate and petroleum ether mixed solvent column chromatography to obtain a product, namely Sotagliflozin (39.09g, 92%).
Claims (10)
1. An intermediate compound 2 having the structure shown below,
wherein Pg is a protecting group.
2. Intermediate compound 2 according to claim 1, characterized in that Pg is benzyl or 4-methoxybenzyl (PMB).
3. The synthesis method of the intermediate compound 2 is characterized by comprising the steps of protecting hydroxyl in the L-xylose derivative compound 1 by using a Pg protecting group to obtain an L-xylose derivative compound 2;
4. a process for the synthesis of intermediate compound 2 according to claim 3, characterized by comprising the steps of:
(1) protecting the L-xylose derivative compound 1A with TBSCl under proper conditions to obtain a compound 1B;
(2) protecting the hydroxyl group in the compound 1B with Pg as a protecting group to obtain a compound 1C
(3) Deprotecting the compound 1C under the action of TBAF and completing cyclization reaction to obtain a compound 1D;
(4) carrying out oxidation reaction on the compound 1D to obtain a compound 1E;
(5) carrying out condensation reaction on the compound shown in the formula 1E and morpholine to obtain an intermediate compound 2;
5. intermediate compound 4 having the structure shown below:
wherein Pg is a protecting group.
6. Intermediate compound 4 according to claim 5, characterized in that Pg is benzyl or 4-methoxybenzyl (PMB).
7. The synthesis method of the intermediate compound 4 is characterized by comprising the steps of reacting a compound shown in a formula 3 with an intermediate compound 2 after undergoing a Grignard exchange reaction to obtain an intermediate compound 4;
wherein, X represents halogen Br or I.
8. The method for synthesizing the intermediate compound 4 according to claim 7, wherein the grignard exchange reaction is performed by using isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or a complex of the isopropyl magnesium chloride, the cyclohexyl magnesium chloride or the n-butyl magnesium chloride and lithium chloride to perform grignard exchange with the compound 3, or directly extracting halogen by using butyl lithium or sec-butyl lithium to obtain an aryl lithium reagent; the reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, trifluoromethylbenzene or dichloromethane.
9. A method for synthesizing a compound 6 with a structure shown as follows, which is characterized by comprising the following steps:
(1) carrying out reduction reaction on the compound 4 under a proper system to reduce carbonyl to obtain an intermediate compound 5;
wherein Pg is a protecting group;
(2) deprotecting the compound shown in the formula 5 under the action of acid and completing cyclization reaction to obtain an intermediate compound 6;
10. the method for synthesizing compound 6 according to claim 9, wherein in the deprotection reaction of step (2), when Pg protecting group is PMB, acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol, n-butanol, tert-butanol or acetonitrile; when the Pg protecting group is benzyl, the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid; the catalyst is selected from palladium carbon, palladium hydroxide and palladium oxide; the reducing agent is selected from ammonium formate or hydrogen; the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, isopropanol, n-butanol or tert-butanol.
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