CN108948045A - A kind of preparation method of tesirolimus - Google Patents
A kind of preparation method of tesirolimus Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of tesirolimus.The preparation method includes: step 1: under alkaline condition, 2,2; 5- trimethyl -1; 3- dioxane -5- carboxylic acid in a solvent, agitation and dropping 2,4 under room temperature; the solution of 6- trichloro-benzoyl chloride; after the reaction was completed, cool down, the double protection compounds of rapamycin are added; then alkaline solution is added dropwise, reaction obtains conjugating intermediate.Step 2: conjugating intermediate is dissolved in solvent, cooling, and inorganic acid solution is added dropwise, and deprotection obtains tesirolimus.It is this preparation method simple process, easy to operate, and reaction yield is high, by-product is few, is suitble to industrialized production.
Description
Technical field
The present invention relates to organic compounds to synthesize field, and in particular to a kind of preparation method of tesirolimus.
Background technique
Clear-cell carcinoma (RCC) is one of the most common type type in kidney.Its disease incidence is only second to wing in urological cancer
Guang cancer and account for second, account for the 80%~85% of adult kidney malignant tumour.About 2%~3% is in all cancer patients
RCC patient has 2% to be caused by RCC in all cancer related mortalities.International cancer association report, RCC disease incidence become in rising
Gesture, every 10 annual morbidity rise 2%.
Tesirolimus (temsirolimus, as follows), chemical name: rapamycin 42- [3- hydroxyl -2- (hydroxyl first
Base) -2 Methylpropionic acid ester].The targeting of therapeutic advance kidney is used for by Hui Shi medicine (existing oneself is merged into Pfizer's medicine) exploitation
Property anti-tumor drug and first treatment kidney target therapeutic agent, and be uniquely list specificity inhibit mTOR
The drug of kinases.Most earlier than in May, 2007 listed first in the U.S., trade nameDosage form is injection, specification
For 1ml:25mg, for treating the first-line treatment of advanced renal cell carcinoma, the same year, European drug administration (EMA) approval is listed.
MTOR kinases is for adjusting cell Proliferation, growth and the key protein of cell survival.It is found in research in vitro, replaces western sieve
Department does not lead to the horizontal decline of certain angiogenesis factor such as vascular endothelial growth factor after inhibiting mTOR kinases, and then prevents
The development of new vessels, as a result leads to cancer cell death.Tesirolimus is uniquely can significantly to extend patients with renal cell carcinoma life at present
Deposit the drug of phase.
The synthetic method of existing disclosed tesirolimus has following several:
Method 1: 1994 year, Jerauld, S.Skotnicki etc. report for the first time tesirolimus preparation method and
Bioactivity (US5362718), this method pass through 2, the 2- dihydromethyl propionic acid protected with 2,2- methoxy propane and 2,4,6-
Trichloro-benzoyl chloride reacts to obtain acid anhydrides, then is condensed with rapamycin (Rapamycin), is isolated to intermediate A -1, finally
Deprotection obtains tesirolimus:
The preparation method there are the problem of: (1) in the preparation process of side chain, alkali is made with triethylamine, the alkali in next step
Esterification have an impact, therefore the step need to be reacted and carry out purifying post-processing, remove triethylamine, which is easy to make unstable
Side chain it is rotten.(2) by-product and product that rapamycin 31 and 42 hydroxyl is esterified simultaneously separates difficulty, and total recovery is
20%.
Method two: Shaw, Chia-Cheng etc. improve its synthetic route, and this method is by rapamycin 31,42
Hydroxyl is protected with trim,ethylchlorosilane, then selectivity de- 42 protecting groups and obtain intermediate B -1, then with above-mentioned acid anhydrides
It is condensed to yield intermediate B -2, last Deprotection obtains tesirolimus (WO0123395).This method can propose total recovery
Height is to 47%.
The preparation method is with the regioselectivity for improving esterification, but product yield is not high.
Method three: Warren, Chew etc. use phenyl boric acid protection instead on the basis of Shaw, the synthetic routes such as Chia-Cheng
2,2- dihydromethyl propionic acids finally obtain tesirolimus (US2005033046) with 2- methyl -2,4- pentanediol Deprotection.
The preparation method there are the problem of: phenylboric acid impurity content is high in product, purification steps troublesome, production cost
It is high.
Currently, regioselectivity esterification is the key that synthesis, but the prior art exists during synthesizing tesirolimus
Although there is many improved routes in terms of regioselectivity, yield is not very high；So need to seek new synthetic route with
Solve the problems, such as the synthesis yield of tesirolimus.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthesis technology of tesirolimus, synthesis technology letter
It is single, easy to operate, and reaction yield is high, by-product is few.
Technical solution provided by the invention through the following steps that realize:
Wherein, the double protection compounds of rapamycin are as follows:
Conjugating intermediate compound are as follows:
Step 1: under nitrogen protection, under alkaline condition, 2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids
In a solvent, the solution of 2,4,6- trichloro-benzoyl chloride of agitation and dropping cools down after the reaction was completed under room temperature, and rapamycin is added
Double protection compounds, are then added dropwise alkaline solution, to which after the reaction was completed, post-processing obtains conjugating intermediate.
Step 2: conjugating intermediate being dissolved in solvent, is cooled down, inorganic acid solution is added dropwise, to after the reaction was completed, locate afterwards
Reason, obtains tesirolimus.
Special: in step 1, alkaline condition is by triethylamine, pyridine, 2,6- lutidines, DIPEA and DMAP
What one or more provided, preferred triethylamine；2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids and feeding intake for triethylamine are rubbed
You are than being 1:1.3~1.8, preferably 1:1.5；2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids and 2,4,6- trichloros
The molar ratio of chlorine is 1:1~1.2, preferably 1:1.1；Solvent be one or both of methylene chloride and chloroform, it is excellent
Select methylene chloride；
Alkaline solution is by one or more of triethylamine, pyridine, 2,6- lutidines, DIPEA and DMAP dissolution
It is formed in the in the mixed solvent of dichloromethane or chloroform or both, preferably DMAP is dissolved in methylene chloride and is mixed to form；2,
The molar ratio of 2,5- trimethyl -1,3- dioxane -5- carboxylic acids and DMAP are 1:1.3~1.8, preferably 1:1.5；Thunder pa is mould
Plain double protection compounds and 2, the molar ratio of 2,5- trimethyl -1,3- dioxane -5- carboxylic acids are 1:2.2~3, preferably 1:
2.5；Coupling reaction temperature is -20~-30 DEG C.
It is post-processed in step 1: after reaction process, suitable quantity of water quenching reaction is added, then extracted with organic solvent,
Organic phase successively uses diluted acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing again, after organic phase anhydrous sodium sulfate drying
It is evaporated to obtain conjugating intermediate.Wherein, the preferred 0.25mol/L sulfuric acid of diluted acid；It extracts organic solvent used and is selected from methylene chloride, three
One of chloromethanes.
In step 2, the solvent for dissolving conjugating intermediate is in acetone, butanone, tetrahydrofuran and 2- methyltetrahydrofuran
One or more, preferably tetrahydrofuran.Inorganic acid is one or more of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, preferably sulfuric acid,
Wherein the concentration of sulfuric acid is the aqueous sulfuric acid of 1~3mol/L, the preferably aqueous sulfuric acid of 2mol/L；Conjugating intermediate and sulfuric acid
Molar ratio is 1:5~7, preferably 1:6.Reaction temperature is 0~10 DEG C, preferably 0~5 DEG C.
Step 2 post-processing: after reaction process, being first added suitable quantity of water quenching reaction, then extracted with organic solvent,
Organic phase successively uses saturated sodium bicarbonate aqueous solution, saturated common salt water washing again, and extraction gained organic phase is dry with anhydrous sodium sulfate
It is evaporated to obtain tesirolimus after dry.Wherein, organic solvent ethyl acetate, propyl acetate, isopropyl acetate or other esters are molten
Agent, ethyl acetate.
The advantages of the technical program, is:
1, it uses trim,ethylchlorosilane and mesyl chloride to protect respectively rapamycin 31,42 hydroxyls, selects this thunder pa
The double protection compounds of mycin are as starting material, and when the starting material and side chain are coupled, stereoselectivity is higher, and route is total
Yield is correspondingly improved, and yield is up to 96%.
2, it when step 2 hydrolyzes, because condition is suitable, while hydrolyzing the protecting group of 2 positions, reacts more efficient, shorten anti-
Between seasonable, reduce costs.
3, this route reaction condition is mild, does not need special installation, is easy to amplify, and is suitble to industrialized production.
4, using rapamycin as starting material, the total recovery of route synthesis tesirolimus is up to 72%.
The synthetic route of the double protection compounds of the starting material rapamycin that the technical program is selected is as follows:
The double protection compounds process for production thereof of rapamycin are divided into two steps:
Step 1: in N2Under protection, under alkaline condition, rapamycin is dissolved in solvent；At 0~10 DEG C, stirring drop
Add trim,ethylchlorosilane, keeps rapamycin 31,42 hydroxyl protections complete；Then it hydrolyzes, selectively makes in acid condition
The protection of 42 hydroxyls is taken off.Processing obtains the rapamycin of 31 hydroxyl protections.
Step 2: in N2Under protection, under alkaline condition, the rapamycin of 31 hydroxyl protections is dissolved in solvent, cooling
To -30~-22 DEG C, mesyl chloride is slowly added dropwise, after the reaction was completed, processing obtains the double protection compounds of rapamycin.
It is special:
In the double protection compound producing steps 1 of rapamycin, provide the substance imidazoles of alkaline condition, triethylamine, pyridine,
2, the molar ratio of one or more of 6- lutidines and DIPEA, preferably imidazoles, rapamycin and alkaline matter
For 1:2.5~4, preferably 1:3；Solvent is ethyl acetate, propyl acetate, isopropyl acetate or other esters solvents, preferably second
Acetoacetic ester；Reaction temperature is 0~10 DEG C；The molar ratio of rapamycin and trim,ethylchlorosilane is 1:2.5~4, preferably
1:3；The acid for providing acid condition hydrolysis is preferably sulfuric acid or hydrochloric acid, more preferably hydrochloric acid, the most preferably hydrochloric acid of 1N, and thunder pa is mould
Element and hydrochloric acid molar ratio are 1:0.8~1.5, preferably 1:1.1.
In the double protection compound producing steps 2 of rapamycin, provide alkaline condition substance be triethylamine, pyridine,
The one or more of DIPEA and 2,6- lutidines, preferably DIPEA, the rapamycin and DIPEA of 31 hydroxyl protections are thrown
Material molar ratio is 1:1~1.2；Solvent is one or both of methylene chloride, dichloroethanes and chloroform etc.；Reaction temperature be-
30~-22 DEG C；The rapamycin and mesyl chloride molar ratio of 31 hydroxyl protections are 1:1.05~1.1.
The double protection compounds process for production thereof of rapamycin provided by the invention, embodiment are as follows:
In N2Under protection, 2L glass reaction bottle is added in 91.4g rapamycin, 1200ml ethyl acetate and 20.4g imidazoles,
Stirring cools to 0 DEG C or so；0~10 DEG C of dropwise addition 32.6g trim,ethylchlorosilane of temperature control, continue insulation reaction, TLC detection react into
Journey, until rapamycin fully reacting；0~10 DEG C of temperature of control, is slowly added dropwise 1N hydrochloric acid 110ml, after being added dropwise to complete；TLC detection
Reaction process, until pure water 540ml, liquid separation, aqueous layer with ethyl acetate 300ml/ times is added after the double protection fully reactings of rapamycin
It extracts 2 times；Merge organic layer, is saturated NaHCO with 540ml3Aqueous solution, the washing of 540ml saturated common salt aqueous solution, anhydrous sodium sulfate
It is 4 hours dry；Filtering, removes ethyl acetate under reduced pressure；Milky blister solid is obtained, is the rapamycin of 31 hydroxyl protections；It receives
Rate 92.9%.
In N2Under protection, rapamycin, 1200ml methylene chloride, the 13.2gDIPEA of 91.6g31 hydroxyl protections are added
2L glass reaction bottle, stirring cool to -26 DEG C or so；11.5g mesyl chloride is slowly added dropwise, continues insulation reaction, TLC detection is anti-
Process is answered, until the rapamycin fully reacting of 31 hydroxyl protections；Pure water 800ml, liquid separation, water layer methylene chloride is added
300ml/ extraction 2 times；Merge organic layer, is saturated NaHCO with 600ml3Aqueous solution, the washing of 600ml saturated common salt aqueous solution, nothing
Aqueous sodium persulfate is 4 hours dry；Filtering, removes methylene chloride under reduced pressure；Milky blister solid is obtained to get rapamycin 31,42
The compound of double protections；Yield 93.9%.
Specific embodiment
The present invention is further illustrated below by embodiment.Should correct understanding: the embodiment of the present invention be only
Be for illustrating the present invention, rather than limiting the invention, so, to of the invention simple under the premise of method of the invention
It improves and belongs to the scope of protection of present invention.
Embodiment 1
In N2Under protection, by 38.3g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 28.9g triethylamine, after stirring and dissolving, starts that 53.7g2 is added dropwise, 4,6- trichloro-benzoyl chlorides are dripped to finish and be protected
Temperature reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, rapamycin is then added
The methylene chloride 1160ml solution of double protection compound 106.3g；After twenty minutes, -20 DEG C of temperature control, 34.9g4- bis- is added dropwise in stir about
The methylene chloride 700ml solution of dimethylaminopyridine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g/ times, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 92.1%.
In 5L glass reaction bottle, conjugating intermediate 105g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C, delays
Slow that 229.8ml 2mol/L aqueous sulfuric acid is added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, reaction
After, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses ethyl acetate respectively
1000ml/ extraction twice, merges organic layer, water-soluble with 2000ml saturated sodium bicarbonate solution, 2000ml saturated common salt respectively
Liquid washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister solid；
Yield 89.2%.
Embodiment 2
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 37.9g triethylamine, after stirring and dissolving, starts that 67.1g2 is added dropwise, 4,6- trichloro-benzoyl chlorides are dripped to finish and be protected
Temperature reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, rapamycin is then added
The methylene chloride 1160ml solution of double protection compound 106.3g；After twenty minutes, -25 DEG C of temperature control, 45.7g4- bis- is added dropwise in stir about
The methylene chloride 700ml solution of dimethylaminopyridine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g/ times, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 96.3%.
In 5L glass reaction bottle, conjugating intermediate 109.5g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C,
287.5ml 2mol/L aqueous sulfuric acid is slowly added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process,
After completion of the reaction, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses acetic acid respectively
Ethyl ester 1000ml/ times extraction twice, merges organic layer, uses 2000ml saturated sodium bicarbonate solution, 2000ml saturated common salt respectively
Aqueous solution washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister
Solid；Yield 93.0%.
Embodiment 3
In N2Under protection, by 52.2g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 54.5g triethylamine, after stirring and dissolving, starts that 87.8g2 is added dropwise, 4,6- trichloro-benzoyl chlorides are dripped to finish and be protected
Temperature reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, rapamycin is then added
The methylene chloride 1160ml solution of double protection compound 106.3g；After twenty minutes, -30 DEG C of temperature control, 65.8g4- bis- is added dropwise in stir about
The methylene chloride 700ml solution of dimethylaminopyridine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g × 2, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 94.4%.
In 5L glass reaction bottle, conjugating intermediate 107.3g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C,
328.7ml 2mol/L aqueous sulfuric acid is slowly added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, instead
After answering, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses acetic acid second respectively
Ester 1000ml/ times extraction twice, merges organic layer, uses 2000ml saturated sodium bicarbonate solution, 2000ml saturated salt solution respectively
Solution washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, it is solid to obtain faint yellow blister
Body；Yield 87.5%.
Embodiment 4
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 48.4gN, N- diisopropylethylamine, after stirring and dissolving, starts that 67.1g2,4,6- trichloro-benzenes first are added dropwise
Acyl chlorides drips and finishes insulation reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, then plus
Enter the methylene chloride 1160ml solution of the double protection compound 106.3g of rapamycin；Stir about after twenty minutes, -25 DEG C of temperature control, drips
The methylene chloride 700ml solution for adding 37.9g triethylamine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g/ times, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 92.1%.
In 5L glass reaction bottle, conjugating intermediate 102.7g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C,
269.7ml 2mol/L aqueous sulfuric acid is slowly added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process,
After completion of the reaction, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses acetic acid respectively
Ethyl ester 1000ml/ times extraction twice, merges organic layer, uses 2000ml saturated sodium bicarbonate solution, 2000ml saturated common salt respectively
Aqueous solution washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister
Solid；Yield 89.0%.
Embodiment 5
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 29.6g pyridine, after stirring and dissolving, starts that 67.1g2 is added dropwise, 4,6- trichloro-benzoyl chlorides drip Bi Baowen
Reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, it is double that rapamycin is then added
Protect the methylene chloride 1160ml solution of compound 106.3g；After twenty minutes, -25 DEG C of temperature control, 45.7g 4- bis- is added dropwise in stir about
The methylene chloride 700ml solution of dimethylaminopyridine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g/ times, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 90.7%.
In 5L glass reaction bottle, conjugating intermediate 100.4g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C,
263.6ml 2mol/L aqueous sulfuric acid is slowly added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, instead
After answering, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses acetic acid second respectively
Ester 1000ml/ times extraction twice, merges organic layer, uses 2000ml saturated sodium bicarbonate solution, 2000ml saturated salt solution respectively
Solution washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, it is solid to obtain faint yellow blister
Body；Yield 90.5%.
Embodiment 6
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 37.9g triethylamine, after stirring and dissolving, starts that 67.1g2 is added dropwise, 4,6- trichloro-benzoyl chlorides are dripped to finish and be protected
Temperature reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, rapamycin is then added
The methylene chloride 1160ml solution of double protection compound 106.3g；After twenty minutes, -25 DEG C of temperature control, 48.3gN, N- is added dropwise in stir about
The methylene chloride 700ml solution of diisopropylethylamine, drips off insulation reaction；TLC detects reaction process, after completion of the reaction, is added
The stirring of 3000g pure water, liquid separation；Water layer is extracted 2 times with methylene chloride 800g/ times, is merged organic layer and is used 0.25mol/L sulphur respectively
Sour 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g washing, anhydrous sodium sulfate 500g are 3~4 hours dry；It crosses
Filter, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield 89.2%.
In 5L glass reaction bottle, conjugating intermediate 97g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C, slowly
254.7ml2mol/L aqueous sulfuric acid is added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, has reacted
1000ml drinking water is added into reaction solution by Bi Hou, and 2000ml ethyl acetate stirs, liquid separation, and water layer uses ethyl acetate respectively
1000ml/ extraction twice, merges organic layer, water-soluble with 2000ml saturated sodium bicarbonate solution, 2000ml saturated common salt respectively
Liquid washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister solid；
Yield 91.3%.
Comparative example 1
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 48.4gN, N- diisopropylethylamine, after stirring and dissolving, starts that 67.1g2,4,6- trichloro-benzenes first are added dropwise
Acyl chlorides drips and finishes insulation reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, then plus
Enter methylene chloride (1160ml) solution of double protection compound (the being detailed in above-mentioned reaction route) 112g of rapamycin；Stir about 20 divides
Zhong Hou, is added dropwise methylene chloride (700ml) solution of 45.7g 4-dimethylaminopyridine, drips off insulation reaction by -25 DEG C of temperature control；
TLC detects reaction process, after completion of the reaction, the stirring of 3000g pure water, liquid separation is added；Water layer is extracted with methylene chloride 800g/ times
2 times, merges organic layer and washed respectively with 0.25mol/L sulfuric acid 2000g, saturated sodium bicarbonate solution 2000g, saturated brine 2000g
It washs, anhydrous sodium sulfate 500g is 3~4 hours dry；Filtering, removes methylene chloride under reduced pressure, obtains yellow blister solid；Yield
78.2%.
In 5L glass reaction bottle, conjugating intermediate 69.8g, 2000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C, delays
Slow that 183.3ml 2mol/L aqueous sulfuric acid is added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, reaction
After, 1000ml drinking water is added into reaction solution, 2000ml ethyl acetate stirs, liquid separation, and water layer uses ethyl acetate respectively
1000ml/ extraction twice, merges organic layer, water-soluble with 2000ml saturated sodium bicarbonate solution, 2000ml saturated common salt respectively
Liquid washing, anhydrous sodium sulfate 500g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister solid；
Yield 84.7%.
Comparative example 2
Prepare 42 methanesulfonic acid protection compounds of rapamycin:
10.0g (10.9mmol) thunder pa is added in 0 DEG C of 25ml pyridine solution by 3.6g (31.6mmol) mesyl chloride
In mycin solution, acquired solution stirs 22 hours at 20 DEG C.It is added 2N HCl (240ml), product is extracted with ethyl acetate, use
Salt water washing, uses MgSO4It is dried and evaporated to yellow solid, upper silica gel chromatographic column, with the dichloromethane solution of 20% ethyl acetate
Elution, obtaining product is white solid, yield 52.2%.
Prepare tesirolimus:
In N2Under protection, by 43.5g2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids, 700ml methylene chloride,
3L glass reaction kettle is added in 48.4gN, N- diisopropylethylamine, after stirring and dissolving, starts that 67.1g2,4,6- trichloro-benzenes first are added dropwise
Acyl chlorides drips and finishes insulation reaction；TLC detects reaction process, end of reaction；Above-mentioned reaction solution is cooled to -20 DEG C, then plus
The methylene chloride (1160ml) for entering compound (structure is shown in above-mentioned reaction route) 99.4g of 42 methanesulfonic acids of rapamycin protection is molten
Liquid；After twenty minutes, -25 DEG C of temperature control, methylene chloride (700ml) solution of 45.7g 4-dimethylaminopyridine is added dropwise in stir about,
Drip off insulation reaction；TLC detects reaction process, after completion of the reaction, the stirring of 3000g pure water, liquid separation is added；Water layer dichloromethane
Alkane 800g/ times extraction 2 times merges organic layer and uses 0.25mol/L sulfuric acid 2000g respectively, saturated sodium bicarbonate solution 2000g, satisfies
It is washed with salt water 2000g, anhydrous sodium sulfate 500g is 3~4 hours dry；Filtering, removes methylene chloride under reduced pressure, and it is solid to obtain yellow blister
Body；Yield 42.1%.
In 5L glass reaction bottle, conjugating intermediate 48g, 1000ml tetrahydrofuran is added, stirs temperature control at 0~5 DEG C, slowly
126ml 2mol/L sulfuric acid solution is added dropwise, drop finishes, and temperature control is stirred to react at 0~5 DEG C, and TLC detects reaction process, end of reaction
Afterwards, 500ml drinking water is added into reaction solution, 1000ml ethyl acetate stirs, liquid separation, and water layer uses ethyl acetate respectively
500ml/ extraction twice, merges organic layer, uses 1000ml saturated sodium bicarbonate solution, 1000ml saturated common salt aqueous solution respectively
Washing, anhydrous sodium sulfate 300g are 3~4 hours dry；Filtering removes ethyl acetate under reduced pressure to doing, obtains faint yellow blister solid；It receives
Rate 83.2%.
Claims (10)
1. a kind of preparation method of tesirolimus, which is characterized in that the preparation method includes the following steps:
Step 1: under nitrogen protection, under alkaline condition, 2,2,5- trimethyl -1,3- dioxane -5- carboxylic acids are molten
In agent, agitation and dropping 2 under room temperature, the solution of 4,6- trichloro-benzoyl chlorides, after the reaction was completed, the double guarantors of rapamycin are added in cooling
The compound of shield, is then added dropwise alkaline solution, to which after the reaction was completed, post-processing obtains conjugating intermediate compound；
Step 2: conjugating intermediate compound is dissolved in solvent, is cooled down, inorganic acid solution is added dropwise, to after the reaction was completed, after
Processing, obtains tesirolimus；
Reaction route are as follows:
2. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1, alkaline condition is
It is provided by one or more of triethylamine, pyridine, 2,6- lutidines, DIPEA and DMAP, preferably triethylamine；2,2,
The molar ratio of 5- trimethyl -1,3- dioxane -5- carboxylic acid and triethylamine is 1:1.3~1.8, preferably 1:1.5.
3. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1,2,2,5- front threes
Base -1,3- dioxane -5- carboxylic acid and 2, the molar ratio of 4,6- trichloro-benzoyl chlorides are 1:1~1.2, preferably 1:1.1.
4. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1, solvent is dichloro
One or both of methane and chloroform, preferably methylene chloride.
5. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1, alkaline solution is
Methylene chloride or three chloromethanes are dissolved in by one or more of triethylamine, pyridine, 2,6- lutidines, DIPEA and DMAP
The in the mixed solvent of alkane or both is formed, and preferably DMAP is dissolved in methylene chloride and is mixed to form；2,2,5- trimethyl -1,3- dioxies
The molar ratio of six ring -5- carboxylic acids and DMAP are 1:1.3~1.8, preferably 1:1.5.
6. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1, rapamycin is double
Compound and 2 is protected, the molar ratio of 2,5- trimethyl -1,3- dioxane -5- carboxylic acids is 1:2.2~3, preferably 1:2.5.
7. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 1, coupling reaction temperature
Degree is -30~-20 DEG C.
8. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 2, in dissolution coupling
The solvent of mesosome is one or more of acetone, butanone, tetrahydrofuran and 2- methyltetrahydrofuran, preferably tetrahydrofuran.
9. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 2, inorganic acid is sulphur
One or more of acid, hydrochloric acid, nitric acid and phosphoric acid, preferably sulfuric acid, conjugating intermediate and sulfuric acid molar ratio are 1:5~7,
It is preferred that 1:6.
10. a kind of preparation method of tesirolimus as described in claim 1, it is characterised in that: in step 2, reaction temperature
It is 0~10 DEG C, preferably 0~5 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1149296A (en) * | 1994-04-18 | 1997-05-07 | 美国家用产品公司 | Rapamycin hydroxyesters, process for their preparation and pharmaceutical compositions containing them |
| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| WO2011051960A2 (en) * | 2009-09-25 | 2011-05-05 | Cadila Healthcare Limited | Process for the preparation of rapamycin derivatives |
| CN103517911A (en) * | 2011-04-01 | 2014-01-15 | 桑多斯股份公司 | Regioselective acylation of rapamycin at the C-42 position |
-
2017
- 2017-05-20 CN CN201710359700.3A patent/CN108948045A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1149296A (en) * | 1994-04-18 | 1997-05-07 | 美国家用产品公司 | Rapamycin hydroxyesters, process for their preparation and pharmaceutical compositions containing them |
| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| WO2011051960A2 (en) * | 2009-09-25 | 2011-05-05 | Cadila Healthcare Limited | Process for the preparation of rapamycin derivatives |
| CN103517911A (en) * | 2011-04-01 | 2014-01-15 | 桑多斯股份公司 | Regioselective acylation of rapamycin at the C-42 position |
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