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CN113372325A - Temsirolimus intermediate compound III - Google Patents

Temsirolimus intermediate compound III Download PDF

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Publication number
CN113372325A
CN113372325A CN202010160909.9A CN202010160909A CN113372325A CN 113372325 A CN113372325 A CN 113372325A CN 202010160909 A CN202010160909 A CN 202010160909A CN 113372325 A CN113372325 A CN 113372325A
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compound
temsirolimus
compound iii
organic base
side chain
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李文姣
白文钦
刘忠
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Lunan Pharmaceutical Group Corp
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound III. The preparation method of the temsirolimus side chain compound III provided by the invention comprises the following steps: under the protection of inert gas, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding organic base, adding trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reaction to obtain a temsirolimus side chain compound III. The intermediate compound III provided by the invention is used for preparing temsirolimus, so that the regioselectivity of rapamycin esterification reaction can be effectively improved, no new impurity is generated, and the method is suitable for industrial production.

Description

Temsirolimus intermediate compound III
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound III.
Background
Temsirolimus (temsirolimus), a derivative of sirolimus, chemically named sirolimus 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate ], was the first product applied for treating cancers in mTOR inhibitor drugs, developed by american hui pharmaceutical company, and approved by FDA through a fast approval channel for the treatment of advanced renal cell carcinoma at 5 months 2007, and has the following structural formula:
Figure BDA0002405751090000011
most of the prior process routes take rapamycin as a main raw material, ester is formed by rapamycin and different side chain protecting groups, and then the protecting groups are removed to obtain temsirolimus, wherein the following reactions are mainly carried out according to the difference of the side chain protecting groups:
the method comprises the following steps: U.S. Pat. Nos. 5,5362718, 6,77983 and 3,9018373 report the reaction of 2, 2-dimethylolpropionic acid protected by 2, 2-methoxypropane and mixed anhydride generated by 2,4, 6-trichlorobenzoyl chloride to form ester as side chain group by using sirolimus or 31-O-trimethylsilylether of sirolimus as raw material, and then hydrolyzing under acidic condition to obtain temsirolimus, the route is as follows:
Figure BDA0002405751090000021
the synthetic method has the defects that the reaction has no regioselectivity, the 31-hydroxyl and the 42-hydroxyl of the rapamycin are easy to esterify when synthesizing temsirolimus, the separation and purification difficulty of the product is high, and the yield is only 60-70%.
The second method comprises the following steps: U.S. patent application 2005033046 uses phenylboronic acid to protect 2, 2-dimethylolpropionic acid, uses mixed acid anhydride generated by 2,4, 6-trichlorobenzoyl chloride as a side chain group, and generates ester-forming reaction with sirolimus or sirolimus 31-O-trimethylsilyl ether, and finally uses 2-methyl-2, 4-pentanediol for deprotection to obtain temsirolimus, wherein the route is as follows:
Figure BDA0002405751090000022
the method adopts high-toxicity phenylboronic acid as a side chain protecting group, is expensive, does not meet the requirement of environmental protection, and is not beneficial to industrial production.
The third method comprises the following steps: in the US2005234086 patent, 2-hydroxymethyl allyl propionate protected by alkyl is taken as a side chain group, reacts with sirolimus under the catalysis of enzyme, and is deprotected to obtain temsirolimus, and the synthetic route is as follows:
Figure BDA0002405751090000031
although the method has high yield, the regioselectivity of 31-position active hydroxyl and 42-position active hydroxyl exists, 31-esterification impurities and 31, 42-diester byproducts are generated, and the production cost is greatly increased due to enzyme catalysis, so that the method is not beneficial to industrial production.
Therefore, the problem to be solved at present is to explore a process route for synthesizing the side chain protecting group of temsirolimus, which has the advantages of high regioselectivity, simple operation, short production period, higher yield and more suitability for industrial production.
Disclosure of Invention
In order to solve the problems of poor regioselectivity, low yield, low purity, difficult product separation and the like in the preparation process of the side chain protecting group of temsirolimus in the prior art, the invention provides a novel compound for the side chain protecting group of temsirolimus and a preparation method of the compound; the method has the advantages of short reaction route, simple and convenient operation, milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.
The invention is realized by the following technical scheme:
a temsirolimus side chain compound represented by formula III:
Figure BDA0002405751090000032
a preparation method of temsirolimus side chain compound III comprises the following steps: under the protection of inert gas, adding a compound I, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding an organic base, adding a compound II, namely trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reacting to obtain a temsirolimus side chain compound III, wherein the reaction route is as follows:
Figure BDA0002405751090000041
preferably, the organic base may be selected from one or a combination of triethylamine, pyridine, 2, 6-lutidine, N-diisopropylethylamine, and triethylamine is particularly preferred.
In a preferable embodiment, the feeding molar ratio of the compound I, the compound II and the organic base is 1: 1.0-1.5: 1.2-2.5, and particularly preferably 1:1.1: 1.5.
Preferably, the organic solvent is one or a combination of dichloromethane, N-dimethylformamide, acetonitrile, chloroform and tetrahydrofuran, wherein dichloromethane is particularly preferred.
In a preferable scheme, the temperature of the added organic base is-10 ℃, and particularly preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, adding deionized water (the volume ratio of the solvent to the deionized water is 1:1) into the reaction solution, stirring and crystallizing to obtain a side chain compound III; the crystallization temperature is-5 to 5 ℃.
The use of compound III for the preparation of temsirolimus.
The application of the compound III in preparing an important intermediate compound V of temsirolimus, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid sirolimus 31-O-trimethylsilylether-42-ester, comprises the following steps: dissolving mono-protected sirolimus, namely a compound IV and organic base in an organic solution, adding a side chain compound III at controlled temperature, and reacting at room temperature to obtain an intermediate compound V, wherein the synthetic route is as follows:
Figure BDA0002405751090000042
preferably, the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine, and N, N-diisopropylethylamine is particularly preferred.
Preferably, the organic solvent is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, wherein dichloromethane is particularly preferred.
Preferably, the feeding molar ratio of the compound IV, the organic base and the compound III is as follows: 1: 4.0-7.0: 2.0-4.0, and particularly preferably 1:6.0: 2.5.
In a preferred scheme, the temperature of adding the side chain compound III is-10 ℃, and preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: TLC detecting reaction, adding purified water into the reaction solution, extracting with organic solvent, mixing organic phases, washing with sodium bicarbonate solution and saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2: 1); the extraction solvent is one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Compared with the prior art, the invention has the following technical effects:
1. provides a new temsirolimus intermediate compound III and a new method for preparing an important temsirolimus intermediate by using the compound simply, conveniently and efficiently, the whole synthesis method has simple and convenient operation, high reaction yield and high purity of the obtained product;
2. the intermediate compound III provided by the invention for preparing temsirolimus can effectively improve the regioselectivity of rapamycin esterification reaction and effectively prevent the generation of new impurities.
In conclusion, the invention provides a novel compound and a novel method for synthesizing an important temsirolimus intermediate by using the compound, the method avoids using dangerous chemical reagents, the synthesized intermediate does not generate new impurities, the traditional catalyst is replaced by a green catalyst, the reaction is milder, the method is economic and environment-friendly, the yield is higher, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The structure of the novel compound obtained by the invention is confirmed:
structural characterization of Compound III
Figure BDA0002405751090000051
High resolution mass spectrum of compound III: ESI-HRMS: 307.0420[ M + H ] M/z]+；1H-NMR(400MHz,CDCl3)：4.08～4.17(d,J＝8.6Hz,2H)，3.79～3.85(d,J＝8.4Hz,2H)，1.56(s,3H)，1.29(s,6H)；13C NMR(100MHz,CDCl3)：δ178.4,118.3,114.8,69.6,69.4,42.5,26.8,26.7,16.2.
Example 1
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of dichloromethane, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding triethylamine (15.18g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of dichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound III, wherein the yield is 98.7%, and the HPLC purity is 99.88%.
Example 2
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of trichloromethane, stirring and dissolving, cooling the system to 10 ℃ after dissolving, adding triethylamine (12.14g, 0.12mol), controlling the temperature to 10 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of trichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 96.2% and the HPLC purity is 99.82%.
Example 3
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mLN, N-dimethylformamide, stirring and dissolving, cooling the system to-10 ℃ after dissolving, adding triethylamine (25.30g, 0.25mol), controlling the temperature to-10 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature after completing the dropwise addition, adding 120mL of deionized water into reaction liquid, adding 120mL of ethyl acetate for extraction, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 95.1%, and the HPLC purity is 99.78%.
Example 4
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL acetonitrile, stirring and dissolving, cooling the system to-15 ℃ after dissolving, adding triethylamine (10.12g, 0.1mol), controlling the temperature to-15 ℃, dropwise adding trifluoromethanesulfonic acid trimethyl silicone grease (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL deionized water into the reaction liquid after the reaction is finished, adding 120mL dichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 92.7% and the HPLC purity is 99.71%.
Example 5
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL acetonitrile, stirring and dissolving, cooling the system to-5 ℃ after dissolving, adding triethylamine (27.32g, 0.27mol), controlling the temperature to-5 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL deionized water into the reaction liquid after the reaction is finished, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 92.1% and the HPLC purity is 99.68%.
Example 6
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of dichloromethane, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding pyridine (11.87g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (22.23g, 0.1mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 94.3% and the HPLC purity is 99.81%.
Example 7
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL tetrahydrofuran, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding 2, 6-dimethylpyridine (16.07g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (33.34g, 0.15mol), stirring and reacting at room temperature after completing the dropwise addition, adding 120mL deionized water into the reaction solution, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III with the yield of 95.1% and the HPLC purity of 99.76%.
Example 8
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL tetrahydrofuran, stirring and dissolving, cooling the system to 15 ℃ after dissolving, adding N, N-diisopropylethylamine (16.07g, 0.15mol), controlling the temperature to 15 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (37.78g, 0.17mol), stirring at room temperature for reaction after completing the dropwise addition, adding 120mL deionized water into the reaction liquid, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III with the yield of 86.5% and the HPLC purity of 99.70%.
Preparation of Compound V
Example 9
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (77.55g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 98.8% yield and 99.87% HPLC purity.
Example 10
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (51.70g, 0.4mol) into 1LN, N-dimethylformamide, stirring at room temperature to dissolve, controlling the temperature to be-10 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the single-protection sirolimus is completely reacted, adding purified water (1L) into the mixture, and extracting water with dichloromethane (500mL multiplied by 2)Combining the phases, washing the organic phase with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 95.3% yield and 99.82% HPLC purity.
Example 11
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (90.47g, 0.7mol) into 1L acetonitrile, stirring at room temperature to dissolve, controlling the temperature to 10 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L) into the mixture, extracting an aqueous phase with trichloromethane (500mL multiplied by 2), combining the organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying the mixture with anhydrous sodium sulfate, concentrating the mixture under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 94.6% yield and 99.76% HPLC purity.
Example 12
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (45.23g, 0.35mol) into 1L tetrahydrofuran, stirring at room temperature to dissolve, controlling the temperature to 15 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L) into the mixture, extracting an aqueous phase with trichloromethane (500mL multiplied by 2), combining the organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying the organic phase with anhydrous sodium sulfate, concentrating the mixture under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 86.6% yield with an HPLC purity of 99.72%.
Example 13
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (96.93g, 0.75mol) into 1L of trichloromethane, stirring at room temperature to dissolve, controlling the temperature to be-15 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until all the mono-protected sirolimus is reacted, and adding purified water (A), (B), (C), (1L), extracting the aqueous phase with chloroform (500 mL. times.2), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 84.8% yield and 99.68% HPLC purity.
Example 14
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and triethylamine (60.72g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to 0 ℃, adding side chain compound III (61.21g, 0.2mol), reacting at room temperature until all the single-protection sirolimus reacts, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with a saturated sodium bicarbonate solution and a saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 94.8% yield and 99.83% HPLC purity.
Example 15
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and pyridine (47.46g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be-5 ℃, adding side chain compound III (122.42g, 0.4mol), reacting at room temperature until all the single-protection sirolimus reacts, adding purified water (1L), extracting an aqueous phase by dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase by saturated sodium bicarbonate solution and saturated saline in sequence, drying by anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 95.4% yield and 99.77% HPLC purity.
Example 16
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and 4-dimethylamino pyridine (73.30g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding a side chain compound III (55.09g, 0.18mol), reacting at room temperature until all the mono-protected sirolimus is reacted, and adding purified sirolimus into the mixtureWater (1L), extracting the aqueous phase with dichloromethane (500 mL. times.2), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating to dryness under reduced pressure, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 85.3% yield and 99.75% HPLC purity.
Example 17
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N-methylmorpholine (60.69g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding side chain compound III (128.54g, 0.42mol), reacting at room temperature until all the mono-protected sirolimus is reacted, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 84.5% yield with HPLC purity 99.68%.

Claims (10)

1. A temsirolimus intermediate compound represented by formula III:
Figure FDA0002405751080000011
2. the intermediate compound III according to claim 1, characterized in that the preparation process comprises the following steps: under the protection of inert gas, adding a compound I, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding an organic base, adding a compound II, namely trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reacting to obtain a temsirolimus side chain compound III, wherein the reaction route is as follows:
Figure FDA0002405751080000012
3. the method according to claim 2, wherein the organic base is one or a combination of triethylamine, pyridine, 2, 6-lutidine, N-diisopropylethylamine.
4. The method according to claim 2, wherein the compound I, the compound II and the organic base are fed in a molar ratio of 1:1.0 to 1.5:1.2 to 2.5.
5. The preparation method according to claim 2, wherein the organic solvent is one or a combination of dichloromethane, N-dimethylformamide, acetonitrile, chloroform and tetrahydrofuran; the temperature of the added organic base is-10 to 10 ℃.
6. Use of compound III according to claim 1 for the preparation of temsirolimus.
7. A process for preparing an important intermediate 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid sirolimus 31-O-trimethylsilylether-42-ester of temsirolimus from the compound III of claim 1, comprising the steps of: dissolving mono-protected sirolimus, namely a compound IV and organic base in an organic solution, adding a side chain compound III at controlled temperature, and reacting at room temperature to obtain an intermediate compound V, wherein the synthetic route is as follows:
Figure FDA0002405751080000013
8. the preparation method according to claim 7, wherein the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine.
9. The method according to claim 7, wherein the organic solvent is selected from one of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, and toluene, or a combination thereof.
10. The preparation method according to claim 7, wherein the feeding molar ratio of the compound IV, the organic base and the compound III is as follows: 1: 4.0-7.0: 2.0-4.0.
CN202010160909.9A 2020-03-10 2020-03-10 Temsirolimus intermediate compound III Withdrawn CN113372325A (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DRABOWICZ, J 等: "Product class 1: alkanesulfonic acids and acyclic derivatives", SCIENCE OF SYNTHESIS, vol. 39, pages 17 - 122, XP008143984 *
白文钦等: "坦西莫司的合成工艺优化", 中国医药工业杂志, vol. 49, no. 8, pages 1095 - 1099 *

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Application publication date: 20210910