CN108440452A - A kind of key intermediate 1- of almotriptan（4- amino-benzyl sulfonyls）The preparation method of pyrrolidines - Google Patents
A kind of key intermediate 1- of almotriptan（4- amino-benzyl sulfonyls）The preparation method of pyrrolidines Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Abstract
The invention discloses the preparation method of a kind of key intermediate 1 of almotriptan (4 aminobenzene methyl sulphonyl) pyrrolidines, key step is as follows：1) Vilsmeier reagents are prepared with BTC and DMF, p-nitrophenyl methanesulfonic acid is raw material, with Vilsmeier reagent sulfonylations under the conditions of base catalysis, generates p-nitrophenyl mesyl chloride；2) using 4-Nitrobenzenesulfonyl chloride as raw material, nucleophilic addition elimination reaction is carried out with pyrroles under base catalysis, 1 (4 nitrobenzene methyl sulphonyl) pyrrolidines is obtained through processing after reaction；3) 1 (4 nitrobenzene methyl sulphonyl) pyrrolidines is passed through hydrogen under metallic catalyst and carries out catalytic hydrogenation reaction; it is evaporated under reduced pressure after anhydrous sodium sulfate drying after merging organic phase, obtains 1 (4 aminobenzene methyl sulphonyl) pyrrolidines.The present invention proposes the preparation method of the key intermediate of almotriptan synthesis, makes it have the characteristics of synthesizing economy, environment friendly, simple process.
Description
Technical field
The present invention relates to pharmaceutical technology field, key intermediate 1- (the 4- amino-benzyls of specifically a kind of almotriptan
Sulfonyl) pyrrolidines preparation method.
Background technology
Almotriptan (Almotriptan), entitled 3- [2- (dimethylamine) ethyl] -5- (the pyrrolidin-1-yl sulphonyl first of chemistry
Base) -1H- indoles, a kind of 5-HT for sieve company research and development of liking to be beautiful for Spain1B/1DReceptor stimulating agent, clinic are mainly used for migraine
Treatment, structural formula is as follows：
In existing synthetic technology, WO2008151584, WO2009016414 have used indole synthesis method to synthesize
Almotriptan, and be all initial compounds from 1- (4- amino-benzyls sulfonyl) pyrrolidines, by diazo reaction, reduction, hydrazone
Form protection and cyclization methylate to obtain product.Synthetic route is as follows：
Heck connections have synthesized almotriptan in disclosing one in WO2006129190, still from 1- (4- amino-benzyls
Sulfonyl) halogenated, coupling is begun to pass through in pyrrolidines to obtain product, but the method needs the examination of the costliness such as n-BuLi
Agent and post-processing difficulty etc., improper large-scale industrialization etc..Synthetic route is as follows：
To sum up：Almotriptan synthetic method is more, but is all mostly from 1- (4- amino-benzyls sulfonyl) pyrroles
Alkane is initial compounds, so propose a kind of intermediate synthetic method of key, makes it have and synthesizes economy, environmental-friendly
Property, simple process be very it is necessary to.
Invention content
The purpose of the present invention is to provide a kind of key intermediate 1- of almotriptan (4- amino-benzyls sulfonyl) pyrroles
The preparation method of alkane is coughed up, to solve the problems mentioned in the above background technology.
To achieve the above object, the present invention provides the following technical solutions：
A kind of preparation method of the key intermediate 1- of almotriptan (4- amino-benzyls sulfonyl) pyrrolidines, master
Want that steps are as follows：
Step 1：It is spare with triphosgene (BTC) and dinethylformamide (DMF) preparation Vilsmeier reagents, to nitro
Benzene methanesulfonic acid is raw material, with Vilsmeier reagent sulfonylations under the conditions of base catalysis, monitors reaction process with TLC, generates
P-nitrophenyl mesyl chloride；
Step 2：The 4-Nitrobenzenesulfonyl chloride obtained using step 1 adds under base catalysis with pyrroles's progress nucleophilic as raw material
At-elimination reaction, is monitored and reacted with TLC, after being extracted by saturated sodium bicarbonate, saturated salt solution after reaction, organic phase nothing
Vacuum distillation obtains 1- (4- Nitro-benzyls sulfonyl) pyrrolidines after aqueous sodium persulfate drying；
Step 3：Above-mentioned 1- obtained by the reaction (4- Nitro-benzyls sulfonyl) pyrrolidines, is passed through under metallic catalyst
Hydrogen carries out catalytic hydrogenation reaction, and it is 3-4 to adjust PH after reaction, after aqueous layer with ethyl acetate extracts 2 times after extraction, water layer
It is 13 to adjust PH again, and ethyl acetate extracts 2-3 times, is evaporated under reduced pressure after anhydrous sodium sulfate drying after merging organic phase, obtains 1-
(4- amino-benzyls sulfonyl) pyrrolidines.
As a further solution of the present invention：The solvation of BTC and DMF reactions is selected from dichloromethane in the step 1
One or several kinds of mixed solvents in alkane, dichloroethanes, tetrahydrofuran, dioxane, chloroform.
As further scheme of the invention：P-nitrophenyl methanesulfonic acid and Vilsmeier reagents in the step one
Sulfonylation solvent selection dichloromethane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, the benzene of progress
One or several kinds of mixed solvents.
As further scheme of the invention：The nucleophilic that the step two p-nitrophenyl mesyl chloride is carried out with pyrroles
Addition-elimination reaction solvent selection dichloromethane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene,
One or several kinds of mixed solvents in chlorobenzene, toluene.
As further scheme of the invention：The solvent selection methanol of the reduction reaction of the step trinitro-, second
Alcohol, n-butanol, dichloromethane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene, toluene one kind or
Several mixed solvents.
As further scheme of the invention：The temperature that in the step 1 prepared by Vilsmeier reagents is -10 DEG C -0
DEG C, the nucleophilic addition-elimination in 25-60 DEG C, the step two of the reaction temperature of sulfonylation is anti-in the step one
The temperature answered is 45-80 DEG C, and the temperature of nitro-reduction reaction is 35-60 DEG C in the step three.
As further scheme of the invention：The reaction time that in the step 1 prepared by Vilsmeier reagents is 30-
60min；The reaction time of sulfonylation is 60min-4h in the step 1；Nucleophilic addition-elimination in the step two
The reaction time of reaction is 30min-6h；The reaction time of nitro-reduction reaction is 30min-12h in the step three.
As further scheme of the invention：Triphosgene and DMF during in the step 1 prepared by Vilsmeier reagents
Ratio is 0.33: 1-1.2.
As further scheme of the invention：, the ratio of p-nitrophenyl methanesulfonic acid and pyrroles are 1 in the step two
∶1-2。
Compared with prior art, the beneficial effects of the invention are as follows：The present invention is proposed synthesizes almotriptan by intermediate
Preparation method, make it have synthesis economy, environment friendly, simple process the characteristics of.
Specific implementation mode
Technical scheme of the present invention is described in more detail With reference to embodiment.
A kind of preparation method of the key intermediate 1- of almotriptan (4- amino-benzyls sulfonyl) pyrrolidines, master
Want that steps are as follows：
Step 1：It is spare with triphosgene (BTC) and dinethylformamide (DMF) preparation Vilsmeier reagents, to nitro
Benzene methanesulfonic acid is raw material, with Vilsmeier reagent sulfonylations under the conditions of base catalysis, monitors reaction process with TLC, generates
P-nitrophenyl mesyl chloride (formula 1) is not processed and directly carries out next step reaction；
Step 2：The 4-Nitrobenzenesulfonyl chloride obtained using step 1 adds under base catalysis with pyrroles's progress nucleophilic as raw material
At-elimination reaction, is monitored and reacted with TLC, after being extracted by saturated sodium bicarbonate, saturated salt solution after reaction, organic phase nothing
Vacuum distillation obtains 1- (4- Nitro-benzyls sulfonyl) pyrrolidines (formula 2) after aqueous sodium persulfate drying；
1HNMR(CDCl3)：1.87-1.92 (m, 4H), 3.25-3.28 (t, 4H), 4.35 (s, 2H), 7.59-7.61 (d,
2H), 8.25-8.27 (d, 2H), MS (ESI)；271(100)([M+100]+)
Step 3：Above-mentioned 1- obtained by the reaction (4- Nitro-benzyls sulfonyl) pyrrolidines, is passed through under metallic catalyst
Hydrogen carries out catalytic hydrogenation reaction, and it is 3-4 to adjust PH after reaction, after aqueous layer with ethyl acetate extracts 2 times after extraction, water layer
It is 13 to adjust PH again, and ethyl acetate extracts 2-3 times, is evaporated under reduced pressure after anhydrous sodium sulfate drying after merging organic phase, obtains 1-
(4- amino-benzyls sulfonyl) pyrrolidines (formula 3)；
1HNMR(CDCl3)：1.85-1.87 (m, 4H), 3.15-3.21 (t, 4H), 4.12 (s, 2H), 7.21-7.28 (d,
2H), 7.86-8.10 (d, 2H), MS (ESI)；241(100)([M+100]+)
The solvation of BTC and DMF reactions is selected from dichloromethane, dichloroethanes, tetrahydrofuran, dioxy in the step 1
One or several kinds of mixed solvents in six rings, chloroform；
The sulfonylation solvent selection two that p-nitrophenyl methanesulfonic acid is carried out with Vilsmeier reagents in the step one
One or several kinds of mixed solvents of chloromethanes, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene；
The solvent selection two for nucleophilic addition-elimination reaction that the step two p-nitrophenyl mesyl chloride is carried out with pyrroles
One or several kinds in chloromethanes, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene, chlorobenzene, toluene
Mixed solvent；
Solvent selection methanol, ethyl alcohol, n-butanol, dichloromethane, two chloroethenes of the reduction reaction of the step trinitro-
One or several kinds of mixed solvents of alkane, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene, toluene.
The temperature that in the step 1 prepared by Vilsmeier reagents is -10 DEG C -0 DEG C, and sulfonylation is anti-in the step one
The temperature of the reaction temperature answered nucleophilic addition-elimination reaction in 25-60 DEG C, the step two is 45-80 DEG C, the step
The temperature of nitro-reduction reaction is 35-60 DEG C in rapid three；
One kind in the step 1 neutral and alkali catalyst choice triethylamine, pyridine；Nucleophilic addition-in the step two
One or more of elimination reaction neutral and alkali catalyst choice triethylamine, pyridine, sodium hydroxide, potassium hydroxide, lithium amide, institute
Metallic catalyst is selected from Pb/C, iron powder or zinc powder in the step of stating three.
The reaction time that in above-mentioned step one prepared by Vilsmeier reagents is 30-60min；Sulphur in above-mentioned steps one
The reaction time of acylation reaction is 60min-4h；The reaction time of nucleophilic addition-elimination reaction is in the step two
30min-6h；The reaction time of nitro-reduction reaction is 30min-12h in the step three.
Triphosgene and the ratio of DMF are 0.33: 1-1.2 during in above-mentioned step (1) prepared by Vilsmeier reagents, institute
The ratio of p-nitrophenyl methanesulfonic acid and pyrroles are 1: 1-2 in the step of stating (2).
Embodiment one：
Step 1：Prepare p-nitrophenyl mesyl chloride：
It takes and is cooled to 0 DEG C under 7.3gDMF (0.1mol) ice bath hereinafter, magnetic agitation, tri- photochromic BTC of 9.86g
(0.033mol) is dissolved in the anhydrous methylene chloride of 10ml, is slowly dropped into DMF, reaction controlling 0 DEG C hereinafter, being added dropwise after
It is stirred to react 30min, it is Vilsmeier reagents to see that white solid generates；21.6g p-nitrophenyls methanesulfonic acid (0.1mol) is used
10ml anhydrous methylene chlorides dissolve, and are slowly dropped into Vilsmeier reagent systems, 60 DEG C of reactions, and (expansion is mutually for TLC detections：Acetic acid
Ethyl ester: it petroleum ether=2: 1) after reacting 2h, after system cooling, concentrates spare for the system of 10ml；
Step 2：The preparation of 1- (4- Nitro-benzyls sulfonyl) pyrrolidines：
The p-nitrophenyl mesyl chloride system 10ml of step 1 is taken, triethylamine 10.1g (0.1mol), pyrroles 6.7g is added
(0.1mol) is dissolved in dichloromethane 10ml, instills p-nitrophenyl mesyl chloride system, and after 30min is added dropwise to complete, 60 DEG C of heat preservations are anti-
2h, TLC detections, expansion phase is answered (ethyl acetate: petroleum ether=4: 1), system to be let cool after the completion of reaction, extract 2-3 with water successively
Secondary, saturated sodium bicarbonate extracts 2-3 times, and saturated salt solution extracts 2-3 times, and anhydrous sodium sulfate dries organic phase, and inspection is distilled
To faint yellow solid, 23.76g, yield 88% are obtained after dry；
Step 3：The preparation of 1- (4- amino-benzyls sulfonyl) pyrrolidines：
1- (the 4- Nitro-benzyls sulfonyl) pyrrolidines (0.1mol) in 26.5g step 2 is taken to be dissolved with 20ml methanol,
5% palladium carbon is added, hydrogen is 4 atmospheric pressure, reacts 1h, is filtered to remove palladium carbon, and adjusting PH is 3-4, water layer acetic acid after extraction
After ethyl ester extracts 2 times, it is 13 that water layer adjusts PH again, and ethyl acetate extracts 2-3 times, and anhydrous sodium sulfate is dried after merging organic phase
After be evaporated under reduced pressure, obtain white solid 19.7g, yield 82.12%.
Embodiment two：
Step 1：The preparation of p-nitrophenyl mesyl chloride：
It takes and is cooled to 0 DEG C under 7.3gDMF (0.1mol) ice bath hereinafter, magnetic agitation, 9.86gBTC (0.033mol) are dissolved in
It in the anhydrous tetrahydro furan of 10ml, is slowly dropped into DMF, reaction controlling is at 0 DEG C hereinafter, being stirred to react 30min after being added dropwise.
21.6g p-nitrophenyls methanesulfonic acid (0.1mol) 10ml anhydrous tetrahydro furans dissolve, and are slowly dropped into Vilsmeier reagent systems,
40 DEG C reaction, TLC detection (expansion be mutually：Ethyl acetate: it petroleum ether=2: 1) after reacting 3.5h, after system cooling, concentrates and is
The system of 10ml is spare；
Step 2：The preparation of 1- (4- Nitro-benzyls sulfonyl) pyrrolidines
The p-nitrophenyl mesyl chloride system 10ml of step 1 is taken, pyridine 7.91g (0.1mol), pyrroles 6.7g is added
(0.1mol) is dissolved in dichloromethane 10ml, instills p-nitrophenyl mesyl chloride system, and after 30min is added dropwise to complete, 60 DEG C of heat preservations are anti-
2h, TLC detections, expansion phase is answered (ethyl acetate: petroleum ether=4: 1), system to be let cool after the completion of reaction, extract 2-3 with water successively
Secondary, saturated sodium bicarbonate extracts 2-3 times, and saturated salt solution extracts 2-3 times, and anhydrous sodium sulfate dries organic phase, and inspection is distilled
To faint yellow solid, 20.43g, yield 90% are obtained after dry；
Step 3：The preparation of 1- (4- amino-benzyls sulfonyl) pyrrolidines：
1- (4- Nitro-benzyls sulfonyl) pyrrolidines (0.1mol) of 26.5g step 2 products is taken, it is molten with 20ml ethyl alcohol
5% palladium carbon is added in solution, and hydrogen is 4 atmospheric pressure, reacts 2h, is filtered to remove palladium carbon, and adjusting PH is 3-4, water layer second after extraction
After acetoacetic ester extracts 2 times, it is 13 that water layer adjusts PH again, and ethyl acetate extracts 2-3 times, and anhydrous sodium sulfate is dry after merging organic phase
Vacuum distillation, obtains white solid 21.65g, yield 90.21% after dry.
Embodiment three：
Step 1：The preparation of p-nitrophenyl mesyl chloride
It takes and is cooled to 0 DEG C under 8.76gDMF (0.121mol) ice bath hereinafter, magnetic agitation, 9.86gBTC (0.033mol) are molten
It in the anhydrous dichloroethanes of 10ml, is slowly dropped into DMF, reaction controlling is at 0 DEG C hereinafter, being stirred to react after being added dropwise
45min.21.6g p-nitrophenyls methanesulfonic acid (0.1mol) the anhydrous dichloroethanes dissolvings of 10ml, are slowly dropped into Vilsmeier reagents
System, 60 DEG C reaction, TLC detection (expansion be mutually：Ethyl acetate: petroleum ether=2: 1) dense after system cooling after reacting 3.5h
The system for being condensed to 10ml is spare；
Step 2：The preparation of 1- (4- Nitro-benzyls sulfonyl) pyrrolidines
The product p-nitrophenyl mesyl chloride system 10ml of step 1 is removed, triethylamine 11.1g (0.11mol), pyrroles is added
7.37g (0.11mol) is dissolved in dichloroethanes 10ml, instills p-nitrophenyl mesyl chloride system, after 30min is added dropwise to complete, 60 DEG C
Insulation reaction 2.52h, TLC detection, expansion phase (ethyl acetate: petroleum ether=4: 1), let cool system after the completion of reaction, use successively
Water extracts 2-3 times, and saturated sodium bicarbonate extracts 2-3 times, and saturated salt solution extracts 2-3 times, and anhydrous sodium sulfate dries organic phase, inspection
It tests distillation and obtains faint yellow solid, 25.4g, yield 94% are obtained after dry；
Step 3：The preparation of 1- (4- amino-benzyls sulfonyl) pyrrolidines
Take product 1- (4- Nitro-benzyls sulfonyl) pyrrolidines (0.1mol) of 26.5g step 2 molten with 20ml ethyl alcohol
The iron powder of 0.1 equivalent is added in solution, and hydrogen is 4 atmospheric pressure, reacts 2h, is filtered to remove iron powder, and adjusting PH is 3-4, water after extraction
After layer is extracted with ethyl acetate 2 times, it is 13 that water layer adjusts PH again, and ethyl acetate extracts 2-3 times, merges anhydrous sulphur after organic phase
It is evaporated under reduced pressure after sour sodium drying, obtains white solid 18.0g, yield 75.1%.
Example IV：
Step 1：The preparation of p-nitrophenyl mesyl chloride
It takes and is cooled to 0 DEG C under 8.76gDMF (0.12mol) ice bath hereinafter, magnetic agitation, 9.86gBTC (0.033mol) are molten
It in the anhydrous dioxane of 10ml, is slowly dropped into DMF, reaction controlling is at 0 DEG C hereinafter, being stirred to react after being added dropwise
45min.21.6g p-nitrophenyls methanesulfonic acid (0.1mol) 10ml anhydrous dioxanes dissolve, and are slowly dropped into Vilsmeier reagents
System, 60 DEG C reaction, TLC detection (expansion be mutually：Ethyl acetate: petroleum ether=2: 1) after reacting 4h, after system cooling, concentration
It is spare for the system of 10ml；
Step 2：The preparation of 1- (4- Nitro-benzyls sulfonyl) pyrrolidines
The product p-nitrophenyl mesyl chloride system 10ml of step 1 is taken, triethylamine 11.1g (0.11mol), pyrroles is added
7.37g (0.11mol) is dissolved in dioxane 10ml, instills p-nitrophenyl mesyl chloride system, after 30min is added dropwise to complete, 70 DEG C
Insulation reaction 2h, TLC detection, expansion phase (ethyl acetate: petroleum ether=4: 1), let cool system after the completion of reaction, are extracted successively with water
It takes 2-3 times, saturated sodium bicarbonate extracts 2-3 times, and saturated salt solution extracts 2-3 times, and anhydrous sodium sulfate dries organic phase, examines and steams
It evaporates to obtain faint yellow solid, 23.89g, yield 88.5% is obtained after dry；
Step 3：The preparation of 1- (4- amino-benzyls sulfonyl) pyrrolidines
Take product 1- (4- Nitro-benzyls sulfonyl) pyrrolidines (0.1mol) of 26.5g step 2 molten with 20ml ethyl alcohol
The iron powder of 0.15 equivalent is added in solution, and hydrogen is 4 atmospheric pressure, reacts 8h, is filtered to remove iron powder, adjusting PH is 3-4, after extraction
After aqueous layer with ethyl acetate extracts 2 times, it is 13 that water layer adjusts PH again, and ethyl acetate extracts 2-3 times, anhydrous after merging organic phase
It is evaporated under reduced pressure after sodium sulphate drying, obtains white solid 19.23g, yield 80.2%.
Embodiment five：
Step 1：The preparation of p-nitrophenyl mesyl chloride
It takes and is cooled to 0 DEG C under 8.76gDMF (0.12mol) ice bath hereinafter, magnetic agitation, 9.86gBTC (0.033mol) are molten
It in the anhydrous chloroform of 10ml, is slowly dropped into DMF, reaction controlling is at 0 DEG C hereinafter, being stirred to react 45min after being added dropwise.
21.6g p-nitrophenyls methanesulfonic acid (0.1mol) 10ml anhydrous chloroforms dissolve, and are slowly dropped into Vilsmeier reagent systems, 60 DEG C
Reaction, TLC detection (expansion be mutually：Ethyl acetate: petroleum ether=2: 1) after reacting 4h, after system cooling, the body for 10ml is concentrated
It is spare；
Step 2：The preparation of 1- (4- Nitro-benzyls sulfonyl) pyrrolidines
The product p-nitrophenyl mesyl chloride system 10ml of step 1 is taken, triethylamine 11.1g (0.11mol), pyrroles is added
7.37g (0.11mol) is dissolved in chloroform 10ml, instills p-nitrophenyl mesyl chloride system, after 30min is added dropwise to complete, 60 DEG C of heat preservations
2h, TLC detections are reacted, expansion phase (ethyl acetate: petroleum ether=4: 1), system is let cool after the completion of reaction, extracts 2- with water successively
3 times, saturated sodium bicarbonate extracts 2-3 times, and saturated salt solution extracts 2-3 times, and anhydrous sodium sulfate dries organic phase, and inspection is distilled
To faint yellow solid, 24.0g, yield 89% are obtained after dry；
Step 3：The preparation of 1- (4- amino-benzyls sulfonyl) pyrrolidines
Take product 1- (4- Nitro-benzyls sulfonyl) pyrrolidines (0.1mol) of 26.5g step 2 molten with 20ml ethyl alcohol
The zinc powder of 0.1 equivalent is added in solution, and hydrogen is 4 atmospheric pressure, reacts 8h, is filtered to remove zinc powder, and adjusting PH is 3-4, water after extraction
After layer is extracted with ethyl acetate 2 times, it is 13 that water layer adjusts PH again, and ethyl acetate extracts 2-3 times, merges anhydrous sulphur after organic phase
It is evaporated under reduced pressure after sour sodium drying, obtains white solid 18.86g, yield 78.6%.
The better embodiment of the present invention is explained in detail above, but the present invention is not limited to above-mentioned embodiment party
Formula, one skilled in the relevant art within the scope of knowledge, can also be without departing from the purpose of the present invention
Various changes can be made.
Claims (9)
1. a kind of preparation method of key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan, feature
It is, key step is as follows：
Step 1：Spare, the p-nitrophenyl first with triphosgene (BTC) and dinethylformamide (DMF) preparation Vilsmeier reagents
Sulfonic acid is raw material, with Vilsmeier reagent sulfonylations under the conditions of base catalysis, monitors reaction process with TLC, generates to nitre
Base tosylate chloride；
Step 2：The 4-Nitrobenzenesulfonyl chloride obtained using step 1 disappears under base catalysis with pyrroles's progress nucleophilic addition-as raw material
Except reaction, is monitored and reacted with TLC, after being extracted by saturated sodium bicarbonate, saturated salt solution after reaction, organic phase anhydrous slufuric acid
Vacuum distillation obtains 1- (4- Nitro-benzyls sulfonyl) pyrrolidines after sodium drying；
Step 3：Above-mentioned 1- obtained by the reaction (4- Nitro-benzyls sulfonyl) pyrrolidines, hydrogen is passed through under metallic catalyst
Catalytic hydrogenation reaction is carried out, it is 3-4 to adjust PH after reaction, and after aqueous layer with ethyl acetate extracts 2 times after extraction, water layer is again
It is 13 to adjust PH, and ethyl acetate extracts 2-3 times, is evaporated under reduced pressure after anhydrous sodium sulfate drying after merging organic phase, obtains 1- (4- ammonia
Base-benzyl sulfonyl) pyrrolidines.
2. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that in the step 1 BTC and DMF reaction solvation selected from dichloromethane, dichloroethanes,
One or several kinds of mixed solvents in tetrahydrofuran, dioxane, chloroform.
3. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that the sulfonylation that p-nitrophenyl methanesulfonic acid and Vilsmeier reagents carry out in the step one is anti-
Answer the one or several kinds of solvent selection dichloromethane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene
Mixed solvent.
4. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that nucleophilic addition-elimination reaction that the step two p-nitrophenyl mesyl chloride is carried out with pyrroles
Solvent selection dichloromethane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene, chlorobenzene, in toluene
One or several kinds of mixed solvents.
5. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that solvent selection methanol, ethyl alcohol, n-butanol, the dichloro of the reduction reaction of the step trinitro-
Methane, dichloroethanes, tetrahydrofuran, dioxane, chloroform, DMF, DMSO, benzene, one or several kinds of mixing of toluene are molten
Agent.
6. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that the temperature that in the step 1 prepared by Vilsmeier reagents is -10 DEG C -0 DEG C, the step
The temperature of the reaction temperature of sulfonylation nucleophilic addition-elimination reaction in 25-60 DEG C, the step two is 45- in one
80 DEG C, the temperature of nitro-reduction reaction is 35-60 DEG C in the step three.
7. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that the reaction time that in the step 1 prepared by Vilsmeier reagents is 30-60min；The step
The reaction time of sulfonylation is 60min-4h in rapid one；In the step two when the reaction of nucleophilic addition-elimination reaction
Between be 30min-6h；The reaction time of nitro-reduction reaction is 30min-12h in the step three.
8. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that triphosgene and the ratio of DMF are 0.33: 1- during in the step 1 prepared by Vilsmeier reagents
1.2。
9. key intermediate 1- (4- amino-benzyls sulfonyl) pyrrolidines of almotriptan according to claim 1
Preparation method, which is characterized in that, the ratio of p-nitrophenyl methanesulfonic acid and pyrroles are 1: 1-2 in the step two.
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| CN101687788A (en) * | 2006-10-19 | 2010-03-31 | 奥斯拜客斯制药有限公司 | The indoles that replaces |
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| CN101687788A (en) * | 2006-10-19 | 2010-03-31 | 奥斯拜客斯制药有限公司 | The indoles that replaces |
Non-Patent Citations (2)
| Title |
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| YAQIONG LI等: "Helical Antimicrobial Sulfono-γ-AApeptides", 《J. MED. CHEM.》 * |
| 杜西莹: "对氨基苯甲磺酰吡咯烷的制备", 《精细化工》 * |
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Application publication date: 20180824 |