WO2023142238A1 - 一种sglt2抑制剂中间体v-1及其应用 - Google Patents
一种sglt2抑制剂中间体v-1及其应用 Download PDFInfo
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- WO2023142238A1 WO2023142238A1 PCT/CN2022/080950 CN2022080950W WO2023142238A1 WO 2023142238 A1 WO2023142238 A1 WO 2023142238A1 CN 2022080950 W CN2022080950 W CN 2022080950W WO 2023142238 A1 WO2023142238 A1 WO 2023142238A1
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- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 17
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Definitions
- the invention belongs to the technical field of medicinal chemistry, and relates to an SGLT2 inhibitor intermediate V-1 and its application.
- Shown in formula (VI) is a kind of aryl group, heteroaryl group, O-aryl group and O-heteroaryl carbocyclic sugar family compound, is a kind of sodium-dependent glucose transporter 2 (sodium-dependent glucose transporter 2, SGLT2) inhibitor, in the example of CN104909997B, its preparation method is described, but some reaction steps and post-treatment are not suitable for industrial scale-up preparation.
- sodium-dependent glucose transporter 2 sodium-dependent glucose transporter 2, SGLT2
- the target molecule is an all-carbon ring and has many chiral centers.
- the current difficulty in synthesizing this compound lies in the construction of the chiral center ring.
- the control of chirality also has a great risk. Therefore, it is very necessary to find a preparation method that is simple, easy to implement, low in cost, high in yield, good in quality, safe and environmentally friendly, and suitable for industrial production.
- the invention provides an SGLT2 inhibitor intermediate that is simple, easy to implement, low in cost, high in yield, good in quality, safe and environmentally friendly, and suitable for industrial production, and an application thereof.
- the present invention provides a SGLT2 inhibitor intermediate V-1, chemically named as (2S, 3S, 4R, 5R, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) )phenyl)-3,4,5-trihydroxyl-6-(hydroxymethyl)cyclohexane-1-one, the structural formula is as follows:
- R is selected from p-methoxybenzyl, benzyl, trityl, acetyl, benzoyl, pivaloyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldi Phenylsilyl, triisopropylsilyl, 2-tetrahydropyranyl, methoxymethyl or 2-ethoxyethyl.
- the compound represented by formula IV of the present invention can be obtained by referring to the method described in the examples in CN104909997B.
- the preparation method of the SGLT2 inhibitor intermediate V-1 described in the present invention is specifically adding the compound represented by formula IV and the deprotection reagent into a solvent, and reacting at 10-50° C. for 1-10 hours. After the reaction is completed, the Post-treatment, desolventization, and purification to obtain the compound shown in the preparation formula V-1, namely (2S, 3S, 4R, 5R, 6R)-2-(4-chloro-3-(4-ethoxybenzyl)benzene base)-3,4,5-trihydroxy-6-(hydroxymethyl)cyclohexane-1-one.
- the deprotection reagent is palladium on carbon, palladium hydroxide on carbon, tetrabutylammonium bromide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, hydrogen chloride methanol solution, trifluoro One of acetic acid, preferably palladium carbon.
- the amount of the deprotecting reagent used is 5-100 wt%, preferably 10-15 wt%, of the amount of structural formula IV.
- the solvent is one or any combination of tetrahydrofuran, methanol, dichloromethane, ethanol or acetone, preferably tetrahydrofuran.
- the ratio of -chloro-3-(4-ethoxybenzyl)phenyl)cyclohexanone to solvent is 1 g/(5-12) ml.
- the reagent used for refining is methanol, isopropanol, ethanol, acetone, ethyl acetate or acetonitrile, preferably acetonitrile.
- the present invention provides the use of the SGLT2 inhibitor intermediate V-1 in the preparation of the SGLT2 inhibitor represented by formula (VI).
- the method for the compound represented by formula VI is as follows: add intermediate V-1, catalyst and triethylamine to the solvent, add trifluoroacetyl chloride at -5 to 5°C, react at room temperature, wash, After drying and filtering, add diethylaminosulfur trifluoride and absolute ethanol, react at 15-25°C for 60-80h, add potassium carbonate aqueous solution, and react at 20-30°C for 3-5h to obtain compound VI.
- the catalyst in the synthesis of the compound represented by formula VI is selected from DMF or DMAP.
- the molar ratio of intermediate V-1, catalyst and triethylamine in the synthesis of the compound shown in formula VI is 1:(0.1 ⁇ 0.5):(6 ⁇ 8); preferably 1:(0.1 ⁇ 0.2): (6 ⁇ 8).
- the molar ratio of intermediate V-1 to trifluoroacetyl chloride in the synthesis of the compound represented by formula VI is 1:(5-7).
- the molar ratio of intermediate V-1 to diethylaminosulfur trifluoride in the synthesis of the compound represented by formula VI is 1: (10-20), preferably 1:15.
- the weight of absolute ethanol added is 1 ⁇ ⁇ 5 ⁇ of the intermediate V-1, preferably 2 ⁇ ⁇ 3 ⁇ .
- the present invention also provides a method for preparing the SGLT2 inhibitor represented by formula VI:
- R is selected from p-methoxybenzyl, benzyl, trityl, acetyl, benzoyl, pivaloyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldi Phenylsilyl, triisopropylsilyl, 2-tetrahydropyranyl, methoxymethyl or 2-ethoxyethyl; preferably, R is selected from benzyl.
- the starting material 14-iodo-1-chloro-2-(4-ethoxybenzyl)benzene of the present invention can be purchased from the market, and the starting material 2 can be obtained by referring to the method described in the examples in CN104909997B.
- the synthetic method of the compound shown in formula I is specifically: 4-iodo-1-chloro-2-(4-ethoxybenzyl)benzene (i.e. material 1), material 2 and metal reagent Ratio (1.05-1.25): 1.0: (1.0-1.5) is added to the solvent and reacted at -20 ⁇ -70°C for 1 ⁇ 3 hours.
- the mol ratio of 4-iodo-1-chloro-2-(4-ethoxybenzyl)benzene (i.e. material 1), material 2 and metal reagent in the synthesis of compounds shown in formula I is (1.1 -1.2):1:(1.3-1.35).
- reaction temperature in the synthesis of the compound represented by formula I is -25 to -35°C.
- the metal reagent in the synthesis of the compound represented by formula I is isopropylmagnesium chloride-lithium chloride or n-butyllithium.
- the solvent used in the synthesis of the compound shown in formula I is one or a combination of methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and the preferred solvent is tetrahydrofuran or 2-methyltetrahydrofuran ;
- the ratio of material 2 to solvent is 1g/(5 ⁇ 10)ml.
- the side reaction refers to the removal of impurities by the double halogen in compound 1, which is also the most difficult impurity with similar polarity in VI.
- the synthesis method of the compound shown in formula II is specifically: adding the compound of formula I, triethylsilane, and boron trifluoride diethyl ether into the solvent according to the molar ratio of 1.0:(1.5-3.5):(1.1-2.0) , -30 ⁇ 0 ° C reaction for 1-2 hours, after the reaction, the solvent is washed with alkaline water, the water layer is discarded, the solvent is removed, and the compound shown in formula II is purified.
- the molar ratio of the compound of formula I, triethylsilane, and boron trifluoride to diethyl ether in the synthesis of the compound shown in formula II is 1.0: (2.1-2.7): (1.45-1.8).
- reaction temperature in the synthesis of the compound represented by formula II is -28 to -15°C.
- the solvent used in the synthesis of the compound shown in formula II is isopropyl acetate, cyclohexane, dichloromethane, isopropyl ether or acetonitrile, and the preferred solvent is dichloromethane; in some embodiments, formula I
- the ratio of compound to solvent is 1g/(2-15)ml.
- the alkaline water used in the synthesis of the compound represented by formula II is sodium bicarbonate solution, sodium carbonate solution or sodium hydroxide solution, preferably sodium bicarbonate solution.
- the reagent used in the purification of the compound represented by formula II is one or any combination of acetonitrile, isopropanol, methanol, ethanol, isopropyl ether, ethyl acetate or n-heptane, preferably methanol.
- the synthesis method of the compound represented by formula II of the present invention uses recrystallization instead of column chromatography for purification, which is more conducive to industrial scale-up.
- the synthesis method of the compound represented by formula III is as follows: adding the compound represented by formula II and the reducing agent into the solvent according to the molar ratio of 1.0: (1.1-2.5), and reacting at 40-70 ° C for 1-7 hours; After the end, the temperature of the reaction solution was lowered to -5 ⁇ 30°C.
- the molar ratio of the compound shown in formula II: sodium hydroxide: H 2 O 2 was 1.0: (3-10): (3-10), at 15 ⁇ 40
- the oxidation reaction was continued for 12-15 hours at °C, and the reaction was completed, and the reaction solution was washed, extracted, concentrated, and refined to obtain the compound represented by formula III.
- the molar ratio of the compound represented by the formula II to the reducing agent in the synthesis of the compound represented by the formula III is 1.0: (1.4-1.6).
- reaction temperature in the synthesis of the compound represented by formula III is 60-70°C; in some examples, after the reaction is completed, the temperature is lowered to 0-15°C.
- the molar ratio of compound represented by formula II: sodium hydroxide: H 2 O 2 is 1.0: (7.5-9.5): (8.0-9.0).
- the temperature for continuing the oxidation reaction in the synthesis of the compound represented by formula III is 25-33°C.
- the reducing agent in the synthesis of the compound shown in formula III is borane dimethyl sulfide, sodium borohydride, pinacol borane, 8-methoxy-9-borabicyclo[3.3.1]nonane alkane or borane tetrahydrofuran complex, preferably borane dimethyl sulfide or borane tetrahydrofuran complex.
- the solvent used in the synthesis of the compound shown in formula III is one or a combination of toluene, tetrahydrofuran, 1,4-dioxane, and dichloromethane, preferably tetrahydrofuran; in some examples, formula II
- the ratio of compound to solvent shown is 1 g/(6-14) ml.
- the reagent used for purification in the synthesis of the compound shown in formula III is one of acetonitrile, n-heptane, methyl tert-butyl ether, ethanol, isopropyl ether, ethyl acetate or any combination thereof, preferably iso Propyl ether.
- the synthesis method of the compound represented by formula III in the present invention uses recrystallization instead of column chromatography for purification, which is more conducive to industrial scale-up.
- the synthesis method of the compound shown in formula IV is as follows: adding the compound shown in formula III and the oxidizing agent into the solvent according to the molar ratio of 1.0: (1.0-4.0), and reacting for 1-5 hours at -5 ⁇ 30°C; After completion, the reaction solution was washed with water by a reducing agent, the water layer was discarded, the solvent was removed, and the compound represented by formula IV was purified.
- the molar ratio of the compound represented by formula III to the oxidizing agent in the synthesis of the compound represented by formula IV is 1.0: (1.5-1.8).
- reaction temperature in the synthesis of the compound represented by formula IV is 5-15°C.
- the oxidizing agent used in the synthesis of the compound represented by formula IV is manganese dioxide, Dess Martin oxidizing agent, Jones reagent or 2,2,6,6-tetramethylpiperidine oxide, preferably Dess Martin oxidizing agent.
- the solvent used in the synthesis of the compound shown in formula IV is one or a combination of isopropyl ether, dichloromethane, tetrahydrofuran, toluene, acetonitrile, preferably dichloromethane; in some embodiments, formula III
- the ratio of compound to solvent shown is 1 g/(3-15) ml.
- the reagent used in the purification of the compound represented by formula IV is isopropyl ether, isopropanol, ethanol, acetone, ethyl acetate or tetrahydrofuran, preferably the reagent isopropanol.
- the reaction time is about 1-5 hours, which can significantly shorten the time compared with the 12-18 hours of the original research.
- the synthesis method of the compound represented by formula V-1 is as follows: adding the compound represented by formula IV and the deprotection reagent into a solvent, reacting at 10-50°C for 1-10h, after the reaction is completed, post-treatment and desolventization , refining the compound shown in formula V-1.
- the deprotection reagent in the synthesis of the compound shown in formula V-1 is palladium carbon, palladium hydroxide carbon, tetrabutylammonium bromide, 2,3-dichloro-5,6-dicyano-p-benzoquinone , hydrogen chloride methanol solution, and trifluoroacetic acid, preferably palladium carbon.
- the amount of the deprotecting reagent used in the synthesis of the compound represented by formula V-1 is 5-100 wt%, preferably 10-18 wt%, of that of structural formula IV.
- the solvent in the synthesis of the compound represented by formula V-1 is one or any combination of tetrahydrofuran, methanol, dichloromethane, ethanol or acetone, preferably tetrahydrofuran.
- the ratio of the compound of formula IV to the solvent in the synthesis of the compound of formula V-1 is 1 g/(5-12) ml.
- the reagent used in the purification of the compound represented by formula V-1 is methanol, isopropanol, ethanol, acetone, ethyl acetate or acetonitrile, preferably acetonitrile.
- the synthesis method of the compound represented by formula VI is as follows: adding intermediate V-1, catalyst and triethylamine to the solvent, adding trifluoroacetyl chloride at -5 to 5°C, reacting at room temperature, washing, After drying and filtering, add diethylaminosulfur trifluoride and absolute ethanol, react at 15-25°C for 60-80h, add potassium carbonate aqueous solution, and react at 20-30°C for 3-5h to obtain compound VI.
- the catalyst in the synthesis of the compound represented by formula VI is selected from DMF or DMAP.
- the molar ratio of intermediate V-1, catalyst and triethylamine in the synthesis of the compound shown in formula VI is 1:(0.1 ⁇ 0.5):(6 ⁇ 8); preferably 1:(0.1 ⁇ 0.2): (6 ⁇ 8).
- the molar ratio of intermediate V-1 to trifluoroacetyl chloride in the synthesis of the compound represented by formula VI is 1:(5-7).
- the molar ratio of intermediate V-1 to diethylaminosulfur trifluoride in the synthesis of the compound represented by formula VI is 1: (10-20), preferably 1:15.
- the weight of absolute ethanol added is 1 ⁇ ⁇ 5 ⁇ of the intermediate V-1, preferably 2 ⁇ ⁇ 3 ⁇ .
- the present invention provides an intermediate compound V-1 with a full carbon ring and a multichiral center structure and its application in the preparation of VI.
- the preparation process of VI provided by the present invention is simple, low in cost, safe and environmentally friendly, and suitable for industrial production;
- the purity of the final product obtained from compound V-1 is as high as 97%, the yield can reach about 80%, and the chirality is well controlled, which is conducive to providing high-quality SGLT2 inhibitor compounds at a lower cost.
- Fig. 1 is the NMR hydrogen spectrogram of compound V-1
- Fig. 2 is the NMR carbon spectrogram of compound V-1
- Fig. 3 is the IR spectrum of compound V-1;
- Fig. 4 is the UV spectrum of compound V-1;
- Fig. 5 is the LC-MS collection of spectra of compound V-1;
- Fig. 6 is the HPLC spectrum of compound V-1.
- Embodiment 1 R is the preparation of the compound V-1 of benzyl
- reaction progress was detected by HPLC; after the reaction was completed, the reaction solution was slowly added to 65 mL of an aqueous solution containing 6 g of anhydrous Na 2 SO 3 and 5 g of NaHCO 3 , and stirred for 30 minutes. Let stand, separate the liquid, and collect the organic phase. The aqueous phase was extracted with 30 g of dichloromethane, and the organic phases were combined. Wash the organic phase with 30 g of purified water, separate the liquid, collect the organic phase, add 7 g of anhydrous sodium sulfate to dry for 30 min, filter, collect the filtrate, and concentrate under reduced pressure at 30 ⁇ 3°C to obtain a yellow-brown oil.
- Embodiment 2 R is the preparation of the compound V-1 of p-methoxybenzyl
- reaction solution is slowly added to 200g 10% ammonium chloride solution to quench, then add 150g ethyl acetate for extraction, separate the liquids, and the organic phase is washed with 230g saturated sodium chloride, and the organic phase is taken.
- the phase was dried and concentrated under reduced pressure at 40-45° C. until no fraction flowed out to obtain 45.1 g of a brown oil with a yield of 102.4%.
- reaction progress was detected by HPLC; after the reaction was completed, the reaction solution was slowly added to 80 mL of an aqueous solution containing 7.3 g of anhydrous Na 2 SO 3 and 6 g of NaHCO 3 , and stirred for 30 minutes. Let stand, separate the liquid, and collect the organic phase. The aqueous phase was extracted with 38 g of dichloromethane, and the organic phases were combined. Wash the organic phase with 40g of purified water, separate the liquid, collect the organic phase, add 8.2g of anhydrous sodium sulfate to dry for 30min, filter, collect the filtrate, and concentrate under reduced pressure at 30 ⁇ 4°C to obtain a yellow-brown oil.
- Embodiment 3 R is the preparation of the compound V-1 of p-methoxybenzyl
- reaction solution was slowly added to 220g of 10% ammonium chloride solution to quench, and then 170g of ethyl acetate was added for extraction, liquid separation, and the organic phase was washed with 265g of saturated sodium chloride, and the organic phase was dried, and the Concentrate under reduced pressure at 40-45°C until no distillate flows out to obtain 46.8 g of brown oil, with a yield of 106.2%.
- reaction progress was detected by HPLC; after the reaction was completed, the reaction solution was slowly added to 78 mL of an aqueous solution containing 7.0 g of anhydrous Na 2 SO 3 and 5.3 g of NaHCO 3 , and stirred for 30 minutes. Let stand, separate the liquid, and collect the organic phase. The aqueous phase was extracted with 42 g of dichloromethane, and the organic phases were combined. Wash the organic phase with 38 g of purified water, separate the liquid, collect the organic phase, add 5.9 g of anhydrous sodium sulfate to dry for 30 min, filter, collect the filtrate, and concentrate under reduced pressure at 30 ⁇ 5°C to obtain a yellow-brown oil.
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Abstract
一种SGLT2抑制剂中间体V-1及其应用,具体涉及一种如式V-1所示的中间体,以及其在制备SGLT2抑制剂中的应用;所述中间体及其制备SGLT2抑制剂的方法原料易得,操作简单,生产周期短,收率高,适合工业化生产。
Description
本发明属于医药化学技术领域,涉及一种SGLT2抑制剂中间体V-1及其应用。
式(VI)所示的为一种芳基、杂芳基、O-芳基和O-杂芳基碳环糖家族化合物,是一种钠依赖性葡萄糖共转运蛋白2(sodium-dependent glucose transporter 2,SGLT2)抑制剂,在CN104909997B实施例中,记载了其制备方法,但是部分反应步骤和后处理均不适合工业化放大制备。如各步骤后处理均使用了柱层析的方法来固化提纯;氧化步骤反应温度过低,反应速度较慢,增加能耗;氟化步骤反应温度较高,有氟化试剂(沸点30℃)爆炸风险且高温的氟化试剂蒸汽对设备的腐蚀能力变强等问题。
该目标分子为全碳环,并且手性中心较多,目前合成该化合物分子难点在于手性中心环的构建;同时,对于这种多羟基取代结构,手性的控制也有很大的风险。因此,寻找一种简单易行、成本较低、收率较高、质量较好、安全环保、适合工业化生产的制备方法是非常必要的。
发明内容
本发明提供一种简单易行、成本较低、收率较高、质量较好、安全环保、适合工业化生产的SGLT2抑制剂中间体以及其应用。
第一方面,本发明提供一种SGLT2抑制剂中间体V-1,化学名为(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮,结构式如下:
第二方面,本发明所述SGLT2抑制剂中间体V-1的制备方法:
其中,R选自对甲氧基苄基、苄基、三苯甲基、乙酰基、苯甲酰基、特戊酰基、三甲基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、2-四氢吡喃基、甲氧基甲基或2-乙氧基乙基。
本发明式IV所示化合物可以参照CN104909997B中实施例记载的方法获得。
在一些实例中,本发明所述的SGLT2抑制剂中间体V-1的制备方法,具体为式IV所示化合物与脱保护试剂加入溶剂中,10-50℃反应1-10h,反应结束,经后处理、脱溶剂、精制制得制备式V-1所示化合物,即(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮。
在一些实例中,所述的脱保护试剂为钯碳、氢氧化钯碳、四丁基溴化铵、2,3-二氯-5,6-二氰对苯醌、氯化氢甲醇溶液、三氟乙酸中的一种,优选为钯碳。
在一些实例中,所用脱保护试剂用量为为结构式IV用量的5-100wt%,优选10-15wt%。
在一些实例中,所述溶剂为四氢呋喃、甲醇、二氯甲烷、乙醇或丙酮中的一种或其任意组合,优选四氢呋喃。
在一些实例中,(2R,3R,4R,5S,6S)-3,4,5-三(R保护基氧基)-2-((R保护基氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮与溶剂的比例为1g/(5~12)ml。
在一些实施例中,精制所用的试剂为甲醇、异丙醇、乙醇、丙酮、乙酸乙酯或乙腈,优选乙腈。
第三方面,本发明提供所述SGLT2抑制剂中间体V-1在用于制备式(VI)所示的SGLT2抑制剂中的应用。
在一些实施例中,式VI所示化合物的方法具体为:中间体V-1、催化剂和三乙胺加入到溶剂中,于-5~5℃下加入三氟乙酰氯,室温反应,洗涤、干燥、过滤后加入二乙胺基三氟化硫和无水乙醇,15~25℃反应60~80h,加入碳酸钾水溶液后于20~30℃反应3-5h得VI化 合物。
在一些实施例中,式VI所示化合物的合成中的催化剂选自DMF或DMAP。
在一些实施例中,式VI所示化合物的合成中中间体V-1、催化剂和三乙胺的摩尔比为1:(0.1~0.5):(6~8);优选为1:(0.1~0.2):(6~8)。
在一些实施例中,式VI所示化合物的合成中中间体V-1与三氟乙酰氯的摩尔比为1:(5-7)。
在一些实施例中,式VI所示化合物的合成中中间体V-1与二乙胺基三氟化硫的摩尔比为1:(10~20),优选1:15。
在一些实施例中,式VI所示化合物的合成中无水乙醇加入重量为中间体V-1的1‰~5‰,优选2‰~3‰。
第四方面,本发明还提供一种式VI所示的SGLT2抑制剂的制备方法:
其中,R选自对甲氧基苄基、苄基、三苯甲基、乙酰基、苯甲酰基、特戊酰基、三甲基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、2-四氢吡喃基、甲氧基甲基或2-乙氧基乙基;优选的,R选自苄基。
本发明起始物料14-碘-1-氯-2-(4-乙氧基苄基)苯可以通过市面购买,起始物料2可参照CN104909997B中实施例记载的方法获得。
在一些实例中,式I所示化合物的合成方法具体为:将4-碘-1-氯-2-(4-乙氧基苄基)苯(即物料1)、物料2和金属试剂按照摩尔比(1.05-1.25):1.0:(1.0-1.5)加入到溶剂中,-20~-70℃反应1~3小时。
在一些实例中,式I所示化合物的合成中4-碘-1-氯-2-(4-乙氧基苄基)苯(即物料1)、物料2和金属试剂的摩尔比为(1.1-1.2):1:(1.3-1.35)。
在一些实例中,式I所示化合物的合成中反应温度为-25~-35℃。
在一些实例中,式I所示化合物的合成中金属试剂为异丙基氯化镁-氯化锂或正丁基锂。
在一些实例中,式I所示化合物的合成中所用溶剂为甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、甲苯中的一种或组合物,优选溶剂为四氢呋喃或2-甲基四氢呋喃;在一些实例中物料2与溶剂的比例为1g/(5~10)ml。
本发明所述的式I所示化合物的合成方法,将加料顺序进行调整,能极大程度避免副反应的发生。该副反应指在化合物1发生的双卤素脱除杂质,该杂质也是VI中最难除去的极性相近的杂质。
在一些实例中,式II所示化合物的合成方法具体为:将式I化合物、三乙基硅烷、三氟化硼乙醚按照摩尔比1.0:(1.5-3.5):(1.1-2.0)加入溶剂中,-30~0℃反应1-2小时,反应结束后,溶剂用碱水洗,弃掉水层,脱去溶剂,精制制得式II所示化合物。
在一些实例中,式II所示化合物的合成中式I化合物、三乙基硅烷、三氟化硼乙醚摩尔比为1.0:(2.1-2.7):(1.45-1.8)。
在一些实例中,式II所示化合物的合成中反应温度为-28~-15℃。
在一些实例中,式II所示化合物的合成中所用溶剂为乙酸异丙酯、环己烷、二氯甲烷、异丙醚或乙腈,优选溶剂为二氯甲烷;在一些实施例中,式I化合物与溶剂的比例为1g/(2~15)ml。
在一些实例中,式II所示化合物的合成中的碱水为碳酸氢钠溶液、碳酸钠溶液或氢氧化钠溶液,优选碳酸氢钠溶液。
在一些实例中,式II所示化合物的合成中精制所用试剂为乙腈、异丙醇、甲醇、乙醇、异丙醚、乙酸乙酯或正庚烷中的一种或其任意组合,优选甲醇。
本发明所述的式II所示化合物的合成方法,用重结晶代替了柱层析来提纯,更利于工业放大。
在一些实例中,式III所示化合物的合成方法具体为:将式II所示化合物、还原剂按照摩尔比1.0:(1.1-2.5)加入溶剂中,40~70℃反应1-7小时;反应结束后,反应液降温至-5~30℃,按照式II所示化合物:氢氧化钠:H
2O
2的摩尔比为1.0:(3-10):(3-10),于15~40℃继续氧化反应12-15小时,反应完毕,反应液经洗涤、萃取、浓缩、精制得式III所示化合物。
在一些实例中,式III所示化合物的合成中式II所示化合物和还原剂的摩尔比为1.0:(1.4-1.6)。
在一些实例中,式III所示化合物的合成中反应温度为60~70℃;在一些实例中,反应结束后,降温至度0~15℃。
在一些实例中,式III所示化合物的合成中式II所示化合物:氢氧化钠:H
2O
2的摩尔比为1.0:(7.5-9.5):(8.0-9.0)。
在一些实例中,式III所示化合物的合成中继续氧化反应的温度为25~33℃。
在一些实例中,式III所示化合物的合成中还原剂为硼烷二甲硫醚、硼氢化钠、频哪醇硼烷、8-甲氧基-9-硼杂双环[3.3.1]壬烷或硼烷四氢呋喃络合物,优选硼烷二甲硫醚或硼烷四氢呋喃络合物。
在一些实例中,式III所示化合物的合成中所用溶剂为甲苯、四氢呋喃、1,4-二氧六环、二氯甲烷中的一种或组合物,优选四氢呋喃;在一些实例中,式II所示化合物与溶剂的比例为1g/(6~14)ml。
在一些实例中,式III所示化合物的合成中精制所用试剂为乙腈、正庚烷、甲基叔丁基醚、乙醇、异丙醚、乙酸乙酯中的一种或其任意组合,优选异丙醚。
本发明所述的式III所示化合物的合成方法,用重结晶代替了柱层析来提纯,更利于工业放大。
在一些实例中,式IV所示化合物的合成方法具体为:将式III所示化合物和氧化剂按照摩尔比1.0:(1.0-4.0)加入溶剂中,-5~30℃反应1-5小时;反应结束后,反应液用还原剂进行水洗,弃掉水层,脱去溶剂,精制制得式IV所示化合物。
在一些实例中,式IV所示化合物的合成中式III所示化合物和氧化剂的摩尔比为1.0:(1.5-1.8)。
在一些实例中,式IV所示化合物的合成中反应温度为5~15℃。
在一些实例中,式IV所示化合物的合成中所用氧化剂为二氧化锰、戴斯马丁氧化剂、琼斯试剂或2,2,6,6-四甲基哌啶氧化物,优选戴斯马丁氧化剂。
在一些实例中,式IV所示化合物的合成中所用溶剂为异丙醚、二氯甲烷、四氢呋喃、甲苯、乙腈中的一种或组合物,优选二氯甲烷;在一些实施例中,式III所示化合物与溶剂的比例为1g/(3~15)ml。
在一些实例中,式IV所示化合物的合成中精制所用试剂为异丙醚、异丙醇、乙醇、丙酮、乙酸乙酯或四氢呋喃,优选试剂异丙醇。
本发明所述的式IV所示化合物的合成方法,反应时间大概在1-5小时,相对于原研的12-18小时,可以显著缩短时间。
在一些实例中,式V-1所示化合物的合成方法具体为:将式IV所示化合物与脱保护试剂加入溶剂中,10-50℃反应1-10h,反应结束,经后处理、脱溶剂、精制制得式V-1所示化合物。
在一些实例中,式V-1所示化合物的合成中脱保护试剂为钯碳、氢氧化钯碳、四丁基溴化铵、2,3-二氯-5,6-二氰对苯醌、氯化氢甲醇溶液、三氟乙酸中的一种,优选为钯碳。
在一些实例中,式V-1所示化合物的合成中所用脱保护试剂用量为为结构式IV用量的5-100wt%,优选10-18wt%。
在一些实例中,式V-1所示化合物的合成中溶剂为四氢呋喃、甲醇、二氯甲烷、乙醇或丙酮中的一种或其任意组合,优选四氢呋喃。
在一些实例中,式V-1所示化合物的合成中式IV化合物与溶剂的比例为1g/(5~12)ml。
在一些实施例中,式V-1所示化合物的合成中精制所用的试剂为甲醇、异丙醇、乙醇、丙酮、乙酸乙酯或乙腈,优选乙腈。
在一些实例中,式VI所示化合物的合成方法具体为:中间体V-1、催化剂和三乙胺加入到溶剂中,于-5~5℃下加入三氟乙酰氯,室温反应,洗涤、干燥、过滤后加入二乙胺基三氟化硫和无水乙醇,15~25℃反应60~80h,加入碳酸钾水溶液后于20~30℃反应3-5h得VI化合物。
在一些实施例中,式VI所示化合物的合成中的催化剂选自DMF或DMAP。
在一些实施例中,式VI所示化合物的合成中中间体V-1、催化剂和三乙胺的摩尔比为1:(0.1~0.5):(6~8);优选为1:(0.1~0.2):(6~8)。
在一些实施例中,式VI所示化合物的合成中中间体V-1与三氟乙酰氯的摩尔比为1:(5-7)。
在一些实施例中,式VI所示化合物的合成中中间体V-1与二乙胺基三氟化硫的摩尔比为1:(10~20),优选1:15。
在一些实施例中,式VI所示化合物的合成中无水乙醇加入重量为中间体V-1的1‰~5‰,优选2‰~3‰。
本发明提供了全碳环、多手性中心结构中间体化合物V-1及其在制备VI中的应用,本发明提供的VI的制备工艺简单,成本低,安全环保,适合工业化生产;通过中间体化合物V-1制得的终产物纯度高达97%以上、收率可达80%左右,且手性控制好,有利于以较低的成本提供高品质的SGLT2抑制剂化合物。
图1为化合物V-1的NMR氢谱图;
图2为化合物V-1的NMR碳谱图;
图3为化合物V-1的IR图谱;
图4为化合物V-1的UV图谱;
图5为化合物V-1的LC-MS图谱;
图6为化合物V-1的HPLC图谱。
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到,或者通过文献报道方法可以获得。
实施例1 R为苄基的化合物V-1的制备
1)(2R,3S,4R)-2,3,4-三(苄氧基)-5-((苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇(式I)
向洁净干燥的反应瓶中加入98g(110ml)无水四氢呋喃,继续加入15.6g(41.86mmol,1.12eq)4-碘-1-氯-2-(4-乙氧基苄基)苯搅拌溶解,氮气置换,降温至-25~-30℃,滴加35.34g(48.39mmol,1.3eq)异丙基氯化镁/氯化锂溶液。滴加完毕,在-25~-30℃继续反应1h,用HPLC检测起始原料剩余。反应完成后,将19.9g(37.22mmol,1.0eq)(4R,5S,6R)-4,5,6-三(苄氧基)-3-((苄氧基)甲基)环己-2-烯-1-酮溶于20g四氢呋喃中,并控温-25~-30℃滴加进反应瓶中,滴加完毕,继续保温搅拌1小时,用HPLC检测反应进程;反应完成后,将反应液缓慢加至130g 10%氯化铵溶液中淬灭,再加入110g乙酸乙酯萃取,分液,有机相用150g饱和氯化钠洗涤,取有机相干燥,于40~45℃减压浓缩至无馏分流出,得棕色油状物31.1g,收率106.9%。
2)(2R,3S,4R,5R)-2,3,4-三(苄氧基)-5-((苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5- 四氢-1,1′-联苯(式II)
向洁净干燥的反应瓶中加入170g(130ml)二氯甲烷,再加入(2R,3S,4R)-2,3,4-三(苄氧基)-5-((苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇29g(37.11mmol,1.0eq),氮气置换后,降温至-25~-15℃,滴加9.7g(83.42mmol,2.25eq)三乙基硅烷,滴加完毕后继续滴加7.9g(55.67mmol,1.50eq)三氟化硼乙醚,滴加完毕继续保温反应1小时;用HPLC检测反应进程;反应完成后,控制温度在15℃以下,向反应液中加入58g纯化水,有机相用88g饱和碳酸氢钠水溶液洗涤至中性,再用88g饱和食盐水洗涤,收集有机相。有机相37±3℃减压浓缩直至无馏分流出,浓缩所得油状物加入110g甲醇加热到70~80℃,后降温至10~15℃,搅拌析晶16小时。抽滤,用30g甲醇淋洗,再抽滤得湿品20.5g,于50±3℃真空干燥12小时淡黄色固体17.04g,纯度95.4%,收率60.0%。
3)(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇(式III)
向干燥、洁净的反应瓶中加入130.0g(146ml)无水四氢呋喃,继续加入15.7g(20.51mmol,1.00eq)的(2R,3S,4R,5R)-2,3,4-三(苄氧基)-5-((苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5-四氢-1,1′-联苯,氮气置换,体系溶清后,控温20~30℃缓慢加入2.4g(30.77mmol,1.50eq)硼烷二甲硫醚溶液。滴加完毕,缓慢加热至60~70℃反应2.5小时。用HPLC检测反应进程;反应完成后,反应液降温至0~10℃,并保温缓慢滴加5mol/L氢氧化钠溶液39.6g(167.0mmol,8.15eq),然后继续保温缓慢滴加30%的过氧化氢溶液18.7g(165.0mmol,8.04eq)。滴加完毕,缓慢升温至25~30℃继续反应15小时。向反应液中加入饱和氯化铵水溶液150g、78g饱和氯化钠溶液搅拌1小时。静置、分液,收集有机相。水相用75g乙酸乙酯萃取一次,合并有机相。有机相用10%Na
2SO
3溶液80g洗涤,收集有机相,并用碘化钾试纸检测不变色。有机相于40~45℃减压浓缩,直至无馏分流出。所得油状物加入35g异丙醚于20~25℃搅拌12h,抽滤,收集湿品在45±3℃真空干燥10h得8.5g类白色固体,纯度92.1%,收率52.9%。
4)制备式IV所示(2R,3R,4R,5S,6S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮
向干燥、洁净的反应瓶中加入75g(58ml)二氯甲烷和7g(8.94mmol,1.0eq)(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇,搅拌溶解。降温至5~12℃,加入5.8g(13.67mmol,1.53eq)戴斯马丁氧化剂,保温8~15℃反应2.5小时。用HPLC检测反应进程;反应完成后,将反应液缓慢加入65mL含有6g无水Na
2SO
3、5g NaHCO
3的水溶液中,搅拌30分钟。静置、分液,收集有机相。水相用30g二氯甲烷萃取,合并有机相。用30g纯化水洗涤有机相,分液,收集有机相,加入7g无水硫酸钠干燥30min, 过滤,收集滤液,于30±3℃进行减压浓缩,得到黄棕色油状物。油状物中加入10g异丙醇,加热至70~80℃溶解,缓慢降温,于20~25℃保温搅拌析晶16小时。过滤、收集物料于真空烘箱中50±3℃干燥10小时,得5.5g(2R,3R,4R,5S,6S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮,纯度为94.7%,收率78.7%。
5)制备式V-1所示的(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮
将5g(6.40mmol,1.0eq)的(2R,3R,4R,5S,6S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮、25g(28ml)四氢呋喃加入到100mL的氢化釜中,搅拌溶清,再加入5%钯碳0.7g搅拌均匀。开启搅拌,转速25Hz。先氮气置换三次,再用氢气置换三次。控温20~30℃,氢气压力0.09~0.13MPa,反应70min,用HPLC检测反应进程;反应完成后,放空氢气,氮气置换三次,过滤除去钯碳,用4g四氢呋喃淋洗滤饼。合并滤液,45±3℃减压浓缩至干,加入8.5g乙腈加热回流。溶清后,缓慢降温,于40~50℃保温析晶2小时。降温至0~10℃继续析晶,并在0~10℃搅拌1小时。过滤,滤饼在50±3℃真空干燥8小时,得2.2g白色粉末状固体,纯度为98.4%,收率81.7%。
6)制备式VI所示的(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟基甲基)环己烷-1,2,3-三醇
将5g(11.9mmol,1.0eq)的(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮、48g(15ml)二氯甲烷、0.09g(1.2mmol,0.1eq)DMF及9g(89.3mmol,7.5eq)三乙胺加入到洁净、干燥的反应瓶中,氮气置换并保护。降温至-5℃~5℃,缓慢滴加11g(83.3mmol,7.0eq)三氟乙酰氯,滴加结束后,在室温反应8小时,HPLC监控反应终点。反应完成后,加入48g(15ml)二氯甲烷稀释反应液,2N盐酸水溶液洗一次、饱和碳酸氢钠水溶液洗一次,饱和食盐水洗涤一次,有机相干燥过夜,过滤后将滤液转移至干燥的反应瓶中,继续加入二乙胺基三氟化硫27g(168mmol,15.0eq)、无水乙醇0.015g(3‰M
SM),加热至20℃反应72h,冰水淬灭、中和、洗涤、分出有机相浓缩至一半料液体积,加入15ml的5%碳酸钾水溶液于20~25℃搅拌4h。过滤,滤饼用水打浆并再次过滤后即得式(VI)粗品。将该粗品投至15ml乙腈中,加热回流。溶清后缓慢降温,于40~50℃保温析晶1小时。降温至0~10℃,并在0~10℃继续搅拌1小时。过滤,滤饼在50±3℃真空干燥8小时,得4.48g白色粉末状固体,纯度为98.8%,收率85.0%。
化合物V-1的表征数据如图1-图6和表1所示。
表1化合物V-1的表征数据
实施例2 R为对甲氧基苄基的化合物V-1的制备
1)(2R,3S,4R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇(式I)
向洁净干燥的反应瓶中加入150g(170ml)无水四氢呋喃,继续加入22.0g(59.04mmol,1.20eq4-碘-1-氯-2-(4-乙氧基苄基)苯搅拌溶解,氮气置换,降温至-25~-30℃,滴加46.4g(63.53mmol,1.30eq)异丙基氯化镁/氯化锂溶液。滴加完毕,在-25~-30℃继续反应1h,用HPLC检测起始原料剩余。反应完成后,将32.0g(48.87mmol,1.0eq)(4R,5S,6R)-4,5,6-三(对甲氧基苄氧基)-3-((对甲氧基苄氧基)甲基)环己-2-烯-1-酮溶于35g四氢呋喃中,并控温-25~-35℃滴加进反应瓶中,滴加完毕,继续保温搅拌1.5小时,用HPLC检测反应进程;反应完成后,将反应液缓慢加至200g 10%氯化铵溶液中淬灭,再加入150g乙酸乙酯萃取,分液,有机相用230g饱和氯化钠洗涤,取有机相干燥,于40~45℃减压浓缩至无馏分流出,得 棕色油状物45.1g,收率102.4%。
2)(2R,3S,4R,5R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5-四氢-1,1′-联苯(式II)
向洁净干燥的反应瓶中加入200g(154ml)二氯甲烷,再加入(2R,3S,4R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇35g(38.83mmol,1.0eq),氮气置换后,降温至-28~-15℃,滴加12.1g(104.06mmol,2.68eq)三乙基硅烷,滴加完毕后继续滴加9.6g(67.63mmol,1.74eq)三氟化硼乙醚,滴加完毕继续保温反应2h;用HPLC检测反应进程;反应完成后,控制温度在10℃以下,向反应液中加入70g纯化水,有机相用110g饱和碳酸氢钠水溶液洗涤至中性,再用110g饱和食盐水洗涤,收集有机相。有机相37±3℃减压浓缩直至无馏分流出,浓缩所得油状物加入140g甲醇加热到70~80℃,后降温至10~18℃,搅拌析晶16小时。抽滤,用40g甲醇淋洗,再抽滤得湿品25.1g,于50±3℃真空干燥10小时淡黄色固体18.9g,纯度94.8%,收率55.0%。
3)(1R,2S,3R,4R,5S,6R)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇(式III)
向干燥、洁净的反应瓶中加入165.0g(185ml)无水四氢呋喃,继续加入18.9g(21.34mmol,1.0eq)的(2R,3S,4R,5R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5-四氢-1,1′-联苯,氮气置换,体系溶清后,控温20~28℃缓慢加入2.6g(32.50mmol,1.52eq)硼烷二甲硫醚溶液。滴加完毕,缓慢加热至60~68℃反应反应2小时。用HPLC检测反应进程;反应完成后,反应液降温至0~8℃,并保温缓慢滴加5mol/L氢氧化钠溶液40.2g(169.6mmol,7.95eq),然后继续保温缓慢滴加30%的过氧化氢溶液20.4g(180.0mmol,8.43eq)。滴加完毕,缓慢升温至25~33℃继续反应12小时。向反应液中加入饱和氯化铵水溶液185g、95g饱和氯化钠溶液搅拌1小时。静置、分液,收集有机相。水相用90g乙酸乙酯萃取一次,合并有机相。有机相用10%Na
2SO
3溶液100g洗涤,收集有机相,并用碘化钾试纸检测不变色。有机相于40~44℃减压浓缩,直至无馏分流出。所得油状物加入41.5g异丙醚于20~25℃搅拌10小时,抽滤,收集湿品在45±3℃真空干燥12h得10.3g类白色固体,纯度93.4%,收率53.4%。
4)制备式IV所示(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮
向干燥、洁净的反应瓶中加入90g(70ml)二氯甲烷和8.3g(9.19mmol,1.0eq)(1R,2S,3R,4R,5S,6R)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇,搅拌溶解。降温至5~15℃,加入6.5g(15.33mmol,1.66eq)戴斯马丁氧 化剂,保温8~12℃反应3小时。用HPLC检测反应进程;反应完成后,将反应液缓慢加入80mL含有7.3g无水Na
2SO
3、6g NaHCO
3的水溶液中,搅拌30分钟。静置、分液,收集有机相。水相用38g二氯甲烷萃取,合并有机相。用40g纯化水洗涤有机相,分液,收集有机相,加入8.2g无水硫酸钠干燥30min,过滤,收集滤液,于30±4℃进行减压浓缩,得到黄棕色油状物。油状物中加入15g异丙醇,加热至70~78℃溶解,缓慢降温,于20~28℃保温搅拌析晶12h。过滤、收集物料于真空烘箱中50±3℃干燥12小时,得6.8g(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮,纯度95.1%,收率82.1%。
5)制备式V-1所示的(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮
将5g(5.55mmol,1.0eq)的(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮、40g(45ml)四氢呋喃加入到100mL的氢化釜中,搅拌溶清,再加入5%钯碳0.85g搅拌均匀。开启搅拌,转速28Hz。先氮气置换三次,再用氢气置换三次。控温20~28℃,氢气压力0.09~0.15MPa,反应80min,用HPLC检测反应进程;反应完成后,放空氢气,氮气置换三次,过滤除去钯碳,用6g四氢呋喃淋洗滤饼。合并滤液,45±2℃减压浓缩至干,加入11g乙腈加热回流。溶清后,缓慢降温,于40~48℃保温析晶2.5小时。降温至0~8℃继续析晶,并在0~10℃搅拌1.5小时。过滤,滤饼在50±2℃真空干燥10小时,得1.9g白色粉末状固体,纯度为99.1%,收率81.3%。
6)制备式VI所示的(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟基甲基)环己烷-1,2,3-三醇
将5g(11.9mmol,1.0eq)的(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮、48g(15ml)二氯甲烷、0.15g(1.2mmol,0.1eq)DMAP及8.4g(83.3mmol,7.0eq)三乙胺加入到洁净、干燥的反应瓶中,氮气置换并保护。降温至-5℃~5℃,缓慢滴加10.2g(77.4mmol,6.5eq)三氟乙酰氯,滴加结束后,在室温反应8小时,HPLC监控反应终点。反应完成后,加入48g(15ml)二氯甲烷稀释反应液,2N盐酸水溶液洗一次、饱和碳酸氢钠水溶液洗一次,饱和食盐水洗涤一次,有机相干燥过夜,过滤后将滤液转移至干燥的反应瓶中,继续加入二乙胺基三氟化硫27g(168mmol,15.0eq)、无水乙醇0.02g(4‰M
SM),加热至20~25℃反应72h,冰水淬灭、中和、洗涤、分出有机相浓缩至一半料液体积,加入20ml的5%碳酸钾水溶液于20~25℃搅拌3h。过滤,滤饼用水打浆并再次过滤后即得式(VI)粗品。将该粗品投至25ml乙腈中,加热回流。溶清后缓慢降温,于40~45℃保温析晶2小时。降温至0~10℃,并在0~10℃继续搅拌1小时。过滤,滤饼在50±3℃真空 干燥8小时,得4.18g白色粉末状固体,纯度为98.0%,收率79.3%。
实施例3 R为对甲氧基苄基的化合物V-1的制备
1)(2R,3S,4R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇(式I)
向洁净干燥的反应瓶中加入180g(202ml)2-甲基四氢呋喃,继续加入22.0g(59.04mmol,1.20eq)4-碘-1-氯-2-(4-乙氧基苄基)苯搅拌溶解,氮气置换,降温至-28~-35℃,滴加17.28g(63.53mmol,1.30eq)2.5M正丁基锂溶液。滴加完毕,在-25~-30℃继续反应1h,用HPLC检测起始原料剩余。反应完成后,将32.0g(48.87mmol,1.0eq)(4R,5S,6R)-4,5,6-三(对甲氧基苄氧基)-3-((对甲氧基苄氧基)甲基)环己-2-烯-1-酮溶于35g四氢呋喃中,并控温-28~-35℃滴加进反应瓶中,滴加完毕,继续保温搅拌1小时,用HPLC检测反应进程;反应完成后,将反应液缓慢加至220g 10%氯化铵溶液中淬灭,再加入170g乙酸乙酯萃取,分液,有机相用265g饱和氯化钠洗涤,取有机相干燥,于40~45℃减压浓缩至无馏分流出,得棕色油状物46.8g,收率106.2%。
2)(2R,3S,4R,5R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5-四氢-1,1′-联苯(式II)
向洁净干燥的反应瓶中加入220g(170ml)二氯甲烷,再加入(2R,3S,4R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4’-氯-3’-(4-乙氧基苄基)-1,2,3,4-四氢-[1,1’-二苯基]-1-醇40g(44.37mmol,1.00eq),氮气置换后,降温至-28~-18℃,滴加13.5g(116.1mmol,2.68eq)三乙基硅烷,滴加完毕后继续滴加10.7g(75.38mmol,1.70eq)三氟化硼乙醚,滴加完毕继续保温反应1.5小时;用HPLC检测反应进程;反应完成后,控制温度在10℃以下,向反应液中加入80g纯化水,有机相用125g饱和碳酸氢钠水溶液洗涤至中性,再用125g饱和食盐水洗涤,收集有机相。有机相37±2℃减压浓缩直至无馏分流出,浓缩所得油状物加入152g甲醇加热到70~75℃,后降温至10~13℃,搅拌析晶12小时。抽滤,用45g甲醇淋洗,再抽滤得湿品28.3g,于50±3℃真空干燥15小时淡黄色固体23.57g,纯度93.7%,收率60.0%。
3)(1R,2S,3R,4R,5S,6R)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇(式III)
向干燥、洁净的反应瓶中加入180g无水四氢呋喃,继续加入23g(25.97mmol,1.00eq)的(2R,3S,4R,5R)-2,3,4-三(对甲氧基苄氧基)-5-((对甲氧基苄氧基)甲基)-4′-氯-3′-(4-乙氧基苄基)-2,3,4,5-四氢-1,1′-联苯,氮气置换,体系溶清后,控温20~24℃缓慢加入3.22g(40.26mmol,1.55eq)硼烷四氢呋喃络合物。滴加完毕,缓慢加热至60~65℃反应3小时。用HPLC检测反应进程;反应完成后,反应液降温至0~5℃,并保温缓慢滴加5mol/L氢氧化 钠溶液55.6g(234.6mmol,9.03eq),然后继续保温缓慢滴加30%的过氧化氢溶液26.1g(230.3mmol,8.87eq)。滴加完毕,缓慢升温至25~30℃继续反应10小时。向反应液中加入饱和氯化铵水溶液201g、105g饱和氯化钠溶液搅拌1.5小时。静置、分液,收集有机相。水相用102g乙酸乙酯萃取一次,合并有机相。有机相用10%Na
2SO
3溶液108g洗涤,收集有机相,并用碘化钾试纸检测不变色。有机相于40~45℃减压浓缩,直至无馏分流出。所得油状物加入45g异丙醚于20~28℃搅拌12小时,抽滤,收集湿品在45±2℃真空干燥16h得13.1g类白色固体,纯度92.8%,收率55.8%。
4)制备式IV所示(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮
向干燥、洁净的反应瓶中加入75g(58ml)二氯甲烷和10g(11.07mmol,1.00eq)(1R,2S,3R,4R,5S,6R)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己醇,搅拌溶解。降温至5~12℃,加入2.7g(17.28mmol,1.56eq)2,2,6,6-四甲基哌啶氧化物,保温10~15℃反应5小时。用HPLC检测反应进程;反应完成后,将反应液缓慢加入78mL含有7.0g无水Na
2SO
3、5.3g NaHCO
3的水溶液中,搅拌30分钟。静置、分液,收集有机相。水相用42g二氯甲烷萃取,合并有机相。用38g纯化水洗涤有机相,分液,收集有机相,加入5.9g无水硫酸钠干燥30min,过滤,收集滤液,于30±5℃进行减压浓缩,得到黄棕色油状物。油状物中加入16.5g异丙醇,加热至68~75℃溶解,缓慢降温,于20~25℃保温搅拌析晶8h。过滤、收集物料于真空烘箱中50±3℃干燥10小时,得7.5g(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮,纯度94.8%,收率75.2%。
5)制备式V-1所示(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮
将5g(5.55mmol,1.00eq)的(2R,3R,4R,5S,6S)-3,4,5-三(对甲氧基苄氧基)-2-((对甲氧基苄氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮、20g(22ml)四氢呋喃、15g(20ml)甲醇加入到100mL的氢化釜中,搅拌溶清,再加入10%氢氧化钯碳0.5g搅拌均匀。开启搅拌,转速25Hz。先氮气置换三次,再用氢气置换三次。控温20~25℃,氢气压力0.09~0.12MPa,反应60min,用HPLC检测反应进程;反应完成后,放空氢气,氮气置换三次,过滤除去钯碳,用5.5g四氢呋喃淋洗滤饼。合并滤液,45±2℃减压浓缩至干,加入12g乙腈加热回流。溶清后,缓慢降温,于40~44℃保温析晶1小时。降温至0~5℃继续析晶,并在0~5℃搅拌1小时。过滤,滤饼在50±2℃真空干燥8小时,得1.85g白色粉末状固体,纯度为99.3%,收率79.2%。
6)制备式VI所示的(1R,2R,3S,4S,6R)-4-(4-氯-3-(乙氧基苄基)苯基)-5,5-二氟-6-(羟 基甲基)环己烷-1,2,3-三醇
将5g(11.9mmol,1.0eq)的(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮、48g(15ml)二氯甲烷、0.18g(2.4mmol,0.2eq)DMAP及8g(65.5mmol,5.5eq)三乙胺加入到洁净、干燥的反应瓶中,氮气置换并保护。降温至0℃~5℃,缓慢滴加7.9g(59.5mmol,5.0eq)三氟乙酰氯,滴加结束后,在室温反应10小时,HPLC监控反应终点。反应完成后,加入32g(10ml)二氯甲烷稀释反应液,2N盐酸水溶液洗一次、饱和碳酸氢钠水溶液洗一次,饱和食盐水洗涤一次,有机相干燥过夜,过滤后将滤液转移至干燥的反应瓶中,继续加入二乙胺基三氟化硫27g(168mmol,15.0eq)、无水乙醇0.01g(2‰M
SM),加热至20℃反应72h,冰水淬灭、中和、洗涤、分出有机相浓缩至一半料液体积,加入10ml的5%碳酸钾水溶液于25~30℃搅拌3h。过滤,滤饼用水打浆并再次过滤后即得式(VI)粗品。将该粗品投至20ml乙腈中,加热回流。溶清后缓慢降温,于40~50℃保温析晶2小时。降温至0~10℃,并在0~10℃继续搅拌1小时。过滤,滤饼在50±3℃真空干燥8小时,得4.13g白色粉末状固体,纯度为99.0%,收率78.3%。
本领域的普通技术人员在不偏离本发明的原理和精神的情况下,可以对本发明的化合物以及方法进行多种修饰和变化,以达到相同的技术效果,这些都属于与本发明相同或等同的范围。
Claims (11)
- 权利要求1所述的SGLT2抑制剂中间体V-1的制备方法:其中,R选自对甲氧基苄基、苄基、三苯甲基、乙酰基、苯甲酰基、特戊酰基、三甲基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、2-四氢吡喃基、甲氧基甲基或2-乙氧基乙基;优选的所述方法为式IV所示化合物与脱保护试剂加入溶剂中,10-50℃反应1-10h,反应结束,经后处理、脱溶剂、精制制得制备式V-1所示化合物,即(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-3,4,5-三羟基-6-(羟基甲基)环己烷-1-酮;优选的,所述的脱保护试剂为钯碳、氢氧化钯碳、四丁基溴化铵、2,3-二氯-5,6-二氰对苯醌、氯化氢甲醇溶液、三氟乙酸中的一种,优选为钯碳;优选的,所用脱保护试剂用量为结构式IV用量的5-100wt%,优选10-15wt%;优选的,所述溶剂为四氢呋喃、甲醇、二氯甲烷、乙醇或丙酮中的一种或其任意组合,优选四氢呋喃;优选的,(2R,3R,4R,5S,6S)-3,4,5-三(R保护基氧基)-2-((R保护基氧基)甲基)-6-(4-氯-3-(4-乙氧基苄基)苯基)环己酮与溶剂的比例为1g/(5~12)ml;优选的,精制所用的试剂为甲醇、异丙醇、乙醇、丙酮、乙酸乙酯或乙腈,优选乙腈。
- 根据权利要求3所述的应用,其特征在于,方法具体为:中间体V-1、催化剂和三乙胺加入到溶剂中,于-5~5℃下加入三氟乙酰氯,室温反应,洗涤、干燥、过滤后加入二乙胺基三氟化硫和无水乙醇,15~25℃反应60~80h,加入碳酸钾水溶液后于20~30℃反应3-5h得VI化合物;优选的,式VI所示化合物的合成中的催化剂选自DMF或DMAP;优选的,式VI所示化合物的合成中中间体V-1、催化剂和三乙胺的摩尔比为1:(0.1~0.5):(6~8);优选为1:(0.1~0.2):(6~8);优选的,式VI所示化合物的合成中中间体V-1与三氟乙酰氯的摩尔比为1:(5-7);优选的,式VI所示化合物的合成中中间体V-1与二乙胺基三氟化硫的摩尔比为1:(10~20),优选1:15;优选的,式VI所示化合物的合成中无水乙醇加入重量为中间体V-1的1‰~5‰,优选2‰~3‰。
- 根据权利要求5所述的方法,其特征在于,式I所示化合物的合成方法具体为:将4-碘-1-氯-2-(4-乙氧基苄基)苯(即物料1)、物料2和金属试剂按照摩尔比(1.05-1.25):1.0:(1.0-1.5)加入到溶剂中,-20~-70℃反应1~3小时;优选的,式I所示化合物的合成中4-碘-1-氯-2-(4-乙氧基苄基)苯(即物料1)、物料2和金属试剂的摩尔比为(1.1-1.2):1:(1.3-1.35);优选的,式I所示化合物的合成中反应温度为-25~-35℃;优选的,式I所示化合物的合成中金属试剂为异丙基氯化镁-氯化锂或正丁基锂;优选的,式I所示化合物的合成中所用溶剂为甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、甲苯中的一种或组合物,优选溶剂为四氢呋喃或2-甲基四氢呋喃;更优选物料2与溶剂的比例为1g/(5~10)ml。
- 根据权利要求5所述的方法,其特征在于,式II所示化合物的合成方法具体为:将式I化合物、三乙基硅烷、三氟化硼乙醚按照摩尔比1.0:(1.5-3.5):(1.1-2.0)加入溶剂中,-30~0℃反应1-2小时,反应结束后,溶剂用碱水洗,弃掉水层,脱去溶剂,精制制得式II所示化合物;优选的,式II所示化合物的合成中式I化合物、三乙基硅烷、三氟化硼乙醚摩尔比为1.0:(2.1-2.7):(1.45-1.8);优选的,式II所示化合物的合成中反应温度为-28~-15℃;优选的,式II所示化合物的合成中所用溶剂为乙酸异丙酯、环己烷、二氯甲烷、异丙醚或乙腈,优选溶剂为二氯甲烷;在一些实施例中,式I化合物与溶剂的比例为1g/(2~15)ml;优选的,式II所示化合物的合成中的碱水为碳酸氢钠溶液、碳酸钠溶液或氢氧化钠溶液,优选碳酸氢钠溶液;优选的,式II所示化合物的合成中精制所用试剂为乙腈、异丙醇、甲醇、乙醇、异丙醚、乙酸乙酯或正庚烷中的一种或其任意组合,优选甲醇。
- 根据权利要求5所述的方法,其特征在于,式III所示化合物的合成方法具体为:将式II所示化合物、还原剂按照摩尔比1.0:(1.1-2.5)加入溶剂中,40~70℃反应1-7小时;反应结束后,反应液降温至-5~30℃,按照式II所示化合物:氢氧化钠:H 2O 2的摩尔比为1.0:(3-10):(3-10),于15~40℃继续氧化反应12-15小时,反应完毕,反应液经洗涤、萃取、浓缩、精制得式III所示化合物;优选的,式III所示化合物的合成中式II所示化合物和还原剂的摩尔比为1.0:(1.4-1.6);优选的,式III所示化合物的合成中反应温度为60~70℃;优选的,反应结束后,降温至0~15℃;优选的,式III所示化合物的合成中式II所示化合物:氢氧化钠:H 2O 2的摩尔比为1.0:(7.5-9.5):(8.0-9.0);优选的,式III所示化合物的合成中继续氧化反应的温度为25~33℃;优选的,式III所示化合物的合成中还原剂为硼烷二甲硫醚、硼氢化钠、频哪醇硼烷、8-甲氧基-9-硼杂双环[3.3.1]壬烷或硼烷四氢呋喃络合物,优选硼烷二甲硫醚或硼烷四氢呋喃络合物;优选的,式III所示化合物的合成中所用溶剂为甲苯、四氢呋喃、1,4-二氧六环、二氯甲烷中的一种或组合物,优选四氢呋喃;优选的,式II所示化合物与溶剂的比例为1g/(6~14)ml;优选的,式III所示化合物的合成中精制所用试剂为乙腈、正庚烷、甲基叔丁基醚、乙醇、异丙醚、乙酸乙酯中的一种或其任意组合,优选异丙醚。
- 根据权利要求5所述的方法,其特征在于,式IV所示化合物的合成方法具体为:将式III所示化合物和氧化剂按照摩尔比1.0:(1.0-4.0)加入溶剂中,-5~30℃反应1-5小时;反应结束后,反应液用还原剂进行水洗,弃掉水层,脱去溶剂,精制制得式IV所示化合物;优选的,式IV所示化合物的合成中式III所示化合物和氧化剂的摩尔比为1.0:(1.5-1.8);优选的,式IV所示化合物的合成中反应温度为5~15℃;优选的,式IV所示化合物的合成中所用氧化剂为二氧化锰、戴斯马丁氧化剂、琼斯试剂或2,2,6,6-四甲基哌啶氧化物,优选戴斯马丁氧化剂;优选的,式IV所示化合物的合成中所用溶剂为异丙醚、二氯甲烷、四氢呋喃、甲苯、乙腈中的一种或组合物,优选二氯甲烷;在一些实施例中,式III所示化合物与溶剂的比例为1g/(3~15)ml;优选的,式IV所示化合物的合成中精制所用试剂为异丙醚、异丙醇、乙醇、丙酮、乙酸乙酯或四氢呋喃,优选试剂异丙醇。
- 根据权利要求5所述的方法,其特征在于,式V-1所示化合物的合成方法具体为:将式IV所示化合物与脱保护试剂加入溶剂中,10-50℃反应1-10h,反应结束,经后处理、脱溶剂、精制制得式V-1所示化合物;优选的,式V-1所示化合物的合成中脱保护试剂为钯碳、氢氧化钯碳、四丁基溴化铵、2,3-二氯-5,6-二氰对苯醌、氯化氢甲醇溶液、三氟乙酸中的一种,优选为钯碳;优选的,式V-1所示化合物的合成中所用脱保护试剂用量为结构式IV用量的5-100wt%,优选10-18wt%;优选的,式V-1所示化合物的合成中溶剂为四氢呋喃、甲醇、二氯甲烷、乙醇或丙酮中的一种或其任意组合,优选四氢呋喃;优选的,式V-1所示化合物的合成中式IV化合物与溶剂的比例为1g/(5~12)ml;优选的,式V-1所示化合物的合成中精制所用的试剂为甲醇、异丙醇、乙醇、丙酮、乙酸乙酯或乙腈,优选乙腈。
- 根据权利要求5所述的方法,其特征在于,式VI所示化合物的合成方法具体为:中间体V-1、催化剂和三乙胺加入到溶剂中,于-5~5℃下加入三氟乙酰氯,室温反应,洗涤、干燥、过滤后加入二乙胺基三氟化硫和无水乙醇,15~25℃反应60~80h,加入碳酸钾水溶液后于20~30℃反应3-5h得VI化合物;优选的,式VI所示化合物的合成中的催化剂选自DMF或DMAP;优选的,式VI所示化合物的合成中中间体V-1、催化剂和三乙胺的摩尔比为1:(0.1~0.5):(6~8);优选为1:(0.1~0.2):(6~8);优选的,式VI所示化合物的合成中中间体V-1与三氟乙酰氯的摩尔比为1:(5-7);优选的,式VI所示化合物的合成中中间体V-1与二乙胺基三氟化硫的摩尔比为1:(10~20),优选1:15;优选的,式VI所示化合物的合成中无水乙醇加入重量为中间体V-1的1‰~5‰,优选2‰~3‰。
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BOEHM MARCUS F, PRESTWICH' GLENN D: "FLUORINATED ANALOGS AND TRITIATED ENANTIOMERS OF ~NOSITOL (1 ,3,4)-TRISPHOSPHATE", TETRAHEDRON LETTERS, vol. 29, no. 41, 1 January 1988 (1988-01-01), pages 5217 - 5220, XP093081006, DOI: 10.1016/S0040-4039(00)80720-0 * |
LEO A. PAQUETTE: "Encyclopedia of reagents for organic synthesis; Vol. 7 : Sod - Trim", 15 September 2006, WILEY , Chichester , ISBN: 978-0-470-84289-8, article FAUQ ABDUL H., SINGH RAJENDRA P., MESHRI DAYAL T.: "Diethylaminosulfurtrifluoride", pages: 1 - 14, XP093082360, DOI: 10.1002/047084289X.rd175.pub2 * |
SAWYERE DEBORAH A, POTTER BARRY V L: "Total Synthesis of Fluorinated Analogues of lnositol and lnositol 1.4.5-Trisphosphate", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1 January 1992 (1992-01-01), pages 923 - 932, XP093081007 * |
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