CN107011338B - A kind of preparation method of Suo Feinaxin impurity - Google Patents
A kind of preparation method of Suo Feinaxin impurity Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of Suo Feinaxin impurity, this method obtains Suo Feinaxin impurity with heterochromatic full for starting material, through the reaction synthesis of nine steps.Rationally, raw material is cheap, and reaction condition is mild, strong operability for present invention process design；The Suo Feinaxin impurity that the present invention is prepared, up to 98% or more, yield can be studied for the metabolic mechanism of Suo Feinaxin up to 80% or more and provide test agent, have important application value purity.The present invention opens new synthetic method, effectively avoids in API approach finally with treating different things alike or the drawbacks such as the difficult purification of transesterification, yield are low, while also synthesizing for API and providing new method and thinking.
Description
Technical field
The present invention relates to the synthesis of impurity of the drug, and in particular to a kind of preparation method of Suo Feinaxin impurity.
Background technique
Suo Feinaxin is clinically used for the overactive bladder that treatment has urgent urination, frequency symptoms, and can selectively relax bladder
Detrusor reduces the systemic adverse reactions of previous anticholinergic agent, such as dry, constipation, pupil amplification and heartbeat are overrun.
Suo Feina new construction formula are as follows:
The structural formula of Suo Feinaxin impurity:
Drug is specialty goods, and impurity contained in drug is an important factor for influencing drug quality, often to pacify with drug
Full property is related and also related with efficiency in a few cases.Therefore control impurity level is more next during drug development
More by the attention of medical personal, before marketing drugs, it should understand fully impurity source, property, detection method and its limitation, together
Shi Gaishan process conditions, reduce the generation of impurity, and formulate corresponding regulation, guarantee and improve drug quality from many aspects, reduce
The adverse drug reaction of drug.Currently, not yet about Suo Feinaxin impurity with and preparation method thereof report.
Summary of the invention
Goal of the invention: the synthetic technology blank in order to solve Suo Feinaxin impurity, the present invention provides a kind of technological designs
Rationally, strong operability, product is easily purified, purity is high, yield are high, and can realize the system of the Suo Feinaxin impurity of industrialized production
Preparation Method.
A kind of technical solution: preparation method of Suo Feinaxin impurity of the present invention, comprising the following steps:
(1) it takes compound A to be dissolved in low-boiling nonpolar solvent, oxidising agent is added, carry out carbonyl alfa oxygen
Change, reaction obtains intermediate compound I；Wherein, compound A is heterochromatic full, CAS 493-05-0；
(2) intermediate compound I made from step (1) is taken, is dissolved in high boiling nonpolar solvent, compound B is added and carries out
Substitution reaction open loop, obtains intermediate II；Wherein, compound B is phenide organic reagent；
(3) it takes intermediate II made from step (2) to be dissolved in halogen based solvents, chlorination reagent is added and carries out hydroxy chloride
Reaction, is prepared intermediate III；
(4) intermediate III made from step (3) is taken, is dissolved in polar solvent, reducing agent is added and carries out carbonyl reduction,
Intermediate compound IV is prepared；
(5) it takes intermediate compound IV made from step (4) and compound C to be dissolved in polar solvent, alkali is added, carry out nucleophilic and take
In generation, intermediate V is obtained, the compound C is CAS 1074-82-4；
(6) it takes intermediate V made from step (5) to be dissolved in polar solvent, hydrolysing agent is added, during hydrolysis obtains
Mesosome VI；
(7) compound D is dissolved in dry nonpolar solvent, triphosgene is added and is made into active acyl chlorides, reacts
To compound VII, wherein No. CAS of compound D are as follows: 25333-42-0.
(8) intermediate VII made from intermediate VI made from step (6) and step (7) is taken, dry non-pole is dissolved in
Property solvent in, be added organic base occur acylation reaction obtain VIII；
(9) intermediate VIII made from step (8) is taken, is dissolved in non-pole solvent, oxidizing benzylalcohol is added and obtains
Compound IX, as Suo Feinaxin impurity,
It is heterochromatic full in step (1), i.e. Isochroman, CAS:493-05-0；Heterochromatic full and oxidising agent mole
Than being reacted after oxidising agent for 1:2~5, is added at 0~80 DEG C.
It is further preferred that heterochromatic full and oxidising agent the molar ratio is 1:2.5 in step (1), oxidation examination is added
It is reacted after agent at 50 DEG C.
In step (1), the nonpolar solvent is methylene chloride or ether or 1,2- dichloroethanes, in tetrahydrofuran four
Solvent is optionally first, be wherein most preferably 1,2- dichloroethanes.
In step (1), the oxidising agent be selenium dioxide, potassium permanganate, Jones reagent, tertbutanol peroxide, three
Five kinds of oxidants of chromium oxide optional one, wherein most preferably selenium dioxide.
In step (2), the high boiling nonpolar solvent be tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE), it is different
Solvent is optionally first, wherein it is preferable to use dry dioxane in propyl ether four.
In step (2), the phenide organic reagent be phenyl-magnesium-bromide, phenyl-magnesium-chloride, phenyl magnesium iodide or
Tetraphenylphosphonium chloride zinc.It is preferable to use phenyl-magnesium-chlorides.
In step (2), the molar ratio of the intermediate compound I and phenide organic reagent is 1:0.8~3, substitution reaction
Temperature is 0~50 DEG C.
Preferably, in step (2), the molar ratio of the intermediate compound I and phenide organic reagent is 1:2.2, is replaced
Reaction temperature is 20 DEG C.
In step (3), the volume ratio of the halogen based solvents and intermediate II is 2~20:1, the intermediate II and chlorine
The molar ratio for changing reagent is 1:1~5.
Preferably, in step (3), the volume ratio of the halogen based solvents and intermediate II is 15:1, the intermediate II
Molar ratio with chlorination reagent is 1:3.
In step (3), the halogen based solvents are methylene chloride, chloroform, 1,2- dichloroethanes or carbon tetrachloride.It is preferred that
Carbon tetrachloride.
In step (3), the chlorination reagent is thionyl chloride, concentrated hydrochloric acid, carbon tetrachloride, triphenylphosphine or phosphoric
Phosphorus.Triphenylphosphine.
In step (4), the volume ratio of the polar solvent and intermediate III is 2~10:1, the intermediate III with also
The molar ratio of former agent is 1:0.5~2.
Preferably, in step (4), the volume ratio of the polar solvent and intermediate III is 10:1, the intermediate III
Molar ratio with reducing agent is 1:1.5.
In step (4), the polar solvent is methanol, ethyl alcohol, acetonitrile or water.Preferred alcohol.
In step (4), the reducing agent is Lithium Aluminium Hydride, sodium borohydride, sodium cyanoborohydride or palladium carbon catalytic hydrogenation
Reduction.It is preferred that sodium cyanoborohydride.
In step (5), the volume ratio of the polar solvent and intermediate compound IV is 5~25:1, the alkali and intermediate compound IV
Molar ratio is 1:1~5, and reaction temperature is 50 DEG C~100 DEG C.
Preferably, in step (5), the volume ratio of the polar solvent and intermediate compound IV is 15:1, the alkali and intermediate
The molar ratio of IV is 1:3, and reaction temperature is 100 DEG C.
In step (5), the polar solvent is DMF, DMSO or pyridine.It is preferred that DMSO.
In step (5), the alkali of the nucleophilic displacement of fluorine is sodium carbonate, potassium carbonate or triethylamine.It is preferred that sodium carbonate.
In step (6), the hydrolysing agent is hydrazine hydrate, concentrated hydrochloric acid or 6M hydrochloric acid, and hydrolysising reacting temperature is 50~100
℃。
Preferably, in step (6), the hydrolysing agent is hydrazine hydrate, and reaction temperature is 80 DEG C.
In step (6), the molar ratio of the intermediate V and hydrolysing agent is 1:1~1:4, wherein it is preferred that 1:2.
In step (7), the nonpolar solvent of the drying is ethyl acetate, tetrahydrofuran, ether or methylene chloride, described
Reaction temperature is -30 DEG C~25 DEG C.
Preferably, in step (7), the nonpolar solvent tetrahydrofuran of the drying, the reaction temperature is 15 DEG C.
In step (7), the acylating reagent of addition is triphosgene or phosgene, preferably triphosgene.
In step (7), the molar ratio of the compound D and acylating reagent is 0.5-2
In step (8), the nonpolar solvent of the drying is ethyl acetate, tetrahydrofuran, ether or methylene chloride.It is preferred that
Ether.
In step (8), the organic base is triethylamine, n,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine or N-
Methyl morpholine.It is preferred that N, N- diisopropylethylamine.
In step (8), the acylation reaction temperature is -30 DEG C~25 DEG C.It is preferred that 15 DEG C.
In step (8), the molar ratio of the intermediate VI and intermediate VII are 1:1~1:3, wherein it is preferred that 1:1.
In step (9), the molar ratio of the intermediate VIII and oxidant is 1:2~10, and reaction temperature is 25~80 DEG C.
Preferably, in step (9), for the molar ratio of the intermediate VIII and oxidant in 1:4, reaction temperature is 50 DEG C.
In step (9), the nonpolar solvent be ethyl acetate, tetrahydrofuran, methylene chloride, chloroform or 1,2- dichloro
Ethane.It is preferred that methylene chloride.
In step (9), the oxidant is selenium dioxide, manganese dioxide, PCC, PDC or pyridine. sulfur trioxide.It is preferred that
PCC。
The utility model has the advantages that the preparation method of Suo Feinaxin impurity provided by the invention compared to the prior art have it is following excellent
Point: entire technological design rationally, strong operability, have the advantages that reaction efficiency is high, purification is convenient, with high purity, yield is high；It adopts
The Suo Feinaxin impurity being prepared with method provided by the invention, purity is high reachable 98% or more, high income, and isotope
Abundance > 99%.The Suo Feinaxin impurity that the present invention is prepared can for Suo Feinaxin metabolic mechanism research and impurity to pharmacology,
The analysis of toxicity provides test agent, has extremely important meaning.
Detailed description of the invention
Fig. 1 is the process flow chart of the preparation method of Suo Feinaxin impurity of the present invention.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies specific material proportion, process conditions and its result described in example and is merely to illustrate the present invention, without that should will not limit
The present invention described in detail in claims processed.
Embodiment 1
The synthesis of intermediate compound I
Reaction process are as follows:
It takes 100g heterochromatic full (compound A, CAS:493-05-0) to be dissolved in 1L 1, in 2- dichloroethanes, 180g bis- is added
Selenium oxide, 50 DEG C of reactions are overnight.Reaction mixture is filtered, and filter cake uses 50ml1 again, and 2- dichloroethanes washs filter cake, filtrate
It is spin-dried for rear ethyl alcohol recrystallization to purify to obtain the pure intermediate of 80g (I), this intermediate is white solid.
1H NMR (CDCl3,400MHz) δ 3.07 (t, J=5.98Hz, 2H), 4.54 (t, J=5.98Hz, 1H), 7.40
(t, J=5.4Hz, 1H), 8.07 (d, J=7.56Hz, 1H), 7.54 (t, J=7.44Hz, 1H), 8.10 (d, J=7.80Hz,
1H), MS:148.
The synthesis of intermediate II
Reaction process are as follows:
In the dioxane for taking 80g Suo Feinaxin impurity intermediate (I) to be dissolved in, 1094mL 1M phenyl-magnesium-chloride is added
Tetrahydrofuran (THF), 20 DEG C reaction overnight.Reaction mixture ice bath stirring is slowly added to 400mL water quenching reaction, separates
Organic phase, water phase is extracted with ethyl acetate again to be merged afterwards twice, and anhydrous sodium sulfate is dry, and rear pillar chromatography purity, solvent is concentrated
The pure intermediate II of 86g is obtained after collecting pure mobile phase concentration for petroleum ether: ethyl acetate 95:5.
1H NMR(300MHz,CDCl3):d 1.57(s,1H),2.96(t,.0,2H),3.91(m,2H),7.28–7.38
(m,4h),7.42–7.53(m,3H),7.58–7.64(m,1H),7.81–7.84(m,1H).
The synthesis of intermediate III
Reaction process are as follows:
It takes 45g Suo Feinaxin impurity intermediate (II) to be dissolved in 450mL carbon tetrachloride, 156g triphenylphosphine is added, return
Stream reaction 6h.200ml water is added in reaction mixture, separates organic phase, and concentration has column chromatography purifying, and solvent is petroleum ether: two
Chloromethanes=6:1 obtains 43g Suo Feinaxin impurity intermediate (III) after collecting pure mobile phase concentration.
1H NMR(300MHz,CDCl3):d 1.57(s,1H),2.96(t,J6.0,2H),3.7(m,2H),7.28–7.38
(m,4h),7.42–7.53(m,3H),7.58–7.64(m,1H),7.81–7.84(m,1H).
The synthesis of intermediate compound IV
Reaction process are as follows:
It takes 43g Suo Feinaxin impurity intermediate (III) to be dissolved in 350mL ethyl alcohol, 11g sodium cyanoborohydride, room is added
Temperature reaction is overnight.Reaction mixture is quenched with acetone, is then concentrated in ethyl alcohol recrystallization and is obtained in the pure Suo Feinaxin impurity of 38g
Mesosome (IV).
The synthesis of intermediate V
Reaction process are as follows:
Take 38g intermediate (IV) to be dissolved in 300mL DMSO, 40g potassium iodide and 48g sodium carbonate be added, at 70C with
50 DEG C of compound C (CAS:1074-82-4) reactions are overnight.200mL water and 200mL ethyl acetate are added into reaction mixture,
Organic phase is separated, organic phase is washed twice with 100mL saturated salt solution again, is concentrated after anhydrous sodium sulfate is dry, residue column color
Spectrum purification, solvent are dichloromethane-ethyl acetate=4:1, collect pure mobile phase, obtain the pure Suo Feinaxin impurity of 35g
Intermediate (V).
The synthesis of intermediate VI
Reaction process are as follows:
It takes 35g intermediate (V) to be dissolved in 300mL ethyl alcohol, 20mL hydrazine hydrate, back flow reaction 3h is added.Fully reacting, instead
Mixture is answered to be filtered, 250mL methylene chloride is added after being spin-dried in filtrate, obtains a white suspension, filters, after filtrate concentration
Column chromatography purifies to obtain 12g Suo Feinaxin impurity intermediate (VI).
1H NMR (300MHz, CDCl3): 2.85-2.87 (t, 1H), 2.89-2.92 (m, 2H), 3.06-2.12 (m, 1H),
7.05–7.48(m,9H).
The synthesis of intermediate VII
Reaction process are as follows:
It takes 20g compound D (CAS:25333-42-0) to be dissolved in the dry THF of dry 500mL, tri- light of 15g is added
Gas, ice bath, nitrogen protection react 2h, are then followed by the mixing that room temperature reaction obtains Suo Feinaxin impurity intermediate (VII) overnight
Object, reaction mixture are directly spare.
The synthesis of intermediate VIII
Reaction process are as follows:
12g Suo Feinaxin impurity intermediate (VIII) is dissolved in dry 1,2- dichloroethanes, and 10g, N, N- bis- is added
Then wopropyl ethyl amine and 1g DMAP, ice bath, nitrogen gas stirring take the THF of 200mL Suo Feinaxin impurity intermediate (VII) to mix
Object is slowly added dropwise, and reacts at room temperature 3h after being added dropwise.50mL methanol quenching reaction is added, reaction mixture, which is directly concentrated, to be done, so
Rear pillar chromatography purity, solvent are methylene chloride-methanol=95:5, and the mobile phase containing pure product is collected, after concentration
To 12g Suo Feinaxin impurity intermediate (VIII).
The synthesis of Suo Feinaxin impurity IX
Reaction process are as follows:
12g Suo Feinaxin impurity intermediate (VIII) is dissolved in dry chloroform, and 12.3g selenium dioxide, room temperature is added
Reaction overnight, then after reaction mixture filtered, be concentrated after filtrate chloroform, residue is purified by column chromatography,
Solvent methylene chloride: methanol=95:5 collects pure mobile phase, and the pure Suo Feinaxin impurity of 9g is obtained after concentration.
1H NMR (300MHz, CDCl3): 7.79-7.81 (d, 2H), 7.58-7.60 (t, 1H), 7.26-7.40 (6H),
5.3(br 1H),4.65(br 1H),3.44-3.46(m,2H),3.10-3.21(1H),2.6-2.8(6H),1.9-1.96
(1H), 1.25-1.8 (5H), MS+1=379.
Embodiment 2
The synthesis of intermediate compound I
Reaction process are as follows:
It takes 100g heterochromatic full (compound A, CAS:493-05-0) to be dissolved in 1L methylene chloride, 180g titanium dioxide is added
Selenium, 50 DEG C of reactions are overnight.Reaction mixture is filtered, and filter cake washs filter cake with 50ml methylene chloride again, and filtrate is spin-dried for rear second
Alcohol recrystallization purification obtains the pure intermediate of 70g (I), this intermediate is white solid.
1H NMR (CDCl3,400MHz) δ 3.07 (t, J=5.98Hz, 2H), 4.54 (t, J=5.98Hz, 1H), 7.40
(t, J=5.4Hz, 1H), 8.07 (d, J=7.56Hz, 1H), 7.54 (t, J=7.44Hz, 1H), 8.10 (d, J=7.80Hz,
1H), MS:148.
The synthesis of intermediate II
Reaction process are as follows:
In the methyl tertiary butyl ether(MTBE) for taking 80g Suo Feinaxin impurity intermediate (I) to be dissolved in, 1094mL 1M phenylchloride is added
Change the tetrahydrofuran (THF) of magnesium, 20 DEG C of reactions are overnight.Reaction mixture ice bath stirring is slowly added to 400mL water quenching reaction,
Organic phase is separated, water phase is extracted with ethyl acetate again to be merged afterwards twice, and anhydrous sodium sulfate is dry, and rear pillar chromatography purity, exhibition is concentrated
Opening agent is petroleum ether: ethyl acetate 95:5, obtains the pure intermediate II of 76g after collecting pure mobile phase concentration.
1H NMR(300MHz,CDCl3):d 1.57(s,1H),2.96(t,.0,2H),3.91(m,2H),7.28–7.38
(m,4h),7.42–7.53(m,3H),7.58–7.64(m,1H),7.81–7.84(m,1H).
The synthesis of intermediate III
Reaction process are as follows:
It takes 45g Suo Feinaxin impurity intermediate (II) to be dissolved in 450mL chloroform, 156g triphenylphosphine is added, reflux is anti-
Answer 6h.200ml water is added in reaction mixture, separates organic phase, and concentration has column chromatography purifying, and solvent is petroleum ether: dichloromethane
Alkane=6:1 obtains 38g Suo Feinaxin impurity intermediate (III) after collecting pure mobile phase concentration.
1H NMR(300MHz,CDCl3):d 1.57(s,1H),2.96(t,J6.0,2H),3.7(m,2H),7.28–7.38
(m,4h),7.42–7.53(m,3H),7.58–7.64(m,1H),7.81–7.84(m,1H).
The synthesis of intermediate compound IV
Reaction process are as follows:
It takes 43g Suo Feinaxin impurity intermediate (III) to be dissolved in 350mL acetonitrile, 5g sodium borohydride, room temperature reaction is added
Overnight.Reaction mixture is quenched with acetone, is then concentrated in ethyl alcohol recrystallization and is obtained the pure Suo Feinaxin impurity intermediate of 30g
(IV)。
The synthesis of intermediate V
Reaction process are as follows:
Take 38g intermediate (IV) to be dissolved in 300mLDMF, 40g potassium iodide and 48g sodium carbonate be added, at 70C with change
Close object C (CAS:1074-82-4) 50 DEG C of reactions overnight.200mL water and 200mL ethyl acetate are added into reaction mixture, point
From organic phase, organic phase is washed twice with 100mL saturated salt solution again, is concentrated after anhydrous sodium sulfate is dry, residue column chromatography
Purification, solvent are dichloromethane-ethyl acetate=4:1, collect pure mobile phase, obtain in the pure Suo Feinaxin impurity of 30g
Mesosome (V).
The synthesis of intermediate VI
Reaction process are as follows:
It takes 35g intermediate (V) to be dissolved in 300mL ethyl alcohol, 20mL concentrated hydrochloric acid, back flow reaction 5h is added.Fully reacting, instead
Mixture is answered to be filtered, 250mL methylene chloride is added after being spin-dried in filtrate, obtains a white suspension, filters, after filtrate concentration
Column chromatography purifies to obtain 10g Suo Feinaxin impurity intermediate (VI).
1H NMR (300MHz, CDCl3): 2.85-2.87 (t, 1H), 2.89-2.92 (m, 2H), 3.06-2.12 (m, 1H),
7.05–7.48(m,9H).
The synthesis of intermediate VII
Reaction process are as follows:
It takes 20g compound D (CAS:25333-42-0) to be dissolved in the dry ether of dry 500mL, tri- light of 16g is added
Gas, ice bath, nitrogen protection react 3h, are then followed by the mixing that room temperature reaction obtains Suo Feinaxin impurity intermediate (VII) overnight
Object, reaction mixture are directly spare.
The synthesis of intermediate VIII
Reaction process are as follows:
12g Suo Feinaxin impurity intermediate (VIII) is dissolved in dry methylene chloride, and 10g, N, N- diisopropyl is added
Then base ethamine and 1g DMAP, ice bath, nitrogen gas stirring take the THF mixture of 200mL Suo Feinaxin impurity intermediate (VII) slow
It is slow to be added dropwise, 3h is reacted at room temperature after being added dropwise.50mL methanol quenching reaction is added, reaction mixture, which is directly concentrated, to be done, then column
Chromatography purity, solvent are methylene chloride-methanol=95:5, and the mobile phase containing pure product is collected, obtains after concentration
10.3g Suo Feinaxin impurity intermediate (VIII).
The synthesis of Suo Feinaxin impurity IX
Reaction process are as follows:
12g Suo Feinaxin impurity intermediate (VIII) is dissolved in dry chloroform, and 12.3g manganese dioxide, room temperature is added
Reaction overnight, then after reaction mixture filtered, be concentrated after filtrate chloroform, residue is purified by column chromatography,
Solvent methylene chloride: methanol=95:5 collects pure mobile phase, and the pure Suo Feinaxin impurity of 7.9g is obtained after concentration.
1H NMR (300MHz, CDCl3): 7.79-7.81 (d, 2H), 7.58-7.60 (t, 1H), 7.26-7.40 (6H),
5.3(br 1H),4.65(br 1H),3.44-3.46(m,2H),3.10-3.21(1H),2.6-2.8(6H),1.9-1.96
(1H), 1.25-1.8 (5H), MS+1=379.
Claims (10)
1. a kind of preparation method of Suo Feinaxin impurity, which comprises the following steps:
(1) it takes compound A to be dissolved in low-boiling nonpolar solvent, oxidising agent is added, carry out carbonyl alfa oxidation, instead
It should obtain intermediate compound I；Wherein, compound A is heterochromatic full, CAS 493-05-0；
(2) intermediate compound I made from step (1) is taken, is dissolved in high boiling nonpolar solvent, compound B is added and is replaced
Open loop is reacted, intermediate II is obtained；Wherein, compound B is phenide organic reagent；
(3) it takes intermediate II made from step (2) to be dissolved in halogen based solvents, it is anti-that chlorination reagent progress hydroxy chloride is added
It answers, intermediate III is prepared；
(4) intermediate III made from step (3) is taken, is dissolved in polar solvent, reducing agent is added and carries out carbonyl reduction, preparation
Obtain intermediate compound IV；
(5) it takes intermediate compound IV made from step (4) and compound C to be dissolved in polar solvent, alkali is added, carry out nucleophilic displacement of fluorine,
Intermediate V is obtained, the compound C is CAS 1074-82-4；
(6) it takes intermediate V made from step (5) to be dissolved in polar solvent, hydrolysing agent is added, hydrolysis obtains intermediate
VI；
(7) compound D is dissolved in dry nonpolar solvent, triphosgene is added into active acyl chlorides, reaction obtains chemical combination
Object VII, wherein compound D is CAS 25333-42-0；
(8) intermediate VII made from intermediate VI made from step (6) and step (7) is taken, it is molten to be dissolved in dry nonpolarity
In agent, organic base generation acylation reaction is added and obtains VIII；
(9) intermediate VIII made from step (8) is taken, is dissolved in non-pole solvent, oxidizing benzylalcohol is added and obtains chemical combination
Object IX,
In step (1), the nonpolar solvent is methylene chloride or ether or 1,2- dichloroethanes or tetrahydrofuran；It is described
Oxidising agent is selenium dioxide, potassium permanganate, Jones reagent, tertbutanol peroxide, any one in chromium trioxide；
In step (2), the high boiling nonpolar solvent is tetrahydrofuran, in dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether
Any one；The phenide organic reagent is phenyl-magnesium-bromide, phenyl-magnesium-chloride, phenyl magnesium iodide or tetraphenylphosphonium chloride
Zinc；
In step (3), the halogen based solvents are methylene chloride, chloroform, 1,2- dichloroethanes or carbon tetrachloride；The chlorination examination
Agent is thionyl chloride, concentrated hydrochloric acid, carbon tetrachloride, triphenylphosphine or phosphorus pentachloride；
In step (4), the polar solvent is methanol, ethyl alcohol, acetonitrile or water；The reducing agent be Lithium Aluminium Hydride, sodium borohydride,
Sodium cyanoborohydride or palladium carbon catalytic hydrogen reduction；
In step (5), the polar solvent is DMF, DMSO or pyridine；The alkali of the nucleophilic displacement of fluorine be sodium carbonate, potassium carbonate or
Triethylamine；
In step (6), the hydrolysing agent is hydrazine hydrate, concentrated hydrochloric acid or 6M hydrochloric acid；
In step (7), the nonpolar solvent of the drying is ethyl acetate, tetrahydrofuran, ether or methylene chloride；
In step (8), the nonpolar solvent of the drying is ethyl acetate, tetrahydrofuran, ether or methylene chloride；It is described organic
Alkali is triethylamine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, pyridine or N-methylmorpholine；
In step (9), the nonpolar solvent be ethyl acetate, tetrahydrofuran, methylene chloride, chloroform or 1,2- dichloroethanes；
The oxidant is selenium dioxide, manganese dioxide, PCC, PDC or pyridine. sulfur trioxide.
2. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that described heterochromatic in step (1)
Full and oxidising agent molar ratio is 1:2~5, is reacted after oxidising agent is added at 0~80 DEG C.
3. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (2), it is described in
Mesosome I, the molar ratio with phenide organic reagent are 1:0.8~3, and substitution reaction temperature is 0~50 DEG C.
4. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (3), the halogen
The volume ratio of class solvent and intermediate II is 2~20:1, and the molar ratio of the intermediate II and chlorination reagent is 1:1~5.
5. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (4), the polarity
The volume ratio of solvent and intermediate III is 2~10:1, and the ratio molar ratio of the intermediate III and reducing agent is 1:0.5~2.
6. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (5), the polarity
The volume ratio of solvent and intermediate compound IV is 5~25:1, and the ratio molar ratio of the alkali and intermediate compound IV is 1:1~5, reaction temperature
It is 50~100 DEG C.
7. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (6), the water
Solution reagent is hydrazine hydrate, concentrated hydrochloric acid or 6M hydrochloric acid, and hydrolysising reacting temperature is 50~100 DEG C.
8. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (7), the drying
Nonpolar solvent be ethyl acetate, tetrahydrofuran, ether or methylene chloride, the reaction temperature be -30 DEG C~25 DEG C.
9. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (8), the drying
Nonpolar solvent be ethyl acetate, tetrahydrofuran, ether or methylene chloride；The organic base is triethylamine, N, N- diisopropyl
Base ethamine, 4-dimethylaminopyridine, pyridine or N-methylmorpholine；The acylation reaction temperature is -30 DEG C~25 DEG C.
10. the preparation method of Suo Feinaxin impurity according to claim 1, which is characterized in that in step (9), it is described in
The molar ratio of mesosome VIII and oxidant is 1:2~10, and reaction temperature is 25~80 DEG C.
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| US20080287680A1 (en) * | 2004-02-09 | 2008-11-20 | Astellas Pharma Inc. | Solifenacin Succinate-Containing Composition |
| CN105348278A (en) * | 2014-11-14 | 2016-02-24 | 天津市医药集团技术发展有限公司 | Preparation method for impurity of Solifenacin succinate |
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| US20080287680A1 (en) * | 2004-02-09 | 2008-11-20 | Astellas Pharma Inc. | Solifenacin Succinate-Containing Composition |
| CN105348278A (en) * | 2014-11-14 | 2016-02-24 | 天津市医药集团技术发展有限公司 | Preparation method for impurity of Solifenacin succinate |
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| Structure-reactivity relationships in (2-hydroxyethyl)benzophenone photoremovable protecting Groups;Michael C.Pirrung等;《Tetrahedron》;20100226;第66卷;第3147-3151页 |
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