CN106560471A - Rupatadine preparation proces - Google Patents
Rupatadine preparation proces Download PDFInfo
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- CN106560471A CN106560471A CN201610069504.8A CN201610069504A CN106560471A CN 106560471 A CN106560471 A CN 106560471A CN 201610069504 A CN201610069504 A CN 201610069504A CN 106560471 A CN106560471 A CN 106560471A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The invention discloses a rupatadine preparation process, which comprises: S1, preparing methyl 5-methylnicotinate; S2, preparing 5-methyl-3-pyridinemethanol; S3, preparing 3-methyl-5-chloromethylpyridine hydrochloride; and S4, preparing rupatadine. According to the present invention, the preparation process has advantages of low cost, mild reaction condition, simple operation, low requirement on equipment, good product purity and high yield, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to Rupatadine preparing technical field, more particularly to a kind of preparation technology of Rupatadine.
Background technology
Rupatadine is that [1- [(5- methyl -3- pyridine radicals) methyl] -4- piperidines is sub- for the chloro- 6,11- dihydros -11- of 8-
Base] -5H- benzos [5,6] cycloheptane simultaneously [1,2-b] pyridine.Its molecular formula is C26H26ClN3, molecular weight is
415.96, No. CAS is 158876-82-5, and fusing point is 58-61 DEG C.Rupatadine has antihistamine and antagonism
The dual function of platelet activating factor, is mainly used in treatment allergic rhinitises and pollinosis, with wide
Market prospect.Its structural formula is as follows：
At present, the synthetic route of Rupatadine mainly has two kinds.Route 1 is as follows：
Route 2 is as follows：
In above two route, route 1 is short compared to the circuit of route 2, and saves synthesizing amide and acyl
The reduction step of amine, but the yield of route 1 is low, and reaction selectivity is not strong, is also easy to produce double bromination reactions,
Purer product is arrived seldom.
The committed step of route 2 is the reduction step of synthesizing amide and amide.The method of synthesizing amide is mainly
DCC HOBT carry out acid amide condensation, required dehydrant DC and raceme inhibitor C HOBT under the conditions of DMF
Costly, it is relatively costly, and yield is relatively low；The by-product N of generation, N- 1,3-Dicyclohexylureas (DCU) are most
In organic solvent, dissolubility is little, it is difficult to remove.The method of reducing amide has：Report in patent ES2087818
POCl is used in road3/NaBH4Used as the method for reducing agent reducing amide, the method needed column chromatography just obtain
Qualified products, product purity are high, and yield is good but cumbersome, and purifying products difficulty needed chromatographic column, POCl3
Corrosivity are strong, high to equipment requirements.Describe in United States Patent (USP) No.5407941 in tetrahydrofuran solution,
With lithium aluminium hydride reduction as reducing agent method of reducing, but product yield is low, and purity is poor.In Chinese patent
Describe in CN1865259A in tetrahydrofuran, double hydrogen sodium aluminates are used as the method for reducing of reducing agent, but
Product yield is low, purity is poor, and a class solvent load is big.
Therefore need to provide a kind of low for equipment requirements, product yield is high, and good product purity, reagent are cheap
Rupatadine preparation technology.
The content of the invention
Based on the technical problem that background technology is present, the present invention proposes a kind of preparation technology of Rupatadine,
Low cost of the present invention, reaction condition are gentle, simple to operate, low for equipment requirements, good product purity, yield
Height, is adapted to industrialized great production.
A kind of preparation technology of Rupatadine proposed by the present invention, comprises the steps：
S1, preparation 5- methyinicotinates：5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride rises
Temperature, insulation, Evaporation of methanol and thionyl chloride, water on the rocks obtain solution A；The pH=7-9 of solution A is adjusted,
Plus first organic solvent extraction, take organic faciess evaporation obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：Magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, is heated up
Backflow, is cooled to room temperature and obtains solution B；The 5- methyinicotinates obtained in S1 are added in tetrahydrofuran
Dissolving, adjusts temperature, and Deca solution B, insulation are cooled to room temperature and obtain solution C；Methanol is added to be quenched instead
Should, evaporate tetrahydrofuran and methanol obtains concentrate D；Add water in concentrate D after mixing, it is organic plus the second
Solvent extraction, takes organic faciess evaporation and obtains 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By -3 piconol of 5- methyl obtained in S2
It is dissolved in dioxane, Deca thionyl chloride, the temperature that liquid is kept during Deca is 20-30 DEG C, is risen
Temperature, insulation, evaporation obtain -5 chloromethyl pyridine hydrochloride of 3- methyl；
S4, prepare Rupatadine：Filling N2In environment, by desloratadine, potassium carbonate, N, N dimethyl first
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in amide and S3 is mixed, and is heated up, insulation, adds water to mix
It is even, plus the extraction of the 3rd organic solvent, take organic faciess evaporation and obtain Rupatadine.
Preferably, in S1,5- methylnicotinic acids are 1 with the mol ratio of methanol：10-20.
Preferably, in S1,5- methylnicotinic acids are 1 with the mol ratio of thionyl chloride：1-5.
Preferably, in S1,5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride is warming up to 40-100 DEG C,
Insulation 2.5-7.5h, does not stop stirring, adjusts the temperature to 50-60 DEG C in Deca and insulating process, be evaporated under reduced pressure
Methanol and thionyl chloride are removed, room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, solution is adjusted
The pH=7-9 of A, plus the extraction of the first organic solvent, take organic faciess rotary evaporation and obtain 5- methyinicotinates.
Preferably, in S1, it is preferable that thionyl chloride completion of dropping in the 10-30min.
Preferably, in S1, the pH=7-9 of solution A is adjusted with ammonia.
Preferably, in S1, the first organic solvent is ethyl acetate.
Preferably, in S1, plus the extraction of the first organic solvent, add anhydrous sodium sulfate drying in organic faciess to moisture
Content is≤0.5wt%, filters, takes organic faciess rotary evaporation and obtain 5- methyinicotinates.
Preferably, in S2, the mol ratio of 5- methyinicotinates, magnesium chloride and potassium borohydride is 1：1-5：
1-5, wherein, the mol ratio of magnesium chloride and potassium borohydride is 1：1.
Preferably, in S2, magnesium chloride, potassium borohydride, tetrahydrofuran is mixed, 65-70 DEG C is warming up to,
Backflow 0.5-4.5h, is cooled to room temperature and obtains solution B；The 5- methyinicotinates obtained in S1 are added into four
Dissolve in hydrogen furan, it is 0-80 DEG C to adjust temperature, and Deca solution B is incubated 0.5-1.5h, Deca and insulation
During do not stop stirring, be cooled to room temperature and obtain solution C；Add methanol that reaction is quenched, be warming up to 35-45 DEG C,
Rotary evaporation tetrahydrofuran and methanol obtain concentrate D；Add water in concentrate D after mixing, it is organic plus the second
Solvent extraction, takes organic faciess rotary evaporation and obtains 5- methyl -3- piconols.
Preferably, in S2, solution B completion of dropping in the 0.5-2h.
Preferably, in S2, the second organic solvent is ethyl acetate.
Preferably, in S2, plus the extraction of the second organic solvent, coextraction three times, merge organic faciess, plus it is anhydrous
Sodium sulfate drying is filtered, takes organic faciess rotary evaporation and obtain 5- methyl -3- to being≤0.5wt% to moisture
Piconol.
Preferably, in S3, the mol ratio of -3 piconol of 5- methyl and thionyl chloride is 1：1-3.
Preferably, in S3, -3 piconol of 5- methyl obtained in S2 is dissolved in dioxane, is dripped
Plus thionyl chloride, the temperature that liquid is kept during Deca is 20-30 DEG C, is warming up to 60-80 DEG C, is incubated 3-5h,
Stirring is not stopped in Deca and insulating process, reduction vaporization obtains -5 chloromethyl pyridine hydrochloride of 3- methyl.
Preferably, in S3,3-5h is incubated, does not stop stirring in Deca and insulating process, be cooled to 20-30 DEG C,
It is evaporated under reduced pressure after removing thionyl chloride, is warming up to 60-80 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3- first
- 5 chloromethyl pyridine hydrochloride of base.
Preferably, in S4, desloratadine, potassium carbonate, the mol ratio of -5 chloromethylpyridine hydrochloric acid of 3- methyl are
1：1-4：1-3.
Preferably, in S4, filling N2In environment, by desloratadine, potassium carbonate, DMF
Mix with -5 chloromethyl pyridine hydrochloride of 3- methyl obtained in S3, be warming up to 35-65 DEG C, be incubated 15-25h,
Do not stop stirring in insulating process, add water and mix, plus the extraction of the 3rd organic solvent, take organic faciess rotary evaporation
Obtain Rupatadine.
Preferably, in S4, the 3rd organic solvent is dichloromethane.
Preferably, in S4, add water and mix, plus the 3rd organic solvent carries out at least 1 time extraction, Ran Houhe
And organic faciess obtain solution E, wash solution E 2-3 time with water, after stratification, take the supernatant and obtain molten
Liquid F, then subnatant is solution G, adds the 3rd organic solvent to be extracted, take subnatant in solution F
Solution H is obtained, Solution H and solution G mix homogeneously, rotary evaporation are obtained into Rupatadine.
Preferably, in S4, plus the extraction of the 3rd organic solvent, add anhydrous sodium sulfate drying in organic faciess to moisture
Content is≤0.5wt%, filters, takes organic faciess rotary evaporation and obtain Rupatadine.
Tetrahydrofuran in above-mentioned S2 is solvent, does not specify its consumption.
Methanol in above-mentioned S2 is, for reaction is quenched, not specify its consumption.
5- methyl -3- the piconols obtained in above-mentioned S2, can pass through column chromatography or recrystallization is further carried
It is pure.
Dioxane in above-mentioned S3 is solvent, does not specify its consumption.
DMF in above-mentioned S4 is solvent, does not specify its consumption.
The Rupatadine obtained in above-mentioned S4, can pass through column chromatography or recrystallization is further purified.
Above-mentioned " water " is deionized water.
The raw material and reagent that the present invention is selected is cheap and easy to get, low cost；Reaction condition is gentle, consumes energy low, behaviour
Make simple, it is low for equipment requirements, it is adapted to industrialized great production；3- methyl-5-chloros methyl pyridinium chloride and ground
When Luo Tading reacts, the selectivity of 3- methyl-5-chloro methyl pyridinium chlorides is higher, is difficult to generate by-product pair
Chloro-product, the good product purity for obtaining, product yield are high.
Description of the drawings
Fig. 1 is a kind of synthetic route chart of the preparation technology of Rupatadine proposed by the present invention.
Specific embodiment
With reference to Fig. 1, a kind of preparation technology of Rupatadine proposed by the present invention comprises the steps：
S1, preparation 5- methyinicotinates：5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride rises
Temperature, insulation, Evaporation of methanol and thionyl chloride, water on the rocks obtain solution A；The pH=7-9 of solution A is adjusted,
Plus first organic solvent extraction, take organic faciess evaporation obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：Magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, is heated up
Backflow, is cooled to room temperature and obtains solution B；The 5- methyinicotinates obtained in S1 are added in tetrahydrofuran
Dissolving, adjusts temperature, and Deca solution B, insulation are cooled to room temperature and obtain solution C；Methanol is added to be quenched instead
Should, evaporate tetrahydrofuran and methanol obtains concentrate D；Add water in concentrate D after mixing, it is organic plus the second
Solvent extraction, takes organic faciess evaporation and obtains 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By -3 piconol of 5- methyl obtained in S2
It is dissolved in dioxane, Deca thionyl chloride, the temperature that liquid is kept during Deca is 20-30 DEG C, is risen
Temperature, insulation, evaporation obtain -5 chloromethyl pyridine hydrochloride of 3- methyl；
S4, prepare Rupatadine：Filling N2In environment, by desloratadine, potassium carbonate, N, N dimethyl first
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in amide and S3 is mixed, and is heated up, insulation, adds water to mix
It is even, plus the extraction of the 3rd organic solvent, take organic faciess evaporation and obtain Rupatadine.
Below, technical scheme is described in detail by specific embodiment.
Embodiment 1
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride rises
Temperature is incubated 7.5h to 40 DEG C, does not stop stirring, adjust the temperature to 50 DEG C in Deca and insulating process, and decompression is steamed
Send out and remove methanol and thionyl chloride, be cooled to room temperature, add frozen water to obtain solution A；In ice bath, adjust molten
The pH=9 of liquid A, plus ethyl acetate extraction, take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：Magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, is heated up
To 65 DEG C, flow back 4.5h, is cooled to room temperature and obtains solution B；By the 5- methyinicotinates obtained in S1
Dissolve in adding tetrahydrofuran, it is 0 DEG C to adjust temperature, and Deca solution B is incubated 1.5h, Deca and was incubated
Do not stop stirring in journey, be cooled to room temperature and obtain solution C；Add methanol that reaction is quenched, be warming up to 35 DEG C, revolve
Turn evaporation removing tetrahydrofuran and methanol obtains concentrate D；Add water in concentrate D after mixing, plus acetic acid second
Ester is extracted, and is taken ethyl acetate phase rotary evaporation and is obtained 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By -3 piconol of 5- methyl obtained in S2
It is dissolved in dioxane, Deca thionyl chloride, the temperature that liquid is kept during Deca is 30 DEG C, is heated up
To 60 DEG C, 5h is incubated, in Deca and insulating process, does not stop stirring, reduction vaporization obtains -5 chloromethane of 3- methyl
Ylpyridine hydrochloride；
S4, prepare Rupatadine：Filling N2In environment, by desloratadine, potassium carbonate, N, N dimethyl first
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in amide and S3 is mixed, and is warming up to 35 DEG C, is incubated 25h,
Do not stop stirring in insulating process, add water and mix, add methylene chloride extraction, takes dichloromethane phase rotary evaporation
Obtain Rupatadine.
Embodiment 2
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride rises
Temperature is incubated 2.5h to 100 DEG C, does not stop stirring, adjust the temperature to 60 DEG C in Deca and insulating process, reduces pressure
Methanol removed by evaporation and thionyl chloride, are cooled to room temperature, add frozen water to obtain solution A；In ice bath, adjust
The pH=7 of solution A, plus ethyl acetate extraction, take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：Magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, is heated up
To 70 DEG C, flow back 0.5h, is cooled to room temperature and obtains solution B；By the 5- methyinicotinates obtained in S1
Dissolve in adding tetrahydrofuran, it is 80 DEG C to adjust temperature, and Deca solution B is incubated 0.5h, Deca and insulation
During do not stop stirring, be cooled to room temperature and obtain solution C；Add methanol that reaction is quenched, be warming up to 45 DEG C,
Rotary evaporation removes tetrahydrofuran and methanol obtains concentrate D；Add water in concentrate D after mixing, plus acetic acid
Ethyl ester is extracted, and is taken ethyl acetate phase rotary evaporation and is obtained 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By -3 piconol of 5- methyl obtained in S2
It is dissolved in dioxane, Deca thionyl chloride, the temperature that liquid is kept during Deca is 20 DEG C, is heated up
To 80 DEG C, 3h is incubated, in Deca and insulating process, does not stop stirring, reduction vaporization obtains -5 chloromethane of 3- methyl
Ylpyridine hydrochloride；
S4, prepare Rupatadine：Filling N2In environment, by desloratadine, potassium carbonate, N, N dimethyl first
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in amide and S3 is mixed, and is warming up to 65 DEG C, is incubated 15h,
Do not stop stirring in insulating process, add water and mix, add methylene chloride extraction, takes dichloromethane phase rotary evaporation
Obtain Rupatadine.
Embodiment 3
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：1 part of 5- methylnicotinic acid, 10 parts of methanol are mixed by molar part,
5 parts of thionyl chlorides of Deca, thionyl chloride completion of dropping in the 10min, are warming up to 90 DEG C, are incubated 3h, drop
Plus with insulating process in do not stop stirring, adjust the temperature to 58 DEG C, be evaporated under reduced pressure and remove methanol and thionyl chloride,
Room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, the pH=7.5 of solution A is adjusted with ammonia,
Plus ethyl acetate extraction, add anhydrous sodium sulfate drying to moisture to be 0.5wt% in ethyl acetate phase, filter,
Take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：By molar part by 1 part of magnesium chloride, 1 part of potassium borohydride, four
Hydrogen furan is mixed, and is warming up to 66 DEG C, and flow back 4h, is cooled to room temperature and obtains solution B；To obtain in 1 part of S1
5- methyinicotinates add tetrahydrofuran in dissolve, adjust temperature be 10 DEG C, Deca solution B, solution
B completion of dropping in the 2h, is incubated 1.3h, does not stop stirring, be cooled to room temperature and obtain in Deca and insulating process
Solution C；Add methanol that reaction is quenched, be warming up to 35 DEG C, rotary evaporation removes tetrahydrofuran and methanol is obtained
Concentrate D；Add water in concentrate D after mixing, plus ethyl acetate extraction, coextraction three times, merge acetic acid
Ethyl ester phase, plus anhydrous sodium sulfate drying to moisture be 0.5wt%, filter, take ethyl acetate phase rotation
Evaporation obtains 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By the 5- first that molar part will be obtained in 1 part of S2
- 3 piconol of base is dissolved in dioxane, 3 parts of thionyl chlorides of Deca, and liquid is kept during Deca
Temperature is 22 DEG C, is warming up to 75 DEG C, is incubated 3.5h, does not stop stirring, be cooled in Deca and insulating process
30 DEG C, it is evaporated under reduced pressure after removing thionyl chloride, is warming up to 60 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3-
- 5 chloromethyl pyridine hydrochloride of methyl；
S4, prepare Rupatadine：Filling N2In environment, by molar part by 1 part of desloratadine, 1 part of potassium carbonate,
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in DMF and 3 parts of S3 is mixed, and is heated up
To 40 DEG C, 23h is incubated, does not stop stirring in insulating process, add water and mix, add methylene chloride extraction 6 times,
It is then combined with dichloromethane and mutually obtains solution E, washes solution E 2 times with water, after stratification, take upper strata clear
Liquid obtains solution F, then subnatant is solution G, adds methylene chloride and is extracted, remove layer in solution F
Clear liquid obtains Solution H, by Solution H and solution G mix homogeneously, plus anhydrous sodium sulfate drying to moisture is
0.5wt%, filters, and rotary evaporation obtains Rupatadine.
Embodiment 4
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：1 part of 5- methylnicotinic acid, 20 parts of methanol are mixed by molar part,
1 part of thionyl chloride of Deca, thionyl chloride completion of dropping in the 30min, is warming up to 60 DEG C, is incubated 7h, drop
Plus with insulating process in do not stop stirring, adjust the temperature to 52 DEG C, be evaporated under reduced pressure and remove methanol and thionyl chloride,
Room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, the pH=8.5 of solution A is adjusted with ammonia,
Plus ethyl acetate extraction, add anhydrous sodium sulfate drying to moisture to be 0.1wt% in ethyl acetate phase, filter,
Take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：By molar part by 5 parts of magnesium chlorides, 5 parts of potassium borohydrides, four
Hydrogen furan is mixed, and is warming up to 69 DEG C, and flow back 1h, is cooled to room temperature and obtains solution B；To obtain in 1 part of S1
5- methyinicotinates add tetrahydrofuran in dissolve, adjust temperature be 70 DEG C, Deca solution B, solution
B completion of dropping in the 0.5h, is incubated 0.7h, does not stop stirring, be cooled to room temperature and obtain in Deca and insulating process
To solution C；Add methanol that reaction is quenched, be warming up to 45 DEG C, rotary evaporation removes tetrahydrofuran and methanol is obtained
To concentrate D；Add water in concentrate D after mixing, plus ethyl acetate extraction, coextraction three times, merge second
Acetoacetic ester phase, plus anhydrous sodium sulfate drying to moisture be 0.1wt%, filter, take ethyl acetate phase rotation
Turn evaporation and obtain 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By the 5- first that molar part will be obtained in 1 part of S2
- 3 piconol of base is dissolved in dioxane, 1 part of thionyl chloride of Deca, and liquid is kept during Deca
Temperature is 28 DEG C, is warming up to 65 DEG C, is incubated 4.5h, does not stop stirring, be cooled in Deca and insulating process
20 DEG C, it is evaporated under reduced pressure after removing thionyl chloride, is warming up to 80 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3-
- 5 chloromethyl pyridine hydrochloride of methyl；
S4, prepare Rupatadine：Filling N2In environment, by molar part by 1 part of desloratadine, 4 parts of potassium carbonate,
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in DMF and 1 part of S3 is mixed, and is heated up
To 60 DEG C, 17h is incubated, does not stop stirring in insulating process, add water and mix, add methylene chloride extraction 3 times,
It is then combined with dichloromethane and mutually obtains solution E, washes solution E 3 times with water, after stratification, take upper strata clear
Liquid obtains solution F, then subnatant is solution G, adds methylene chloride and is extracted, remove layer in solution F
Clear liquid obtains Solution H, by Solution H and solution G mix homogeneously, plus anhydrous sodium sulfate drying to moisture is
0.1wt%, filters, and rotary evaporation obtains Rupatadine.
Embodiment 5
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：1 part of 5- methylnicotinic acid, 18 parts of methanol are mixed by molar part,
2 parts of thionyl chlorides of Deca, thionyl chloride completion of dropping in the 25min, are warming up to 70 DEG C, are incubated 6.5h,
Do not stop stirring in Deca and insulating process, adjust the temperature to 54 DEG C, be evaporated under reduced pressure and remove methanol and thionyl chloride,
Room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, the pH=8.2 of solution A is adjusted with ammonia,
Plus ethyl acetate extraction, add anhydrous sodium sulfate drying to moisture to be 0.2wt% in ethyl acetate phase, filter,
Take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：By molar part by 4 parts of magnesium chlorides, 4 parts of potassium borohydrides, four
Hydrogen furan is mixed, and is warming up to 68 DEG C, and flow back 1.5h, is cooled to room temperature and obtains solution B；To obtain in 1 part of S1
To 5- methyinicotinates add tetrahydrofuran in dissolve, adjust temperature be 60 DEG C, Deca solution B is molten
Liquid B completion of dropping in the 1.5h, is incubated 0.8h, does not stop stirring, be cooled to room temperature in Deca and insulating process
Obtain solution C；Add methanol that reaction is quenched, be warming up to 42 DEG C, rotary evaporation removes tetrahydrofuran and methanol
Obtain concentrate D；Add water in concentrate D after mixing, plus ethyl acetate extraction, coextraction three times, merge
Ethyl acetate phase, plus anhydrous sodium sulfate drying to moisture be 0.4wt%, filter, take ethyl acetate phase
Rotary evaporation obtains 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By the 5- first that molar part will be obtained in 1 part of S2
- 3 piconol of base is dissolved in dioxane, 1.5 parts of thionyl chlorides of Deca, and liquid is kept during Deca
Temperature be 26 DEG C, be warming up to 68 DEG C, be incubated 4.3h, do not stop in Deca and insulating process stirring, be cooled to
23 DEG C, it is evaporated under reduced pressure after removing thionyl chloride, is warming up to 75 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3-
- 5 chloromethyl pyridine hydrochloride of methyl；
S4, prepare Rupatadine：Filling N2In environment, by molar part by 1 part of desloratadine, 3 parts of potassium carbonate,
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in DMF and 1.5 parts of S3 is mixed, and is risen
Temperature is incubated 18h to 55 DEG C, does not stop stirring in insulating process, and after adding water and mixing, add methylene chloride extraction 5
It is secondary, it is then combined with dichloromethane and mutually obtains solution E, washes solution E 3 times with water, after stratification, take
Layer clear liquid obtains solution F, then subnatant is solution G, adds methylene chloride and is extracted, take in solution F
Subnatant obtains Solution H, and Solution H and solution G mix homogeneously, plus anhydrous sodium sulfate drying are contained to moisture
Measure as 0.2wt%, filter, rotary evaporation obtains Rupatadine.
Embodiment 6
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：1 part of 5- methylnicotinic acid, 14 parts of methanol are mixed by molar part,
4 parts of thionyl chlorides of Deca, thionyl chloride completion of dropping in the 15min, are warming up to 85 DEG C, are incubated 3.5h,
Do not stop stirring in Deca and insulating process, adjust the temperature to 56 DEG C, be evaporated under reduced pressure and remove methanol and thionyl chloride,
Room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, the pH=7.8 of solution A is adjusted with ammonia,
Plus ethyl acetate extraction, add anhydrous sodium sulfate drying to moisture to be 0.4wt% in ethyl acetate phase, filter,
Take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：By molar part by 3 parts of magnesium chlorides, 3 parts of potassium borohydrides, four
Hydrogen furan is mixed, and is warming up to 67 DEG C, and flow back 3.5h, is cooled to room temperature and obtains solution B；To obtain in 1 part of S1
To 5- methyinicotinates add tetrahydrofuran in dissolve, adjust temperature be 20 DEG C, Deca solution B is molten
Liquid B completion of dropping in the 1h, is incubated 1.2h, does not stop stirring, be cooled to room temperature and obtain in Deca and insulating process
To solution C；Add methanol that reaction is quenched, be warming up to 38 DEG C, rotary evaporation removes tetrahydrofuran and methanol is obtained
To concentrate D；Add water in concentrate D after mixing, plus ethyl acetate extraction, coextraction three times, merge second
Acetoacetic ester phase, plus anhydrous sodium sulfate drying to moisture be 0.2wt%, filter, take ethyl acetate phase rotation
Turn evaporation and obtain 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By the 5- first that molar part will be obtained in 1 part of S2
- 3 piconol of base is dissolved in dioxane, 2.5 parts of thionyl chlorides of Deca, and liquid is kept during Deca
Temperature be 24 DEG C, be warming up to 72 DEG C, be incubated 3.7h, do not stop in Deca and insulating process stirring, be cooled to
27 DEG C, it is evaporated under reduced pressure after removing thionyl chloride, is warming up to 65 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3-
- 5 chloromethyl pyridine hydrochloride of methyl；
S4, prepare Rupatadine：Filling N2In environment, by molar part by 1 part of desloratadine, 2 parts of potassium carbonate,
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in DMF and 2.5 parts of S3 is mixed, and is risen
Temperature is incubated 22h to 45 DEG C, does not stop stirring in insulating process, and after adding water and mixing, add methylene chloride extraction 6
It is secondary, it is then combined with dichloromethane and mutually obtains solution E, after washing 2 stratification of solution E with water, takes upper strata
Clear liquid obtains solution F, then subnatant is solution G, adds methylene chloride and is extracted, remove in solution F
Layer clear liquid obtains Solution H, and by Solution H and solution G mix homogeneously, plus anhydrous sodium sulfate drying is to moisture
For 0.4wt%, filter, rotary evaporation obtains Rupatadine.
Embodiment 7
A kind of preparation technology of Rupatadine, comprises the steps：
S1, preparation 5- methyinicotinates：1 part of 5- methylnicotinic acid, 16 parts of methanol are mixed by molar part,
3 parts of thionyl chlorides of Deca, thionyl chloride completion of dropping in the 20min, are warming up to 82 DEG C, are incubated 6h, drop
Plus with insulating process in do not stop stirring, adjust the temperature to 55 DEG C, be evaporated under reduced pressure and remove methanol and thionyl chloride,
Room temperature is cooled to, adds frozen water to obtain solution A；In ice bath, the pH=8 of solution A is adjusted with ammonia, plus
Ethyl acetate is extracted, and adds anhydrous sodium sulfate drying to moisture to be 0.3wt%, filter in ethyl acetate phase,
Take ethyl acetate phase rotary evaporation and obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：By molar part by 2 parts of magnesium chlorides, 2 parts of potassium borohydrides, four
Hydrogen furan is mixed, and is warming up to 67 DEG C, and flow back 2h, is cooled to room temperature and obtains solution B；By what is obtained in S1
5- methyinicotinates are dissolved in adding tetrahydrofuran, and it is 40 DEG C to adjust temperature, Deca solution B, solution B
The completion of dropping in the 1.3h, is incubated 1h, does not stop stirring, be cooled to room temperature and obtain molten in Deca and insulating process
Liquid C；Add methanol that reaction is quenched, be warming up to 40 DEG C, rotary evaporation removes tetrahydrofuran and methanol obtains dense
Contracting thing D；Add water in concentrate D after mixing, plus ethyl acetate extraction, coextraction three times, merge acetic acid second
Ester phase, plus anhydrous sodium sulfate drying to moisture be 0.3wt%, filter, take ethyl acetate phase rotation steam
Send out and obtain 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By the 5- first that molar part will be obtained in 1 part of S2
- 3 piconol of base is dissolved in dioxane, 2 parts of thionyl chlorides of Deca, and liquid is kept during Deca
Temperature is 25 DEG C, is warming up to 70 DEG C, is incubated 4h, does not stop stirring, be cooled to 25 DEG C in Deca and insulating process,
It is evaporated under reduced pressure after removing thionyl chloride, is warming up to 70 DEG C, removing dioxane is evaporated under reduced pressure and obtains 3- methyl -5
Chloromethyl pyridine hydrochloride；
S4, prepare Rupatadine：Filling N2In environment, by molar part by 1 part of desloratadine, 2.5 parts of carbonic acid
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in potassium, DMF and 2 parts of S3 is mixed,
50 DEG C are warming up to, 20h is incubated, in insulating process, do not stop stirring, after adding water and mixing, add methylene chloride extraction
Take 5 times, be then combined with dichloromethane and mutually obtain solution E, wash solution E 2 times with water, take the supernatant and obtain
To solution F, then subnatant is solution G, adds methylene chloride and is extracted, take subnatant in solution F
Solution H is obtained, by Solution H and solution G mix homogeneously, plus anhydrous sodium sulfate drying to moisture is
0.3wt%, filters, and rotary evaporation obtains Rupatadine.
Embodiment 1 and embodiment 2 are not provided proportioning raw materials situation, i.e. raw material and can be reacted with arbitrary proportion,
Because ratio change does not generally affect the carrying out reacted, the height of yield is simply influenced whether.
Fusing point, purity test calculated yield are carried out to embodiment 3-7, it is as a result as shown in the table：
The Rupatadine purity height for preparing of the invention can be obtained by upper table, yield is good.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention not office
Be limited to this, any those familiar with the art the invention discloses technical scope in, according to this
The technical scheme of invention and its inventive concept in addition equivalent or change, should all cover the protection in the present invention
Within the scope of.
Claims (10)
1. a kind of preparation technology of Rupatadine, it is characterised in that comprise the steps：
S1, preparation 5- methyinicotinates：5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride rises
Temperature, insulation, Evaporation of methanol and thionyl chloride, water on the rocks obtain solution A；The pH=7-9 of solution A is adjusted,
Plus first organic solvent extraction, take organic faciess evaporation obtain 5- methyinicotinates；
S2, preparation 5- methyl -3- piconols：Magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, is risen
Temperature backflow, is cooled to room temperature and obtains solution B；The 5- methyinicotinates obtained in S1 are added into tetrahydrofuran
Middle dissolving, adjusts temperature, and Deca solution B, insulation are cooled to room temperature and obtain solution C；Methanol is added to be quenched
Reaction, evaporation tetrahydrofuran and methanol obtain concentrate D；Add water in concentrate D after mixing, plus the second
Organic solvent is extracted, and is taken organic faciess evaporation and is obtained 5- methyl -3- piconols；
S3, -5 chloromethyl pyridine hydrochloride of preparation 3- methyl：By -3 piconol of 5- methyl obtained in S2
It is dissolved in dioxane, Deca thionyl chloride, the temperature that liquid is kept during Deca is 20-30 DEG C,
Heat up, insulation, evaporation obtain -5 chloromethyl pyridine hydrochloride of 3- methyl；
S4, prepare Rupatadine：Filling N2In environment, by desloratadine, potassium carbonate, N, N dimethyl first
- 5 chloromethyl pyridine hydrochloride of 3- methyl obtained in amide and S3 is mixed, and is heated up, insulation, adds water to mix
It is even, plus the extraction of the 3rd organic solvent, take organic faciess evaporation and obtain Rupatadine.
2. the preparation technology of Rupatadine according to claim 1, it is characterised in that in S1,5- first
Base nicotinic acid is 1 with the mol ratio of methanol：10-20.
3. according to claim 1 or the preparation technology of 2 Rupatadines, it is characterised in that in S1,
5- methylnicotinic acids are 1 with the mol ratio of thionyl chloride：1-5.
4. according to any one of claim 1-3 Rupatadine preparation technology, it is characterised in that S1
In, 5- methylnicotinic acids, methanol are mixed, Deca thionyl chloride is warming up to 40-100 DEG C, is incubated 2.5-7.5h,
Do not stop stirring in Deca and insulating process, adjust the temperature to 50-60 DEG C, be evaporated under reduced pressure and remove methanol and chlorination
Sulfoxide, is cooled to room temperature, adds frozen water to obtain solution A；In ice bath, the pH=7-9 of solution A is adjusted,
Plus first organic solvent extraction, take organic faciess rotary evaporation and obtain 5- methyinicotinates；Preferably, chlorination
Sulfoxide completion of dropping in the 10-30min；Preferably, the pH=7-9 of solution A is adjusted with ammonia；Preferably,
First organic solvent is ethyl acetate；Preferably, plus the extraction of the first organic solvent, in organic faciess plus anhydrous sulfur
Sour sodium drying is≤0.5wt% to moisture, filters, takes organic faciess rotary evaporation and obtain 5- methylnicotinic acid first
Ester.
5. according to any one of claim 1-4 Rupatadine preparation technology, it is characterised in that S2
In, the mol ratio of 5- methyinicotinates, magnesium chloride and potassium borohydride is 1：1-5：1-5, wherein, chlorine
The mol ratio for changing magnesium and potassium borohydride is 1：1.
6. according to any one of claim 1-5 Rupatadine preparation technology, it is characterised in that S2
In, magnesium chloride, potassium borohydride, tetrahydrofuran are mixed, 65-70 DEG C is warming up to, flow back 0.5-4.5h,
It is cooled to room temperature and obtains solution B；The 5- methyinicotinates obtained in S1 are added in tetrahydrofuran and are dissolved,
It is 0-80 DEG C to adjust temperature, and Deca solution B is incubated 0.5-1.5h, does not stop stirring in Deca and insulating process,
It is cooled to room temperature and obtains solution C；Add methanol that reaction is quenched, be warming up to 35-45 DEG C, rotary evaporation removes four
Hydrogen furan and methanol obtain concentrate D；Add water in concentrate D after mixing, plus the extraction of the second organic solvent,
Take organic faciess rotary evaporation and obtain 5- methyl -3- piconols；Preferably, solution B Deca in the 0.5-2h
Finish；Preferably, the second organic solvent is ethyl acetate；Preferably, plus the extraction of the second organic solvent, altogether
Extraction three times, merges organic faciess, plus anhydrous sodium sulfate drying is filtered to being≤0.5wt% to moisture,
Take organic faciess rotary evaporation and obtain 5- methyl -3- piconols.
7. according to any one of claim 1-6 Rupatadine preparation technology, it is characterised in that S3
In, the mol ratio of -3 piconol of 5- methyl and thionyl chloride is 1：1-3.
8. according to any one of claim 1-7 Rupatadine preparation technology, it is characterised in that S3
In, -3 piconol of 5- methyl obtained in S2 is dissolved in dioxane, Deca thionyl chloride, is dripped
Plus during keep the temperature of liquid to be 20-30 DEG C, be warming up to 60-80 DEG C, be incubated 3-5h, Deca and guarantor
Stirring is not stopped during temperature, reduction vaporization obtains -5 chloromethyl pyridine hydrochloride of 3- methyl；Preferably, it is incubated
Do not stop stirring in 3-5h, Deca and insulating process, be cooled to 20-30 DEG C, be evaporated under reduced pressure and remove thionyl chloride
Afterwards, 60-80 DEG C is warming up to, removing dioxane is evaporated under reduced pressure and is obtained -5 chloromethyl pyridine hydrochloride of 3- methyl.
9. according to any one of claim 1-8 Rupatadine preparation technology, it is characterised in that S4
In, desloratadine, potassium carbonate, the mol ratio of -5 chloromethylpyridine hydrochloric acid of 3- methyl are 1：1-4：1-3.
10. according to any one of claim 1-9 Rupatadine preparation technology, it is characterised in that S4
In, filling N2In environment, by what is obtained in desloratadine, potassium carbonate, DMF and S3
- 5 chloromethyl pyridine hydrochloride of 3- methyl is mixed, and is warming up to 35-65 DEG C, is incubated 15-25h, in insulating process
Do not stop stirring, add water and mix, plus the extraction of the 3rd organic solvent, take organic faciess rotary evaporation and obtain Lu Pata
It is fixed；Preferably, the 3rd organic solvent is dichloromethane；Preferably, add water and mix, plus the 3rd organic molten
Agent carries out at least 1 time extraction, is then combined with organic faciess and obtains solution E, washes solution E 2-3 time with water,
After stratification, take the supernatant and obtain solution F, then subnatant is solution G, add the 3rd in solution F
Organic solvent is extracted, and is taken subnatant and is obtained Solution H, and Solution H and solution G mix homogeneously revolve
Turn evaporation and obtain Rupatadine；Preferably, plus the extraction of the 3rd organic solvent, in organic faciess plus anhydrous sodium sulfate
It is≤0.5wt% to be dried to moisture, filters, takes organic faciess rotary evaporation and obtain Rupatadine.
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| CN110713481A (en) * | 2019-11-29 | 2020-01-21 | 杭州澳医保灵药业有限公司 | Preparation method of rupatadine |
| CN113121420A (en) * | 2021-05-19 | 2021-07-16 | 北京嘉林药业股份有限公司 | Preparation method of rupatadine fumarate intermediate 5-methyl-3-chloromethyl pyridine hydrochloride |
| CN114920727A (en) * | 2022-05-26 | 2022-08-19 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
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| CN110713481A (en) * | 2019-11-29 | 2020-01-21 | 杭州澳医保灵药业有限公司 | Preparation method of rupatadine |
| CN113121420A (en) * | 2021-05-19 | 2021-07-16 | 北京嘉林药业股份有限公司 | Preparation method of rupatadine fumarate intermediate 5-methyl-3-chloromethyl pyridine hydrochloride |
| CN114920727A (en) * | 2022-05-26 | 2022-08-19 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
| CN114920727B (en) * | 2022-05-26 | 2023-07-25 | 重庆华邦制药有限公司 | Preparation method of rupatadine |
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