CN107337658A - A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- - Google Patents
A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- Download PDFInfo
- Publication number
- CN107337658A CN107337658A CN201610285982.2A CN201610285982A CN107337658A CN 107337658 A CN107337658 A CN 107337658A CN 201610285982 A CN201610285982 A CN 201610285982A CN 107337658 A CN107337658 A CN 107337658A
- Authority
- CN
- China
- Prior art keywords
- chloro
- reaction
- dihydrobenzofuranes
- amino
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *c(cc(c(*)c1)Cl)c1O Chemical compound *c(cc(c(*)c1)Cl)c1O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Abstract
The invention belongs to pharmaceutical technology field, is related to a kind of synthetic method of the carboxylic acid of 4 amino of prucalopride intermediate, 52,3 Dihydrobenzofuranes of chlorine 7.The present invention is using PAS as initiation material; through being esterified, being acylated, halo obtains the methyl hydroxybenzoate of 4 acetamido, 3 bromine, 5 chlorine 2 twice; again with 1; 2 Bromofumes occur substitution reaction and obtain 4 acetamido 3 bromine 2 (2 bromine oxethyl) 5 chloro benzoic ethers, then obtain final product through cyclization, hydrolysis.Raw material of the present invention is easy to get, it is simple to operate it is gentle, with short production cycle, purity is high, security is good, cost is low, is adapted to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of butanedioic acid prucalopride intermediate 4- amino -5- chlorine
The synthetic method of -2,3- Dihydrobenzofuranes -7- carboxylic acids.
Background technology
Chronic constipation is a kind of common disease caused by many factors, and relevant with gastral motion, constipation
It is characterized as that enterocinesia is reduced, excrement scleroma, defecation is not to the utmost and straining at stool.The Colon Movement bag of normal healthy people
Include short-time characteristic contraction, the contraction of long changes with time, tension contraction and huge migrating contractions.Functional consitipation patient
It is broadly divided into Colon absorption delayed-type and the class of passage time normal type two.The former patient may occur in which huge divide a word with a hyphen at the end of a line
Property contraction frequency, duration and amplitude reduction, gastrocolic reflex weaken or disappear, and local changes with time is non-pushes away
The property entered shrinks enhancing so that whole Colon Movement is uncoordinated, and intestinal motility decrease occur in a few patients.When passing through
Between normal patient be primarily present that anal sphincter function is abnormal and Rectal sensation declines.In recent years, with
The influence of the factors such as living standard, life style and dietary structure, aging is serious in addition, makes China's constipation
Incidence is in the trend constantly risen.
Butanedioic acid prucalopride is according to Janssen companies authorization, in 2009 10 by Movetis companies
After the moon is granted in Europe, in January, 2010 lists in Germany, and in March, 2010 lists in Britain.Butanedioic acid Pu Kabi
Profit is benzofuran derivatives, entitled chloro- 2, the 3- dihydros-N of 4- amino -5- [1- (3- the methoxy-propyls) -4- of chemistry
Piperidyl] -7- benzofuran carboxamides are a kind of newfound prokinetic medicines, the medicine has good rush
The effect of lower digestive tract motion, it is capable of the symptom of effective relief of constipation patient.It is bright after Healthy People prucalopride
The aobvious operation for promoting colonic contents, proximal colonic emptying time are accelerated, and gastric emptying and SBTT without
Change, stool interval increase, first time defecation time greatly shorten weekly after medication, the increase of passage of loose stools ratio.
Found for the Therapy study of constipation patient, Colon absorption shortens, stool interval increases, rectum is to expansion
With the sensitiveness increase of electro photoluminescence.Prucalopride does not have any serious side effect to normal person or constipation patient,
It is safe, better tolerance, there are good market prospects.
Butanedioic acid prucalopride is 5-HT4 receptor stimulating agents, and the secretion on intestines and stomach influences less, not exciting
Other acceptors.For Healthy People, prucalopride can shorten on the gastrointestinal tract and Colon absorption, to constipation patient,
Prucalopride can increase stool interval and reduce stool hardness.Higher compared with Cisapride selectivity, effect is more preferable,
It is the new effective medicine of the alternative one kind of patients with chronic constipation and adverse reaction is few.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of butanedioic acid prucalopride intermediate 4- amino -5-
The synthetic method of chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids.
The present invention adopts the following technical scheme that：
Using PAS as initiation material, under catalyst action, esterification reaction of organic acid occurs with methanol, obtains
To the methyl hydroxybenzoate of 4- amino -2；Acetylization reaction occurs with acetylation reagent again and obtains 4- acetamidos -2-
Methyl hydroxybenzoate, 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates are obtained through chloro, then obtained by bromo
To the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3-, bromoethyl obtains the bromo- 2- (2- of 4- acetamidos -3-
Bromine oxethyl) -5- chloro benzoic ethers, then obtain the intermediate 4- ammonia of butanedioic acid prucalopride through cyclization, hydrolysis
The chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of base -5-.
Whole technique comprises the following steps：
(1) the 4- amino-2-hydroxybenzoic acid methyl esters described in formula (II)
By PAS, methanol, catalyst according to mol ratio 1: (4~8): (1.5~4), preferably
Ratio is 1: (5~6.5): (1.8~2.8), catalyst is added dropwise at low temperature, reaction temperature is backflow temperature
Spend, after reaction terminating, adjust pH to 4~5 with aqueous alkali, suction filtration obtains pale solid 4- amino -2- hydroxyls
Methyl benzoate.
Used catalyst includes but is not limited to the concentrated sulfuric acid, p-methyl benzenesulfonic acid, the fourth of metatitanic acid four in above-mentioned preparation method
Ester, thionyl chloride or concentrated hydrochloric acid, preferred catalyst are the concentrated sulfuric acid.
(2) methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2 described in formula (III)
By the 4- amino-2-hydroxybenzoic acids methyl esters prepared, glacial acetic acid, acylating reagent according to mol ratio be 1:
(3.5~9): (0.5~2), it is preferably in a proportion of 1: (4~6.5): (0.7~1.3), 25 DEG C of reaction temperature~
55 DEG C, preferable temperature is 35 DEG C~45 DEG C, is added dropwise acylating reagent in reaction temperature, after reaction terminating, adds water,
Filter, obtain the methyl hydroxybenzoate of white solid 4- acetylaminohydroxyphenylarsonic acids 2.
Acylating reagent used includes but is not limited to acetic anhydride, chloroacetic chloride in above-mentioned preparation method, preferably acylated examination
Agent is acetic anhydride.
(3) the 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates described in formula (IV)
By the methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2 prepared, chlorinating agent according to mol ratio be 1:
(0.8~2), is preferably in a proportion of 1: (1.1~1.5), be added in reaction reagent, reaction temperature be -10 DEG C~
20 DEG C, preferable temperature -6 DEG C~5 DEG C, after reaction terminating, water is added, and pH is adjusted with sodium hydrate aqueous solution
To 4~5, filter, filtrate extraction separates organic phase, is spin-dried for solvent, and the white after obtaining filter cake and being spin-dried for is consolidated
Body 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates.
In above-mentioned preparation method chlorinating agent used include but is not limited to N- chlorosuccinimides, sulfonic acid chloride,
Thionyl chloride, phosphorus trichloride or phosphorus pentachloride, preferably chlorinating agent sulfonic acid chloride, reaction dissolvent used include but
Dichloromethane, ethyl acetate, chloroform, 1,2- dichloroethanes, toluene or carbon tetrachloride are not limited to, is preferably reacted
Solvent is ethyl acetate.
(4) the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3- described in formula (V)
By the 4- acetamido -5- chlorine-2-hydroxyls methyl benzoate prepared, brominated reagent according to mol ratio be 1:
(0.5~1.8), is preferably in a proportion of 1: (1~1.3), it is added in reaction dissolvent, reacts at ambient temperature,
After reaction terminating, water is added, is filtered, filter cake is washed with clear water, obtains the bromo- 5- of white solid 4- acetamidos -3-
Chlorine-2-hydroxyl methyl benzoate.
Brominated reagent used includes but is not limited to N- bromo-succinimides, C5H6Br2N2O2 in above-mentioned preparation method
Or bromine, preferably brominated reagent N- bromo-succinimides, reaction reagent are DMF, four
Hydrogen furans, the mix reagent of acetic acid and water, ethanol, preferred reagent are DMF.
(5) 4- acetamidos -3- bromo- 2- (2- bromine oxethyls) -5- chloro benzoic ethers described in formula (VI)
The bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3-, glycol dibromide, the acid binding agent that will be prepared
It is 1 according to mol ratio: (1.3~2.4): (0.6~1.4), is preferably in a proportion of 1: (1.6~2):
(1.8~1.2), are added in reaction dissolvent, 25 DEG C~65 DEG C of reaction temperature, 35 DEG C~45 DEG C of preferable temperature,
After reaction terminating, add warm water and be cooled to room temperature, be stirred overnight crystallization, filter, with re crystallization from toluene, while hot
Filter, filtrate crystallization, obtain white solid 4- acetamidos -3- bromo- 2- (2- bromine oxethyls) -5- chloro benzoic ethers.
Acid binding agent used includes but is not limited to for potassium carbonate, triethylamine, pyridine, carbonic acid in above-mentioned preparation method
Sodium, preferably acid binding agent are potassium carbonate, reaction dissolvent be DMA, DMF,
Acetone, toluene, preferred reagent DMA.
(6) the chloro- 2,3- Dihydrobenzofuranes -7- methyl formates of 4- acetamidos -5- described in formula (VII)
By 4- acetamidos -3- bromo- 2- (2- the bromine oxethyls) -5- chloro benzoic ethers prepared, zinc powder according to mole
Than for 1: (0.9~2.1), be preferably in a proportion of 1: (1.05~1.5), be added in reaction dissolvent, nitrogen is protected
Under shield, 2h is stirred at room temperature, is warming up to 35 DEG C~70 DEG C of reaction temperature, 45 DEG C~60 DEG C of preferable temperature, reaction
About 24h, TLC monitoring reaction, after reaction terminating, be added dropwise hydrochloric acid, isopropanol, water according to mol ratio (0.3~
0.8): (0.25~0.75): (0.5~1.0), preferred proportion (0.45~0.6): (0.4~0.6):
(0.7~0.9), completion of dropwise addition simultaneously heat up, reaction solution clarification, add cold water to stir cooling crystallization, and suction filtration obtains white
The chloro- 2,3- Dihydrobenzofuranes -7- methyl formates of color solid 4- acetamidos -5-.
Reaction reagent used includes but is not limited to DMAC N,N' dimethyl acetamide, N, N- diformazans in above-mentioned preparation method
Base formamide, acetone, tetrahydrofuran, preferably reaction reagent are DMA.
(7) the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of 4- amino -5- described in formula (VIII)
The chloro- 2,3- Dihydrobenzofuranes -7- methyl formates of 4- acetamidos -5-, the 50% sodium hydroxide water that will be prepared
Solution is according to mol ratio 1: (2~4), it is preferably in a proportion of 1: (2.5~3.8), is added in reaction dissolvent, and
Suitable quantity of water is added, reaction temperature is 65 DEG C~100 DEG C, 80 DEG C~95 DEG C of preferable temperature, TLC monitoring reactions, instead
After should terminating, 5 DEG C of stirring and crystallizings are cooled to, are filtered, filter cake is added to propylene glycol monomethyl ether and the mixing of water is molten
In agent, 80 DEG C~95 DEG C stirrings are warming up to, and watery hydrochloric acid is added dropwise, adjust pH to 3 or so, separate out solid, cooling
To room temperature, stirring and crystallizing, filter, obtain chloro- 2, the 3- Dihydrobenzofuranes -7- carboxylic acids of white solid 4- amino -5-.
It is molten for the mixing of second alcohol and water to include but is not limited to reaction dissolvent for reaction reagent used in above-mentioned preparation method
Agent, propylene glycol monomethyl ether or propylene glycol monomethyl ether and water mixed solvent, preferably reaction dissolvent are propylene glycol monomethyl ether
And water mixed solvent, alkali used is hydrolyzed as sodium hydroxide, potassium hydroxide, preferably lithium hydroxide, sodium hydroxide,
And it is made into 50% aqueous solution.
Raw material of the present invention is easy to get, it is simple to operate it is gentle, with short production cycle, purity is high, security is good, cost is low,
It is adapted to industrialized production.
Embodiment
The butanedioic acid prucalopride intermediate 4- amino -5- chloro- 2,3- Dihydrobenzofuranes of the invention to be synthesized
- 7- carboxylic acids can follow these steps to carry out：
The synthesis of the methyl hydroxybenzoate of 1 4- amino of embodiment -2
PAS (50g, 0.327mol) and methanol (300mL) are added into 1L three-necked bottles, is stirred
After the concentrated sulfuric acid (100mL) is added dropwise under condition of ice bath, during dropwise addition, ensure temperature control between 0~5 DEG C,
After being added dropwise, it is transferred to oil bath and is warming up to 80 DEG C of back flow reaction 6h.TLC monitoring reactions terminate, and are cooled to room
Temperature, add 10mol/L sodium hydroxide solutions (about 200mL) to be adjusted to pH 4~5, separate out a large amount of solids, filter, water
Wash, dry, obtain product 50.3g, yield 92.1%, purity 99.6%, ESI-MS m/z:168[M+H]+,
190[M+Na]+。
The synthesis of the 4- acetamidos of embodiment 2-2 hydroxybenzoic acid methyl esters
2 (108g, 0.65mol) and glacial acetic acid (540mL) are added into 2L three-necked bottles, 40 are warming up to after stirring evenly
DEG C, acetic anhydride (79.2g, 0.78mol) is added dropwise, reaction solution is gradually clarified.Drop finishes, and TLC monitorings, reacts about 1h.
Water (1000mL) is added, separates out a large amount of solids.Filtered after being cooled to room temperature, filter cake is dried after being washed with water, and is obtained
White solid 125g, yield 92.4%, purity 99.9%, ESI-MS m/z:210[M+H]+, 232 [M+Na]+,
207.8[M-H]-, 418.9 [2M+H]+, 440.9 [2M+Na]+。
The synthesis of the 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates of embodiment 3
3 (160g, 0.776mol) and ethyl acetate (1100mL), -5~0 DEG C of dropwise addition sulphur are added into 2L three-necked bottles
Acyl chlorides (134.5g, 0.995mol), control temperature drop in -5~0 DEG C, about 1h finish.After being added dropwise, continue
Stirring reaction 1h, TLC monitoring reaction.After the completion of reaction, reaction solution is poured into water, with 10mol/L hydrogen-oxygens
Change sodium solution and adjust pH 4~5, filter, filtrate extraction separates organic layer, and organic layer is spin-dried for, and obtains largely solid
Body, merge with cake solids, with 5 times of amount ethanol hot beating 30min, filter, dry cake, it is solid to obtain white
Body 151.1g, yield 80%, purity 98.7%, ESI-MS m/z:244[M+H]+, 266 [M+Na]+, 242 [M-H]-。
The synthesis of the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3- of embodiment 4
4 (64g, 0.263mol) and DMF (510mL) are added into 50mL three-necked bottles,
Under agitation, normal temperature adds NBS (61g, 0.342mol), and continues to react under this condition, TLC
Monitoring reaction.After the completion of reaction, water 400mL is added, is filtered, filter cake is washed with water repeatedly, collects filter cake and does
Dry white solid 67.5g, yield 79.5%, purity 92.4%, ESI-MS m/z:324[M+H]+,
345.9[M+Na]+, 322 [M-H]-。
The synthesis of embodiment 5 4- acetamidos -3- bromo- 2- (2- bromine oxethyls) -5- chloro benzoic ethers
5 (90g, 0.28mol), potassium carbonate (42g, 0.30mol) and N, N- bis- are sequentially added into 1L three-necked bottles
Methylacetamide (450mL), stirring at normal temperature 0.5h.Addition 1,2- Bromofumes (104.6g, 0.56mol), 50 DEG C
Stirring reaction 5h.FeCl3Monitoring reaction.After the completion of reaction, the warm water (300mL) of 60 DEG C of addition, insulated and stirred,
Solid is separated out, adds 150mL warm water, is cooled to room temperature, 150mL cold water is added, is stirred overnight crystallization.
Off-white powder about 100g is filtered within second day to obtain, is dried, with 5 times of amount re crystallization from toluene, heat is filtered, and filtrate is put
Crystallization is put, filters to obtain white solid drying, yield 106.6g, yield 89.8%, purity 97.4%, ESI-MS
m/z:429[M+H]+, 451 [M+Na]+, 427 [M-H]-。
The synthesis of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylate methyl esters of the 4- acetamidos -5- of embodiment 6
6 (80g, 0.187mol), zinc powder (14.9g, 0.229mol) and N, N- dimethyl second are added into 1L three-necked bottles
Acid amides (160mL), under nitrogen protection, 2h is stirred at room temperature and is warming up to 50 DEG C of reactions, TLC monitorings are reacted, and 20h is anti-
It should complete.After the completion of reaction, hydrochloric acid (43mL), water (60ml) and isopropanol (40mL) is added dropwise, is warming up to 70 DEG C
Stir 0.5h, solution clarification.Add cold water (300mL), be cooled to room temperature, be stirred overnight, filter, filter cake is thick
Product are recrystallized with propylene glycol monomethyl ether, yield 43.1g, yield, and 85.5%, purity 98.8%, ESI-MS m/z:
270[M+H]+, 292 [M+Na]+, 562 [2M+Na]+。
The synthesis of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of the 4- amino -5- of embodiment 7
Gained intermediate 7 (30g, 0.11mol), water (150mL), propane diols list first are added into the mono- neck bottles of 500mL
Ether (36mL) and 50% sodium hydroxide solution (90mL), 90 DEG C are to slowly warm up under stirring, equality of temperature reaction 8h, TLC
Monitoring reaction.After the completion of reaction, ice bath is cooled to 5 DEG C of stirring 2h, filters, filter cake is added with after appropriate water washing
Into the mono- neck bottles of 500mL, add water (210mL) and propylene glycol monomethyl ether (35mL), reaction solution be warming up to 80 DEG C,
Reaction solution is changed into homogeneous.Watery hydrochloric acid is added dropwise, adjusts pH to 3 or so, separates out solid.Drop, which finishes, is cooled to 10 DEG C of continuation
Stir 2h.Filter, the appropriate water washing of filter cake, dry off-white powder, yield 20.8g, yield 89.8%,
Purity 99%, ESI-MS m/z:214.1[M+H]+, 236.1 [M+Na]+, 448 [2M+Na]+。1H-NMR(400
MHz,DMSO)δ:12.065 (s, 1H), 7.436 (s, 1H), 5.993 (s, 2H), 4.603 (t, J=8.87Hz, 2H),
2.982 (t, J=8.87Hz, 2H).
Claims (10)
- A kind of 1. synthetic method of chloro- 2, the 3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5-, it is characterised in that：Using PAS as initiation material; under catalyst action; esterification reaction of organic acid occurs with methanol; obtain the methyl hydroxybenzoate of 4- amino -2; react to obtain 4- acetamidos -2 hydroxybenzoic acid methyl esters with acetylation reagent again; 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates are obtained through chlorinating agent chloro; bromo obtains the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3-; bromoethyl obtains 4- acetamidos -3- bromo- 2- (2- bromine oxethyls) -5- chloro benzoic ethers, then through cyclization, hydrolyze and produce.
- 2. a kind of synthetic method of chloro- 2, the 3- Dihydrobenzofuranes -7- carboxylic acids of prucalopride intermediate 4- amino -5- as claimed in claim 1, it is characterised in that comprise the following steps：(1) the 4- amino-2-hydroxybenzoic acid methyl esters described in formula (II)Using PAS as initiation material, under catalyst action, esterification reaction of organic acid occurs with methanol and obtains；(2) the 4- acetylaminohydroxyphenylarsonic acid 2 hydroxybenzoic acid methyl esters described in formula (III)The methyl hydroxybenzoate of 4- amino -2 occurs acetylization reaction with acetylation reagent and is made；(3) the 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates described in formula (IV)The methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2 is made by chlorinating agent chlorination；(4) the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3- described in formula (V)4- acetamido -5- chlorine-2-hydroxyl methyl benzoates are made by bromo-reaction；(5) 4- acetamidos -3- bromo- 2- (2- bromine oxethyls) -5- chloro benzoic ethers described in formula (VI)The bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3- are made by being reacted with glycol dibromide；(6) the chloro- 2,3- Dihydrobenzofuranes -7- methyl formates of 4- acetamidos -5- described in formula (VII)The bromo- 2- of 4- acetamidos -3- (2- bromine oxethyls) -5- chloro benzoic ethers being made through ring-closure reaction；(7) the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of 4- amino -5- described in formula (VIII)The chloro- 2,3- Dihydrobenzofuranes -7- carboxylate methyl esters of 4- acetamidos -5- can be made by hydrolysis.
- 3. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2, the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids, it is characterized in that, in the synthetic method of the methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2, described catalyst is the concentrated sulfuric acid, p-methyl benzenesulfonic acid, butyl titanate, thionyl chloride or concentrated hydrochloric acid, the preferably concentrated sulfuric acid；PAS, methanol, catalyst molar ratio 1: (4~8): (1.5~4), it is preferably in a proportion of 1: (5~6.5): (1.8~2.8).
- 4. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2; the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids; it is characterized in that; in the synthetic method of the methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2; acetylation reagent is acetic anhydride or chloroacetic chloride, and preferably acetylation reagent is acetic anhydride；4- amino-2-hydroxybenzoic acids methyl esters, glacial acetic acid, acylating reagent are 1 according to mol ratio: (3.5~9): (0.5~2); it is preferably in a proportion of 1: (4~6.5): (0.7~1.3); 25 DEG C~55 DEG C of reaction temperature, preferable temperature are 35 DEG C~45 DEG C.
- 5. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2, the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids, it is characterized in that, in the synthetic method of 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates, the chlorinating agent is N- chlorosuccinimides, sulfonic acid chloride, thionyl chloride, phosphorus trichloride or phosphorus pentachloride, and preferably chlorinating agent is sulfonic acid chloride；The methyl hydroxybenzoate of 4- acetylaminohydroxyphenylarsonic acids 2 is 1 with chlorinating agent mol ratio: (0.8~2), it is preferably in a proportion of 1: (1.1~1.5), reaction reagent is dichloromethane, ethyl acetate, chloroform, 1,2- dichloroethanes, toluene or carbon tetrachloride, it is preferred that reaction dissolvent is ethyl acetate, reaction temperature is -10 DEG C~20 DEG C, preferable temperature -6 DEG C~5 DEG C.
- 6. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2, the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids, it is characterized in that, in the synthetic method of the bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3-, bromo-reaction reagent is bromine, C5H6Br2N2O2, copper bromide or N- bromo-succinimides, it is preferred that bromo-reaction reagent is N- bromo-succinimides, reaction reagent is N, dinethylformamide, tetrahydrofuran, the mix reagent of acetic acid and water, ethanol, preferred reagent is N, dinethylformamide, 4- acetamido -5- chlorine-2-hydroxyl methyl benzoates, brominated reagent is 1 according to mol ratio: (0.5~1.8), it is preferably in a proportion of 1: (1~1.3).
- 7. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2,The synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids,It is characterized in that,In the synthesis of the bromo- 2- of 4- acetamidos -3- (2- bromine oxethyls) -5- chloro benzoic ethers,Reaction dissolvent is N,N- dimethyl acetamides,N,Dinethylformamide,Acetone,Toluene,It is preferred that N,N- dimethyl acetamides,Acid binding agent used is potassium carbonate,Triethylamine,Pyridine,Sodium carbonate,It is preferred that acid binding agent is potassium carbonate,25 DEG C~65 DEG C of reaction temperature,35 DEG C~45 DEG C of preferable temperature,The bromo- 5- chlorine-2-hydroxyls methyl benzoates of 4- acetamidos -3-,1,2- Bromofumes,Acid binding agent is 1 according to mol ratio: (1.3~2.4): (0.6~1.4),It is preferably in a proportion of 1: (1.6~2): (1.8~1.2),It is added in reaction dissolvent.
- 8. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2, the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids, it is characterized in that, 4- acetamidos -5- chloro- 2, in the synthesis of 3- Dihydrobenzofuranes -7- methyl formates, reaction dissolvent is N, N- dimethyl acetamides, N, dinethylformamide, acetone, it is preferred that reaction dissolvent is N, N- dimethyl acetamides, catalyst is zinc powder, 35 DEG C~70 DEG C of reaction temperature, 45 DEG C~60 DEG C of preferable temperature, the bromo- 2- of 4- acetamidos -3- (2- bromine oxethyls) -5- chloro benzoic ethers, zinc powder mol ratio is 1: (0.9~2.1), preferably 1: (1.05~1.5).
- 9. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 8, the synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids, it is characterized in that, after reaction terminating, hydrochloric acid, isopropanol, water is added dropwise, completion of dropwise addition simultaneously heats up, reaction solution is clarified, cold water is added to stir cooling crystallization, hydrochloric acid, isopropanol, water mol ratio are (0.3~0.8): (0.25~0.75): (0.5~1.0), are preferably (0.45~0.6): (0.4~0.6): (0.7~0.9).
- 10. prucalopride intermediate 4- amino -5- chloro- 2 as claimed in claim 1 or 2,The synthetic method of 3- Dihydrobenzofuranes -7- carboxylic acids,It is characterized in that,4- amino -5- chloro- 2,In the synthesis of 3- Dihydrobenzofuranes -7- carboxylic acids,Reaction dissolvent is second alcohol and water mixed sodium solvent,Propylene glycol monomethyl ether or propylene glycol monomethyl ether and water mixed solvent,It is preferred that reaction dissolvent is propylene glycol monomethyl ether and water mixed solvent,Hydrolysis alkali used is sodium hydroxide,Potassium hydroxide,Lithium hydroxide,It is preferred that sodium hydroxide,And it is made into 50% aqueous solution,65 DEG C~100 DEG C of reaction temperature,80 DEG C~95 DEG C of preferable temperature,4- acetamidos -5- chloro- 2,3- Dihydrobenzofuranes -7- methyl formates,50% sodium hydrate aqueous solution is according to mol ratio 1: (2~4),It is preferably in a proportion of 1: (2.5~3.8).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610285982.2A CN107337658A (en) | 2016-05-03 | 2016-05-03 | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610285982.2A CN107337658A (en) | 2016-05-03 | 2016-05-03 | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107337658A true CN107337658A (en) | 2017-11-10 |
Family
ID=60222877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610285982.2A Pending CN107337658A (en) | 2016-05-03 | 2016-05-03 | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107337658A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108333272A (en) * | 2018-03-02 | 2018-07-27 | 重庆华邦胜凯制药有限公司 | The method of LC-MSMS method separation determination PAS and its related impurities |
| CN114437007A (en) * | 2020-11-05 | 2022-05-06 | 鲁南制药集团股份有限公司 | Preparation method of prucalopride intermediate |
| CN115745929A (en) * | 2022-11-07 | 2023-03-07 | 山东四环药业股份有限公司 | Preparation method of prankari succinate key intermediate |
| CN116082319A (en) * | 2020-06-04 | 2023-05-09 | 南京恒通医药开发有限公司 | Continuous synthesis method of prucalopride succinate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664845A (en) * | 2013-12-27 | 2014-03-26 | 湖南欧亚生物有限公司 | Preparation method of Plk (Polo-like kinase) inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-formic acid |
| CN104016949A (en) * | 2014-06-25 | 2014-09-03 | 天津市炜杰科技有限公司 | Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid |
-
2016
- 2016-05-03 CN CN201610285982.2A patent/CN107337658A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664845A (en) * | 2013-12-27 | 2014-03-26 | 湖南欧亚生物有限公司 | Preparation method of Plk (Polo-like kinase) inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-formic acid |
| CN104016949A (en) * | 2014-06-25 | 2014-09-03 | 天津市炜杰科技有限公司 | Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| 原友志等: "琥珀酸普卡必利的合成", 《中国医药工业杂志》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108333272A (en) * | 2018-03-02 | 2018-07-27 | 重庆华邦胜凯制药有限公司 | The method of LC-MSMS method separation determination PAS and its related impurities |
| CN116082319A (en) * | 2020-06-04 | 2023-05-09 | 南京恒通医药开发有限公司 | Continuous synthesis method of prucalopride succinate |
| CN114437007A (en) * | 2020-11-05 | 2022-05-06 | 鲁南制药集团股份有限公司 | Preparation method of prucalopride intermediate |
| CN114437007B (en) * | 2020-11-05 | 2024-03-19 | 鲁南制药集团股份有限公司 | Preparation method of prizepride intermediate |
| CN115745929A (en) * | 2022-11-07 | 2023-03-07 | 山东四环药业股份有限公司 | Preparation method of prankari succinate key intermediate |
| CN115745929B (en) * | 2022-11-07 | 2024-01-19 | 山东四环药业股份有限公司 | Preparation method of prizepine succinate key intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107337658A (en) | A kind of synthetic method of the chloro- 2,3- Dihydrobenzofuranes -7- carboxylic acids of butanedioic acid prucalopride intermediate 4- amino -5- | |
| CN101279997B (en) | Novel preparation of budesonide | |
| CN105820126B (en) | A kind of preparation method of olaparib | |
| JP2009508861A5 (en) | ||
| CN109942589A (en) | A kind of preparation method of new pranoprofen | |
| CN102127063A (en) | New synthesis technology of anti-cancer drug Raltitrexed | |
| CN109020881A (en) | A kind of Ah pa replaces the preparation method of Buddhist nun | |
| CN106220622A (en) | A kind of preparation method of Palmic acid 9-hydroxy-risperidone | |
| CN102731605B (en) | A kind of purification process of Abiraterone acetate | |
| CN106565616A (en) | Preparation method of antibacterial veterinary drug sulfamonomethoxine sodium | |
| CN107778191A (en) | A kind of preparation method of Iopromide and its intermediate | |
| CN107235957A (en) | A kind of synthetic method for preparing Niraparib | |
| CN102603718A (en) | Synthesis method of cediranib | |
| CN103087017A (en) | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product | |
| CN106831397A (en) | A kind of anthraquinone analog compound and preparation method thereof and medical application | |
| CN107556238A (en) | It is a kind of to block the rich synthetic method for Buddhist nun | |
| CN103145636A (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN106045843A (en) | Production process of calcium (+/-)-3-methyl-2-oxovalerate | |
| CN109516938A (en) | A kind of Alfacalcidol derivative and preparation method thereof | |
| CN102276445B (en) | Colloidal bismuth tartrate compound, medicaments thereof, preparation method thereof and application thereof | |
| CN102659638B (en) | Synthetic method of leonurine | |
| CN104478972A (en) | Method for preparing troxerutin by adopting self-suction type stirred autoclave | |
| CN102010384B (en) | Deuterated cyanophenyl thiazoles derivative for treating gout and hyperur icemia | |
| CN101781311B (en) | Novel preparation method of platelet aggregation inhibition compound | |
| CN102180864A (en) | Preparation method of strontium ranelate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171110 |