CN105175397B - A kind of hydrobromic acid eletriptan synthetic method - Google Patents
A kind of hydrobromic acid eletriptan synthetic method Download PDFInfo
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- CN105175397B CN105175397B CN201510584195.3A CN201510584195A CN105175397B CN 105175397 B CN105175397 B CN 105175397B CN 201510584195 A CN201510584195 A CN 201510584195A CN 105175397 B CN105175397 B CN 105175397B
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a kind of hydrobromic acid eletriptan synthetic method, including following steps:In organic solvent; (R) (methyl of N crassitudes 2) the 5 bromine 1H indoles of 1 acetyl group 3 and metal formation metal complex; metal complex reacts to form aryl borane or aryl-boric acid ester with borane reagent in organic solvent; aryl boric acid is obtained after acid-catalyzed hydrolysis; aryl boric acid and 2 chloroethyl-phenylsulfones are coupled under catalyst, alkali effect and are hydrolyzed into eletriptan; or metal complex is directly coupled with 2 chloroethyl-phenylsulfones and is hydrolyzed into eletriptan, eletriptan finally gives hydrobromic acid eletriptan with hydrobromic acid into salt in organic solvent.This method is simple to operate, safety and stability, cost is low and yield is higher, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of hydrobromic acid eletriptan synthetic method.
Background technology
Hydrobromic acid eletriptan (Eletriptan Hydrobromide, trade name:Relpax), its chemistry entitled (R)-
3- [(1- methyl -2- pyrrolidinyls) methyl] -5- [2- (benzene sulfonyl) ethyl] -1H- indole hydrobromides, molecular formula is
C22H26N2O2S*HBr, alpha-crystal form hydrobromic acid eletriptan is listed as the medicine for the treatment of antimigraine.Structural formula is as follows:
。
As second generation triptan medicine, eletriptan optionally excitement 5HT1B/1DAcceptor, causes intracranial vessel to shrink,
Effectively treatment antimigraine, is compared, eletriptan has the characteristics that with other triptan medicines:Eletriptan is efficient up to 84%,
Remission rate is higher than other triptans within 24 hours.Incidence of side effects is more slightly higher than sumatriptan, but relatively light, without serious side reaction.
The researcher of USA New York headache research institute checked the pharmacokinetic in feminine menstrual phase and lactation period eletriptan
Learn.As a result find, the menstrual cycle does not significantly change the effect of medicine.Medicine in nursing period, milk is considerably less, only accounts for mother
Parent takes the 0.02% of 80mg.And wet nurse is fine to eletriptan tolerance, does not occur the exception of blood pressure, pulse or electrocardiogram,
Do not occur serious side reaction yet.To the women using contraceptive or hormone replacement therapy, the medicine is also resistant to very well.
United States Patent (USP) US5545644 discloses eletriptan preparation method, and synthetic route is as follows:
;
Eletriptan synthesis is all with (R) -3- (N- benzyloxycarbonyl group pyrroles in United States Patent (USP) US5545644, US5607951
Alkane -2- bases carbonyl) the bromo- 1H- indoles of -5- as key intermediate, with phenyl vinyl sulfone in acetonitrile in three (o-methyl-benzenes
Base) under conditions of phosphorus and triethylamine be present, (R) -3- [(1- methyl -2- pyrrolidinyls) is obtained with acid chloride (II) catalyzing and condensing
Methyl] -5- [2- (benzene sulfonyl) vinyl] -1H- indoles, then hydrogen reduction obtains (R) -3- [(1- methyl -2- pyrrolidinyls) first
Base] -5- [2- (benzene sulfonyl) ethyl] -1H- indoles(Eletriptan), process tool is in following deficiency:1)(R) -3- [(1- methyl -
2- pyrrolidinyls) methyl] -5- [2- (benzene sulfonyl) vinyl] -1H- indoles easily occur polymerisation generation dimer so that shadow
Ring final products purity and yield;2)Reactions steps are long, from key intermediate (R) -3- (N- benzyloxycarbonyl group pyrrolidin-2-yl carbonyls
Base) the bromo- 1H- indoles of -5- has three-step reaction, and complex operation, yield is relatively low;3)Hydrogen is used in hydrogenation, hydrogen is
Flammable explosive gas, potential safety hazard is brought to synthesis technique.
In order to reduce the generation of dimer, United States Patent (USP) US5607951 and international monopoly WO0250063 are disclosed according to vertical
Qu Tan improvement preparation method, this method first by indole ring nitrogen-atoms carry out acetylation protection, then with phenyl vinyl sulfone
Hydrolyzed again after condensation reaction, hydro-reduction and be deprotected to obtain eletriptan, this avoid dimer generation, but also extend
Reaction step is poly-, reduces yield, improves cost;Building-up process still suffers from hydro-reduction process, there is potential safety hazard, is unfavorable for
Industrialized production.Synthetic route after improvement is as follows:
。
To better meet global pharmacy needs, the good method of exploitation safety and stability, low cost, selectivity has higher
Practical commercial value.It is therefore desirable to seek that safe, easy to operate, process stabilizing, cost be low, selectivity is good and it is high income according to
Bent smooth preparation method is found, to overcome the defect in prior art.
The content of the invention
Present invention aims to overcome that there is provided a kind of eletriptan synthetic method, this method operation letter for prior art defect
List, safety and stability, cost are low and yield is higher, are adapted to industrialized production.
To achieve the above object, the present invention is adopted the following technical scheme that:
A kind of hydrobromic acid eletriptan synthetic method, it comprises the following steps:
a)In organic solvent one, (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles of -5- with
Metal reaction formation metal complex;
b)Metal complex reacts to form aryl borane or aryl-boric acid ester in organic solvent one with borane reagent, then sour
Catalyzing hydrolysis obtains aryl boric acid;Aryl boric acid is again with 2- chloroethyl-phenylsulfones in organic solvent two, major catalyst, co-catalyst
And be coupled under alkali effect and be hydrolyzed into eletriptan;
Or metal complex directly with 2- chloroethyl-phenylsulfones in organic solvent three, major catalyst, co-catalyst and alkali
It is coupled under effect and is hydrolyzed into eletriptan;
c)Eletriptan obtains hydrobromic acid eletriptan with hydrobromic acid in organic solvent four into salt.
Synthetic route of the present invention is as follows:
, or
。
Specifically, step a)In, metal used is magnesium, zinc or lithium, and metal consumption is (R) -1- acetyl group -3- (N- first
Base pyrrolidines -2- methyl) 1-1.2 times of the bromo- 1H- indoles moles of -5-;Most preferably 1.08 times;
Organic solution one used be tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane, organic solvent one with
(R) the volume mass ratio of -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles of -5- is 3-10ml/g, most preferably
For 6 ml/g;
Reaction temperature be room temperature to reflux temperature, grignard course of reaction is triggered with iodine.
Specifically, in step b)During synthesizing aryl boric acid, borane reagent used is borine or butyl borate, borane reagent
Consumption is 1.1-3.0 times of metal complex mole;The borine is by sodium borohydride and boron trifluoride or boron trichloride reaction
Brand-new and obtain;Reaction time is 10-30h;
Organic solution one used be tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane, organic solvent one with gold
The volume mass ratio for belonging to complex compound is 3-10ml/g, most preferably 6 ml/g;
Acid-catalyzed hydrolysis is specially:Aryl borane or aryl-boric acid ester are hydrolyzed in pH is 0-3 watery hydrochloric acid, hydrolysis temperature
Spend for 0-10 DEG C, hydrolysis time is 0.5-2 hours.
Specifically, in step b)Aryl boric acid or metal complex are coupled and are hydrolyzed into according to vertical song with 2- chloroethyl-phenylsulfones
During smooth, 2- chloroethyl-phenylsulfones consumption is 1.2-2.5 times of aryl boric acid or metal complex mole, most preferably 1.5
Times;
Major catalyst used is double (dibenzalacetone) palladium (0), tetrakis triphenylphosphine palladium (0) or double(Triphenyl
Phosphine)The complex of the palladiums such as nickel chloride or nickel, major catalyst consumption is aryl boric acid or the 0.01-0.1 of metal complex mole
Times, most preferably 0.02 times;
Co-catalyst used be triphenylphosphine and fluorination 4-butyl amine, wherein, triphenylphosphine consumption be aryl boric acid or
0.02-0.2 times of metal complex mole, most preferably 0.04 times;It is aryl boric acid or metal network to be fluorinated 4-butyl amine consumption
0.04-0.4 times of compound mole, most preferably 0.1 times;
Alkali used is potassium carbonate or sodium carbonate, and base amount is aryl boric acid or the 1.5-3.0 of metal complex mole
Times, most preferably 2.0 times;
It is coupled and the temperature of hydrolysis is 40 DEG C to reflux temperature, most preferably 65 DEG C, the reaction time is 5-24 hours.
Specifically, in step b)Aryl boric acid is coupled and is hydrolyzed into during eletriptan with 2- chloroethyl-phenylsulfones, institute
Organic solvent two is mixture more than one or both of dimethylformamide, tetrahydrofuran, second alcohol and water, organic
The volume mass ratio of solvent two and aryl boric acid is 3-15ml/g, most preferably 5 ml/g.
Specifically, in step b)Metal complex is coupled and is hydrolyzed into during eletriptan with 2- chloroethyl-phenylsulfones,
Organic solvent three used is tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane etc., organic solvent three and metal complex
The volume mass ratio of thing is 3-15ml/g, most preferably 5 ml/g.
Further, step c)In, hydrobromic acid consumption is 0.95-1.2 times of eletriptan mole;Most preferably 1.0 times;
Organic solvent four used is acetone, ethanol or 2- propyl alcohol etc., and the volume mass ratio of the consumption of organic solvent four and eletriptan is
15-30ml/g, most preferably 20 ml/g.
Compared to the prior art, beneficial effects of the present invention:
Instant invention overcomes existing eletriptan preparation method cost height, complex operation, technique are unstable and easily generate two
There is provided a kind of new eletriptan synthetic method for the defects such as aggressiveness.The synthetic method is simple to operate, safety and stability, cost are low
And yield is higher, it is adapted to industrialized production.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited protection scope of the present invention
Among described scope of embodiments.
The experimental method of unreceipted actual conditions in the following example, according to the conventional method and condition of this area, or is pressed
According to catalogue selection.
In following Examples 1 and 2, in synthesis (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
During boric acid, the metal complex of generation is directly and borane reagent(That is borine, it is anti-by the sodium borohydride and boron trifluoride being previously added
It should obtain)Acid-catalyzed hydrolysis prepares aryl boric acid, and this step is applicable " treating different things alike " method, and operation can be simplified significantly.
Boron trifluoride normal temperature be gas, be not easy to preserve and use, typically make BFEE compound liquid with
It is easy to use, directly buys ordinary commercial products.
The boric acid of embodiment 1 (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
Under nitrogen protection, by magnesium chips 1.4g(58mmol), tetrahydrofuran 10ml and sodium borohydride 2.3g(60mmol)Put
In 250ml reaction bulbs, less than 0 DEG C is cooled to, BFEE compound 11 .3g is slowly added dropwise(79.5mmol)Tetrahydrochysene
Tetrahydrofuran solution(15ml), it is stirred at room temperature 12 hours after completion of dropping, cools to less than 0 DEG C, adds 1 granule iodine, be slowly added dropwise
(R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) the bromo- 1H- indoles 18.1g of -5-(54mmol)Tetrahydrofuran
(90ml)About 10ml, reaction is further continued for being added dropwise after triggering, and is stirred at room temperature 24 hours after completion of dropping, and reactant is poured into frozen water mixing
In thing 100ml, add watery hydrochloric acid and adjust pH to 2, stir 1 hour, pH to 7, ether are adjusted with sodium carbonate(30ml*3)Carry, saturated salt
Water(50ml)Wash, evaporated under reduced pressure ether obtains the boric acid of (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
15.3g, yield 95%, product is not purified to be directly used in the next step.Synthetic route is as follows:
。
The boric acid of embodiment 2 (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
Under nitrogen protection, by magnesium chips 1.4g(58mmol), tetrahydrofuran 10ml and sodium borohydride 2.3g(60mmol)Put
In 250ml reaction bulbs, less than 0 DEG C is cooled to, boron chloride ether complex 16.5g is slowly added dropwise(86.3mmol)Tetrahydrochysene
Tetrahydrofuran solution(15ml), it is stirred at room temperature 12 hours after completion of dropping, cools to less than 0 DEG C, adds 1 granule iodine, be slowly added dropwise
(R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) the bromo- 1H- indoles 18.1g of -5-(54mmol)Tetrahydrofuran
(90ml)About 10ml, reaction is further continued for being added dropwise after triggering, and is stirred at room temperature 24 hours after completion of dropping, and reactant is poured into frozen water mixing
In thing 100ml, add 10% watery hydrochloric acid and adjust pH to 2, stir 1 hour, pH to 7, ether are adjusted with sodium carbonate(30ml*3)Carry, saturation
Salt solution(50ml)Wash, evaporated under reduced pressure ether obtains the boric acid of (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
15.2 g, yield 94%, product is not purified to be directly used in the next step.
The boric acid of embodiment 3 (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
Under nitrogen protection, by magnesium chips 1.4g(58mmol)Added with 1 iodine in reaction bulb, addition (R) -1- acetyl group -
3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles 18.1g of -5-(54mmol)Drying tetrahydrofuran(50ml), first drip
Plus a small amount of solution, after reaction triggers, about 40 DEG C of dropping temperature is kept, back flow reaction 10 hours, are as cold as room temperature after completion of dropping, obtain
Metal complex liquid(That is Grignard solution), be as cold as less than -15 DEG C it is standby.
Separately take butyl borate 31g(135mmol)Plus tetrahydrofuran 20ml, less than -15 DEG C are cooled to, in strong agitation
Under, Grignard solution is added drop-wise in butyl borate solution, -15 DEG C are stirred below 4 hours, are slowly warming up to and are stirred at room temperature 2 hours,
Add 10% dilute hydrochloric acid solution and adjust pH to 2, stir 2 hours, pH to 7, ether are adjusted with sodium carbonate liquor(30ml*3)Carry, saturated salt
Water(50ml)Wash, evaporated under reduced pressure ether obtains the boric acid of (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5
14.4 g, yield 89%, product is not purified to be directly used in the next step.
The catalyst preparation of embodiment 4
Double (dibenzalacetone) palladiums (0)
Under agitation by the sour sodium 5.0g of palladous chloride(Na2PdCl4, 17.0mmol), dibenzalacetone 12g(51mmol)
About 60 DEG C are heated to methanol 50ml mixture, continues to stir 30 minutes after dissolving, adds sodium acetate 1.6g(20mmol), stir
Mix and room temperature is as cold as after 15 minutes, separate out light tan solid, filtering is washed with water, acetone, and solid 9.3g, yield are obtained after drying
134-135 DEG C of 95%, mp.
It is double(Triphenylphosphine)Nickel chloride
By triphenylphosphine 10g(38mmol)It is dissolved in ethanol 40ml, is added dropwise by nickel chloride 4.5g(NiCl2 6H2O,
19mmol)The solution added after ethanol 120ml dissolvings, flows back 0.5 hour after being added dropwise to complete, and is as cold as room temperature, separates out color solid, mistake
Filter, ether washing, obtains dark blue solid 9.7g, yield 78%, 250 DEG C of mp after vacuum drying.
Four(Triphenylphosphine)Palladium(0)
Take palladium bichloride 1.77g(10mmol), triphenylphosphine 13.1g(0.05mmol)Put into and react with dimethyl sulfoxide 120ml
In bottle, 130 DEG C are heated under nitrogen protection, is stirred 30 minutes, and solution is in yellow, adds hydrazine hydrate 1ml, there is yellow solid analysis
Go out, drop to room temperature, fast filtering, respectively with ethanol, ether filter wash cake, is dried in vacuo to obtain yellow solid 10.4g, yield 90%.
Embodiment 5 (R) -3- [(1- methyl -2- pyrrolidinyls) methyl] -5- [2- (benzene sulfonyl) ethyl] -1H- indoles(According to
Vertical Qu Tan)
The boric acid 10g of (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5 is added in reaction bulb
(33mmol), tetrahydrofuran 40ml, water 1ml, double (dibenzalacetone) palladium (0) 0.38g(0.66mmol), triphenylphosphine
0.35g(1.32mmol), fluorination 4-butyl amine 0.85g(3.3mmol), potassium carbonate 9.6g(70mmol)With 2- chloroethyl-phenylsulfones
10.1g(49mmol), 65 DEG C are reacted 10 hours after nitrogen displacement deoxygenation, remove tetrahydrofuran, residue after the completion of reaction under reduced pressure
2M sodium carbonate liquors 30ml and ethyl acetate 30ml is added, stirs 30 minutes, separates organic layer, water layer uses ethyl acetate again(10*
2)Extract, combined ethyl acetate layer adds water 30ml, pH to 2 is adjusted with watery hydrochloric acid, stirs 10 minutes, separates water layer, and organic layer is used
1M hydrochloric acid(10ml*2)Combining water layer after extraction, 40% sodium hydroxide solution adjusts pH to 11, separates out precipitation, filters, vacuum drying,
Obtain yellow solid eletriptan 9.8g, yield 77%.
Embodiment 6 (R) -3- [(1- methyl -2- pyrrolidinyls) methyl] -5- [2- (benzene sulfonyl) ethyl] -1H- indoles(According to
Vertical Qu Tan)
The boric acid 10g of (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -1H- indoles -5 is added in reaction bulb
(33mmol), it is dimethylformamide 30ml, water 1ml, double(Triphenylphosphine)Nickel chloride 0.43g(0.66mmol), triphenylphosphine
0.35g(1.32mmol), fluorination 4-butyl amine 0.85g(3.3mmol), potassium carbonate 9.6g(70mmol)With 2- chloroethyl-phenylsulfones
10.1g(49mmol), 65 DEG C are reacted 10 hours after nitrogen displacement deoxygenation, and room temperature is dropped to after the completion of reaction, add 2M potassium carbonate molten
Liquid 30ml and ethyl acetate 30ml, stirs 30 minutes, separates organic layer, water layer uses ethyl acetate again(10*2)Extract, merge second
Ethyl acetate layer, adds water 30ml, and pH to 2 is adjusted with watery hydrochloric acid, stirs 10 minutes, separates water layer, organic layer 1M hydrochloric acid(10ml*
2)Combining water layer after extraction, 40% sodium hydroxide solution adjust pH to 11, separate out precipitation, filter, vacuum drying, obtain yellow solid according to
Found bent smooth 10.3g, yield 81%.
Embodiment 7 (R) -3- [(1- methyl -2- pyrrolidinyls) methyl] -5- [2- (benzene sulfonyl) ethyl] -1H- indoles(According to
Vertical Qu Tan)
Under nitrogen protection, zinc powder is considered to be worth doing 3.8g(58mmol), 1 iodine, tetrahydrofuran 10ml be placed in 250ml reaction bulbs
In, (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles 18.1g of -5- are slowly added dropwise(54mmol)Four
Hydrogen furans(50ml)About 10ml, reaction is further continued for being added dropwise after triggering, and temperature rising reflux drops to room temperature after 6 hours and obtains zinc after completion of dropping
Complex compound.
To zinc complex(About 54mmol)It is middle to add four(Triphenylphosphine)Palladium(0)0.76g(0.66mmol), triphenylphosphine
0.35g(1.32mmol), potassium carbonate 9.6g(70mmol), stir 0.5 hour, be warming up to 60 DEG C, 2- chloroethyl-phenylsulfones are added dropwise
11.2g(55mmol)Tetrahydrofuran(10ml)Solution, continues to react 12 hours after being added dropwise to complete, drops to room temperature, add 2M carbon
Acid sodium solution 30ml and ethyl acetate 30ml, stirs 30 minutes, separates organic layer, water layer uses ethyl acetate again(10*2)Extract,
Combined ethyl acetate layer, adds water 30ml, and pH to 2 is adjusted with watery hydrochloric acid, stirs 10 minutes, separates water layer, organic layer 1N hydrochloric acid
(10ml*2)Combining water layer after extraction, 40% sodium hydroxide solution adjusts pH to 11, separates out precipitation, filters, vacuum drying, get Yi Li
Bent smooth 13.4g, yield 65%.
The hydrobromic acid eletriptan of embodiment 8
By eletriptan 10.0g(26.2mmol)In isopropanol 140ml input three-necked bottles, 0-5 DEG C, dropwise addition are cooled to
62% hydrobromic acid 2.4g(26.2mmol), stirred 1 hour after being added dropwise to complete, then temperature rising reflux 1 hour cools to 0-5 DEG C of stirring
24 hours, solid is separated out, filtering, acetone filter wash cake is dried in vacuo to obtain slightly yellow solid 10.1g, yield 83%.
Elementary analysis:C:56.91%;H:5.79%;N:6.15%(Theoretical value:C22H26N2O2S HBr:C:57.02%;H:
5.87%;N:6.04%).
The hydrobromic acid eletriptan of embodiment 9
By eletriptan 10.0g(26.2mmol)In acetone 220ml input three-necked bottles, 0-5 DEG C is cooled to, 62% is added dropwise
Hydrobromic acid 2.4g(26.2mmol), stirred 1 hour after being added dropwise to complete, temperature rising reflux 1 hour, then cool to 0-5 DEG C of stirring 24
Hour, solid is separated out, filtering, acetone filter wash cake is dried in vacuo to obtain slightly yellow solid 11g, yield 91%.
Elementary analysis:C:56.85%;H:5.73%;N:6.12%(Theoretical value:C22H26N2O2S HBr:C:57.02%;H:
5.87%;N:6.04%).
Claims (7)
1. a kind of hydrobromic acid eletriptan synthetic method, it is characterised in that comprise the following steps:
a)In organic solvent one, (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles of -5- and metal
Reaction forms metal complex;
b)Metal complex reacts to form aryl borane or aryl-boric acid ester in organic solvent one with borane reagent, then acid catalysis
Hydrolysis obtains aryl boric acid;Aryl boric acid is again with 2- chloroethyl-phenylsulfones in organic solvent two, major catalyst, co-catalyst and alkali
It is coupled under effect and is hydrolyzed into eletriptan;
Or metal complex is directly acted on 2- chloroethyl-phenylsulfones in organic solvent three, major catalyst, co-catalyst and alkali
It is lower to be coupled and be hydrolyzed into eletriptan;
c)Eletriptan obtains hydrobromic acid eletriptan with hydrobromic acid in organic solvent four into salt;
Metal used is magnesium or zinc, and metal consumption is that (R) -1- acetyl group -3- (N- methylpyrrolidin- 2- methyl) -5- is bromo-
1-1.2 times of 1H- indoles moles;
Borane reagent used is borine or butyl borate, and borane reagent consumption is 1.1-3.0 times of metal complex mole.
2. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that step a)In,
Organic solution one used is tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane, organic solvent one and (R) -1-
The volume mass ratio of acetyl group -3- (N- methylpyrrolidin- 2- methyl) bromo- 1H- indoles of -5- is 3-10ml/g.
3. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that in step b)Synthesizing aryl boric acid
During, organic solution one used is tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane, organic solvent one and metal
The volume mass ratio of complex compound is 3-10ml/g;
Reaction time is 10-30h;
Acid-catalyzed hydrolysis is specially:Aryl borane or aryl-boric acid ester are hydrolyzed in pH is 0-3 watery hydrochloric acid, and hydrolysis temperature is
0-10 DEG C, hydrolysis time is 0.5-2 hours.
4. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that in step b)Aryl boric acid or gold
Category complex compound is coupled and is hydrolyzed into during eletriptan with 2- chloroethyl-phenylsulfones,
2- chloroethyl-phenylsulfones consumption is 1.2-2.5 times of aryl boric acid or metal complex mole;
Major catalyst used is double (dibenzalacetone) palladium, tetrakis triphenylphosphine palladium or double(Triphenylphosphine)Nickel chloride, it is main
Catalyst amount is 0.01-0.1 times of aryl boric acid or metal complex mole;
Co-catalyst used be triphenylphosphine and tetrabutylammonium, wherein, triphenylphosphine consumption be aryl boric acid or metal
0.02-0.2 times of complex compound mole, tetrabutylammonium consumption is aryl boric acid or metal complex mole
0.04-0.4 times;
Alkali used is potassium carbonate or sodium carbonate, and base amount is 1.5-3.0 times of aryl boric acid or metal complex mole;
It is coupled and the temperature of hydrolysis is 40 DEG C to reflux temperature, the reaction time is 5-24 hours.
5. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that in step b)Aryl boric acid and 2-
Chloroethyl-phenylsulfone is coupled and is hydrolyzed into during eletriptan,
Organic solvent two used is mixture more than one or both of dimethylformamide, tetrahydrofuran and ethanol,
The volume mass ratio of organic solvent two and aryl boric acid is 3-15ml/g.
6. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that in step b)Metal complex with
2- chloroethyl-phenylsulfones are coupled and are hydrolyzed into during eletriptan,
Organic solvent three used is tetrahydrofuran, dioxane or 1,2- dimethoxy-ethane, organic solvent three and metal network
The volume mass ratio of compound is 3-15ml/g.
7. hydrobromic acid eletriptan synthetic method as claimed in claim 1, it is characterised in that step c)In,
Hydrobromic acid consumption is 0.95-1.2 times of eletriptan mole;
Organic solvent four used is the volume mass ratio of acetone, ethanol or 2- propyl alcohol, the consumption of organic solvent four and eletriptan
For 15-30ml/g.
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