CN108948046B - Intermediate of temsirolimus and preparation method thereof - Google Patents
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Abstract
The invention provides a temsirolimus intermediate, which has better selectivity and higher yield when used for preparing temsirolimus. The intermediate has the following structural formula:
Description
Technical Field
The invention relates to the field of organic compound synthesis, and particularly relates to a temsirolimus intermediate and a preparation method thereof.
Background
Renal Cell Carcinoma (RCC) is one of the most common types of kidney cancer. The incidence rate of the cancer is second to bladder cancer in urinary system tumor, and accounts for 80% -85% of adult kidney malignant tumor. Approximately 2% to 3% of all cancer patients are RCC patients, and 2% of all cancer-related deaths are caused by RCC. The international cancer society reports that the incidence of RCC is on the rise, with an incidence of 2% per 10 years.
Temsirolimus (temsirolimus), chemical name: rapamycin 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate]. The Huishi medicine (which is now combined with the Peucedanum medicine) is used for developing a targeted antitumor drug for treating advanced kidney cancer, is also the first targeted therapeutic drug for treating the kidney cancer, and is the only drug which is on the market and specifically inhibits mTOR kinase. First marketed in the United states in 5 months of 2007 under the trade name
The preparation formulation is injection, and the specification is 1 ml: 25mg, first line therapy for the treatment of advanced renal cell carcinoma, approved for marketing by the European Medicines Agency (EMA) in the same year. mTOR kinase is an important protein for regulating cell proliferation, growth and cell survival. In vitro studies show that after the temsirolimus inhibits the mTOR kinase, the level of certain vascular growth factors such as vascular endothelial growth factor is reduced, so that the development of new blood vessels is prevented, and cancer cells die. Currently, temsirolimus is the only drug capable of remarkably prolonging the survival time of patients with renal cancer. The temsirolimus has the following structural formula:
the existing synthesis methods of temsirolimus include the following steps:
the method comprises the following steps: in 1994, juerauld, s.skotnicki et al, first reported a process for the preparation of temsirolimus and its biological activity (US5362718) by reacting 2, 2-dimethylolpropionic acid protected with 2, 2-methoxypropane with 2,4, 6-trichlorobenzoyl chloride to give an anhydride, which was then condensed with Rapamycin (Rapamycin) to give intermediate a-1 by isolation and finally deprotecting to give temsirolimus:
the preparation method has the following problems: (1) during the preparation of the side chain, triethylamine is used as a base, the base has an influence on the next esterification reaction, so that the reaction in the step needs to be subjected to purification post-treatment to remove triethylamine, and the step is easy to deteriorate unstable side chains. (2) The separation of the by-product of the simultaneous esterification of the 31-and 42-hydroxyl groups from the product is difficult, with an overall yield of 20%.
The second method comprises the following steps: shaw, Chia-Cheng et al improved the synthetic route by protecting the hydroxyl group at position 31, 42 of rapamycin with trimethylchlorosilane, then selectively deprotecting position 42 to give intermediate B-1, condensing with the above anhydride to give intermediate B-2, and finally deprotecting the group to give temsirolimus (WO 0123395). The method can improve the total yield to 47%. The preparation method has the following problems: the reaction steps are multiple, and the operation process is complicated.
The third method comprises the following steps: warren, Chew et al protected 2, 2-dimethylolpropionic acid with phenylboronic acid based on Shaw, Chia-Cheng et al synthetic route and finally deprotected with 2-methyl-2, 4-pentanediol to give temsirolimus (US 2005033046):
the preparation method has the following problems: the reaction steps are multiple, the operation process is complicated, and the production cost is high.
The existing preparation method of temsirolimus mainly comprises coupling of single-protection rapamycin or rapamycin and a side chain, and then deprotection to obtain temsirolimus, wherein the total yield is lower than 50%.
Disclosure of Invention
The invention aims to provide a temsirolimus intermediate and a preparation method thereof. When the intermediate is used for preparing temsirolimus, the selectivity is better, the yield is higher, and the intermediate is suitable for industrial production.
The intermediate of temsirolimus provided by the invention is shown as a formula II-1, and the structural formula is as follows: :
the preparation method of the temsirolimus intermediate provided by the invention comprises the following steps:
the preparation method of the temsirolimus intermediate provided by the invention comprises the following two steps:
step 1: in N2Under protection, rapamycin is dissolved in a solvent under an alkaline condition; dropwise adding trimethylchlorosilane while stirring at the temperature of 0-10 ℃ to completely protect the 31-42 hydroxyl groups of the rapamycin; then hydrolyzing under acidic condition to selectively remove the protection of 42-hydroxyl to obtain the rapamycin protected by 31-hydroxyl.
Step 2: in N2Under the protection, rapamycin protected by 31-hydroxyl is dissolved in a solvent under the alkaline condition, the temperature is reduced to-30 to-22 ℃, and methanesulfonyl chloride is slowly dripped for reaction to obtain an intermediate II-1 of temsirolimus.
Preferably, in step 1,
the substance providing the alkaline condition is one or more of imidazole, triethylamine, pyridine, 2, 6-dimethylpyridine and DIPEA, preferably imidazole, and the feeding molar ratio of rapamycin to the alkaline substance is 1: 2.5-4, preferably 1: 3;
the solvent is ethyl acetate, propyl acetate, isopropyl acetate or other ester solvents, and preferably ethyl acetate;
step 1, the reaction temperature is 0-10 ℃;
the feeding molar ratio of the rapamycin to the trimethylchlorosilane is 1: 2.5-4, preferably 1: 3;
the acid providing the acidic condition is sulfuric acid or hydrochloric acid, preferably hydrochloric acid, most preferably 1N hydrochloric acid, and the feeding molar ratio of rapamycin to hydrochloric acid is 1: 0.8 to 1.5, preferably 1: 1.1.
preferably, in step 2,
the substance providing the alkaline condition is one or more of triethylamine, pyridine, DIPEA and 2, 6-dimethylpyridine, preferably DIPEA, and the feeding molar ratio of rapamycin protected by 31-hydroxy and DIPEA is 1: 1 to 1.2;
the solvent is one or two of dichloromethane, dichloroethane, chloroform and the like;
the reaction temperature is-30 to-22 ℃;
feeding molar ratio of rapamycin protected by 31-hydroxy and methanesulfonyl chloride is 1: 1.05 to 1.1.
The intermediate II-1 of temsirolimus in the technical scheme provided by the invention has higher selectivity and higher yield in the step of docking with a side chain. The preparation method of the intermediate II-1 of temsirolimus has mild conditions and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples of specific embodiments, but the present invention is not limited thereto.
Example 1
In N2Under protection, 91.4g of rapamycin, 1200ml of ethyl acetate and 17g of imidazole are added into a 2L glass reaction bottle, and the temperature is reduced to about 0 ℃ by stirring; controlling the temperature to be 0-10 ℃, and dripping 27g of trimethyl silicon chlorideKeeping the temperature for reaction, and detecting the reaction progress by TLC until the rapamycin completely reacts; controlling the temperature to be 0-10 ℃, slowly dripping 80mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300ml of ethyl acetate per time; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 91.2%.
In N2Under protection, 89.3g of rapamycin protected by 31-hydroxy, 1200ml of dichloromethane and 11.6g of DIPEA are added into a 2L glass reaction bottle, and the temperature is reduced to about-22 ℃ by stirring; slowly dripping 10.8g of methanesulfonyl chloride, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-site hydroxyl completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300 ml/time of dichloromethane for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 90.6%.
Example 2
In N2Under protection, 91.4g of rapamycin, 1200ml of ethyl acetate and 20.4g of imidazole are added into a 2L glass reaction bottle, and the temperature is reduced to about 0 ℃ by stirring; controlling the temperature to be 0-10 ℃, dropwise adding 32.6g of trimethylchlorosilane, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin completely reacts; controlling the temperature to be 0-10 ℃, slowly dripping 110mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300ml of ethyl acetate per time; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 92.9%.
In N2Under protection, 91.6g of rapamycin protected by 31-hydroxy and 1200ml of rapamycinMethyl chloride and 13.2g of DIPEA are added into a 2L glass reaction bottle, and the temperature is reduced to about minus 26 ℃ by stirring; slowly adding 11.5g of methanesulfonyl chloride dropwise, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-site hydroxyl completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300 ml/time of dichloromethane for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 93.9%.
Example 3
In N2Under protection, 91.4g of rapamycin, 1200ml of ethyl acetate and 27.2g of imidazole are added into a 2L glass reaction bottle, and the temperature is reduced to about 0 ℃ by stirring; controlling the temperature to be 0-10 ℃, dropwise adding 43.2g of trimethylchlorosilane, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until the rapamycin completely reacts; controlling the temperature to be 0-10 ℃, slowly dripping 150mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300ml of ethyl acetate per time; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 90.1%.
In N2Under protection, 84.2g of rapamycin protected by 31-hydroxy, 1200ml of dichloromethane and 12.2g of DIPEA are added into a 2L glass reaction bottle, and the temperature is reduced to about minus 30 ℃ by stirring; slowly dripping 10.8g of methanesulfonyl chloride, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-site hydroxyl completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300 ml/time of dichloromethane for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 90.2%.
Example 4
In N2Under protection, 91.4g of rapamycin and 1200ml of BAdding ethyl acetate and 64.6g of DIPEA into a 2L glass reaction bottle, and stirring and cooling to about 0 ℃; controlling the temperature to be 13 ℃, dropwise adding 43.2g of trimethylchlorosilane, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin completely reacts; controlling the temperature to be 13 ℃, slowly dripping 185mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300 ml/time of petroleum ether; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 87.2%.
In N2Under protection, 84.2g of rapamycin protected by 31-hydroxy, 1200ml of dichloromethane, 8.8g of 2 and 6-lutidine are added into a 2L glass reaction bottle, and stirred and cooled to about-20 ℃; slowly dripping 10.8g of methanesulfonyl chloride, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-site hydroxyl completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300ml of ethyl acetate for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating the solvent under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 85.8%.
Example 5
In N2Under protection, 91.4g of rapamycin, 1200ml of ethyl acetate and 36.6g of DMAP are added into a 2L glass reaction bottle, and the mixture is stirred and cooled to about 0 ℃; controlling the temperature to be 13 ℃, dropwise adding 43.2g of trimethylchlorosilane, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin completely reacts; controlling the temperature to be 13 ℃, slowly dripping 185mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300 ml/time of petroleum ether; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 83.1%.
In N2Under protection, 84.2g of rapamycin protected by 31-hydroxy, 1200ml of dichloromethane and 10.4g of DMAP are added into a 2L glass reaction bottle, and the mixture is stirred and cooled to about-20 ℃; slowly dripping 10.8g of methanesulfonyl chloride, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-site hydroxyl completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300ml of ethyl acetate for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating the solvent under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 83.2%.
Example 6
In N2Under protection, 43.5g of 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid, 700ml of dichloromethane and 37.9g of triethylamine are added into a 3L glass reaction kettle, stirred and dissolved, and then 67.1g of 2,4, 6-trichlorobenzoyl chloride is added dropwise, and the heat preservation reaction is carried out after the dropwise addition is finished; detecting the reaction process by TLC, and finishing the reaction; cooling the reaction liquid to about-20 ℃, and then adding 1160ml of dichloromethane solution containing 106.3g of rapamycin double-protection compound; stirring for about 20 minutes, controlling the temperature to be about-20 ℃, dropwise adding 700ml of dichloromethane solution of 45.7g of 4-dimethylaminopyridine, and carrying out heat preservation reaction after dropwise adding; detecting the reaction process by TLC, adding 3000g of purified water after the reaction is finished, stirring, and separating; extracting the water layer for 2 times by using 800g of dichloromethane, combining the organic layers, washing the combined organic layers by using 2000g of 0.25mol/L sulfuric acid, 2000g of saturated sodium bicarbonate solution and 2000g of saturated saline water respectively, and drying the combined organic layers for 3 to 4 hours by using 500g of anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure to obtain yellow bubble solid; the yield thereof was found to be 96.3%.
Adding 109.5g of coupling intermediate and 2000ml of tetrahydrofuran into a 5L glass reaction bottle, stirring, controlling the temperature to be 0-5 ℃, slowly dropwise adding 287.5ml of 2mol/L sulfuric acid aqueous solution, controlling the temperature to be 0-5 ℃ after dropwise adding, stirring, reacting, detecting the reaction process by TLC, after the reaction is finished, adding 1000ml of drinking water and 2000ml of ethyl acetate into the reaction solution, stirring, separating liquid, extracting the water layer twice by using 1000ml of ethyl acetate respectively, combining organic layers, washing by using 2000ml of saturated sodium bicarbonate solution and 2000ml of saturated salt aqueous solution respectively, and drying 500g of anhydrous sodium sulfate for 3-4 hours; filtering, and evaporating ethyl acetate under reduced pressure to dryness to obtain yellowish foamy solid; the yield thereof was found to be 93.0%.
Comparative example 1
In N2Under protection, 91.4g of rapamycin, 1200ml of ethyl acetate and 20.4g of imidazole are added into a 2L glass reaction bottle, and the temperature is reduced to about 0 ℃ by stirring; controlling the temperature to be 0-10 ℃, dropwise adding 32.4g of trimethylchlorosilane, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin completely reacts; controlling the temperature to be 0-10 ℃, slowly dripping 110mL of 1N hydrochloric acid, and finishing dripping; detecting the reaction progress by TLC, adding 540ml of pure water after the rapamycin double-protection reaction is completed, separating the liquid, and extracting the water layer for 2 times by using 300ml of ethyl acetate per time; the organic layers were combined and washed with 540ml of saturated NaHCO3Washing the aqueous solution with 540ml of a saturated saline solution, and drying the mixture over anhydrous sodium sulfate for 4 hours; filtering, and distilling under reduced pressure to remove ethyl acetate; obtaining milk white bubble-shaped solid which is rapamycin protected by 31-bit hydroxyl; the yield thereof was found to be 92.9%.
In N2Under protection, 91.6g of rapamycin protected by 31-hydroxy, 1200ml of dichloromethane and 13.2g of DIPEA are added into a 2L glass reaction bottle, and the temperature is reduced to about minus 26 ℃ by stirring; slowly dripping 28.8g of trifluoromethanesulfonic anhydride, continuing to perform heat preservation reaction, and detecting the reaction progress by TLC until rapamycin protected by 31-hydroxy completely reacts; adding 800ml of pure water, separating, and extracting the water layer with 300 ml/time of dichloromethane for 2 times; the organic layers were combined and washed with 600ml saturated NaHCO3Washing the aqueous solution with 600ml of saturated saline solution, and drying the mixture for 4 hours by anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure; obtaining milky white bubble-shaped solid, namely an intermediate II-1; the yield thereof was found to be 80.9%.
In N2Under protection, 43.5g of 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid, 700ml of dichloromethane and 48.4g of N, N-diisopropylethylamine are added into a 3L glass reaction kettle, stirred and dissolved, 67.1g of 2,4, 6-trichlorobenzoyl chloride is added dropwise, and the heat preservation reaction is carried out after the dropwise addition is finished; detecting the reaction process by TLC, and finishing the reaction; cooling the reaction liquid to about-20 ℃, and then adding 112g of dichloromethane (1160ml) solution of rapamycin double-protection compound (see the reaction route for details); after stirring for about 20 minutes, controlling the temperature to be about minus 20 ℃, dropwise adding 45.7g of dichloromethane (700ml) solution of 4-dimethylaminopyridine, and preserving the temperature after finishing dropping; detecting the reaction process by TLC, adding 3000g of purified water after the reaction is finished, stirring, and separating; extracting the water layer for 2 times by using 800g of dichloromethane, combining the organic layers, washing the combined organic layers by using 2000g of 0.25mol/L sulfuric acid, 2000g of saturated sodium bicarbonate solution and 2000g of saturated saline water respectively, and drying the combined organic layers for 3 to 4 hours by using 500g of anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure to obtain yellow bubble solid; the yield thereof was found to be 78.2%.
Adding 69.8g of coupling intermediate and 2000ml of tetrahydrofuran into a 5L glass reaction bottle, stirring, controlling the temperature to be 0-5 ℃, slowly dropwise adding 183.3ml of 2mol/L sulfuric acid aqueous solution, controlling the temperature to be 0-5 ℃ after dropwise adding, stirring, reacting, detecting the reaction process by TLC, after the reaction is finished, adding 1000ml of drinking water and 2000ml of ethyl acetate into the reaction solution, stirring, separating liquid, extracting the water layer twice by using 1000ml of ethyl acetate respectively, combining organic layers, washing by using 2000ml of saturated sodium bicarbonate solution and 2000ml of saturated salt aqueous solution respectively, and drying 500g of anhydrous sodium sulfate for 3-4 hours; filtering, and evaporating ethyl acetate under reduced pressure to dryness to obtain yellowish foamy solid; the yield thereof was found to be 84.7%.
Comparative example 2
Preparation of rapamycin 42-methanesulfonic acid protected compound:
a solution of 3.6g (31.6mmol) of methanesulfonyl chloride in 25ml of pyridine is added to 10.0g (10.9mmol) of Rapamil at 0 deg.CTo the solution, the resulting solution was stirred at 20 ℃ for 22 hours. 2N HCl (240ml) was added and the product was extracted with ethyl acetate, washed with brine, MgSO4Drying, evaporation to a yellow solid, chromatography on silica gel eluting with 20% ethyl acetate in dichloromethane afforded the product as a white solid in 52.2% yield.
Preparing temsirolimus:
in N2Under protection, 43.5g of 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid, 700ml of dichloromethane and 48.4g of N, N-diisopropylethylamine are added into a 3L glass reaction kettle, stirred and dissolved, 67.1g of 2,4, 6-trichlorobenzoyl chloride is added dropwise, and the heat preservation reaction is carried out after the dropwise addition is finished; detecting the reaction process by TLC, and finishing the reaction; cooling the reaction liquid to about-20 ℃, and then adding 99.4g of dichloromethane (1160ml) solution of a compound (the structure is shown in the reaction route) protected by 42-position methanesulfonic acid of rapamycin; after stirring for about 20 minutes, controlling the temperature to be about minus 20 ℃, dropwise adding 45.7g of dichloromethane (700ml) solution of 4-dimethylaminopyridine, and preserving the temperature after finishing dropping; detecting the reaction process by TLC, adding 3000g of purified water after the reaction is finished, stirring, and separating; extracting the water layer for 2 times by using 800g of dichloromethane, combining the organic layers, washing the combined organic layers by using 2000g of 0.25mol/L sulfuric acid, 2000g of saturated sodium bicarbonate solution and 2000g of saturated saline water respectively, and drying the combined organic layers for 3 to 4 hours by using 500g of anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure to obtain yellow bubble solid; the yield thereof was found to be 42.1%.
Adding 48g of coupling intermediate and 1000ml of tetrahydrofuran into a 5L glass reaction bottle, stirring, controlling the temperature to be 0-5 ℃, slowly dropwise adding 126ml of 2mol/L sulfuric acid solution, controlling the temperature to be 0-5 ℃ after dropwise adding, stirring and reacting, detecting the reaction process by TLC, after the reaction is finished, adding 500ml of drinking water and 1000ml of ethyl acetate into the reaction solution, stirring, separating, extracting the water layer twice by 500ml of ethyl acetate respectively, combining the organic layers, washing by 1000ml of saturated sodium bicarbonate solution and 1000ml of saturated saline solution respectively, and drying by 300g of anhydrous sodium sulfate for 3-4 hours; filtering, and evaporating ethyl acetate under reduced pressure to dryness to obtain yellowish foamy solid; the yield thereof was found to be 83.2%.
Claims (2)
1. An intermediate of temsirolimus is shown as a formula II-1, and the structural formula is as follows:
2. a process for preparing temsirolimus from the temsirolimus intermediate of claim 1, characterized by the steps of:
step 1: in N2Under protection, 43.5g of 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid, 700ml of dichloromethane and 37.9g of triethylamine are added into a 3L glass reaction kettle, stirred and dissolved, and then 67.1g of 2,4, 6-trichlorobenzoyl chloride is added dropwise, and the heat preservation reaction is carried out after the dropwise addition is finished; detecting the reaction process by TLC, and finishing the reaction; cooling the reaction liquid to-20 ℃, and then adding 1160ml of dichloromethane solution containing 106.3g of rapamycin double-protection compound; stirring for 20 minutes, controlling the temperature to be 20 ℃ below zero, dropwise adding a dichloromethane 700ml solution of 45.7g of 4-dimethylaminopyridine, and keeping the temperature for reaction after dropwise adding; detecting the reaction process by TLC, adding 3000g of purified water after the reaction is finished, stirring, and separating; extracting the water layer for 2 times by using 800g of dichloromethane, combining the organic layers, washing the combined organic layers by using 2000g of 0.25mol/L sulfuric acid, 2000g of saturated sodium bicarbonate solution and 2000g of saturated saline water respectively, and drying the combined organic layers for 3 to 4 hours by using 500g of anhydrous sodium sulfate; filtering, and evaporating dichloromethane under reduced pressure to obtain yellow bubble solid;
step 2: adding 109.5g of coupling intermediate and 2000ml of tetrahydrofuran into a 5L glass reaction bottle, stirring, controlling the temperature to be 0-5 ℃, slowly dropwise adding 287.5ml of 2mol/L sulfuric acid aqueous solution, controlling the temperature to be 0-5 ℃ after dropwise adding, stirring, reacting, detecting the reaction process by TLC, after the reaction is finished, adding 1000ml of drinking water and 2000ml of ethyl acetate into the reaction solution, stirring, separating liquid, extracting the water layer twice by using 1000ml of ethyl acetate respectively, combining organic layers, washing by using 2000ml of saturated sodium bicarbonate solution and 2000ml of saturated salt aqueous solution respectively, and drying 500g of anhydrous sodium sulfate for 3-4 hours; filtering, and evaporating ethyl acetate under reduced pressure to dryness to obtain pale yellow foamy solid.
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