CN106518862A - Preparation method of impurity in penehyclidine hydrochloride - Google Patents
Preparation method of impurity in penehyclidine hydrochloride Download PDFInfo
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- CN106518862A CN106518862A CN201610853807.9A CN201610853807A CN106518862A CN 106518862 A CN106518862 A CN 106518862A CN 201610853807 A CN201610853807 A CN 201610853807A CN 106518862 A CN106518862 A CN 106518862A
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- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Abstract
The invention discloses a preparation method of an impurity in penehyclidine hydrochloride. The preparation method comprises the following steps: taking alpha-phenyl-alpha-cyclopentyl-alpha-hydroxyl ethyl p-toluene sulfonate and 3-quinuclidinol as the raw materials, carrying out reactions for a while under an alkaline condition, performing a post treatment to obtain 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethyoxyl)ethyoxyl] quinuclidine hydrochloride free alkali, carrying out salt forming reactions between the free alkali and hydrogen chloride, and performing refinement to obtain hydrochloride of the free alkali. The preparation method can prominently increase the impurity content during the preparation process, the operation difficulty is reduced, moreover, the preparation method is suitable for massive production and is capable of obtaining a qualified high purity impurity; and the impurity purity measured by HPLC is 100%.
Description
Technical field
The present invention relates in pharmaceutical technology field, more particularly to a kind of amyl ethyl quin ether hydrochloride impurity preparation method.
Background technology
Amyl ethyl quin ether hydrochloride (Penehyclidine Hydrochloride), chemical entitled 3- (2- cyclopenta -2- hydroxyls -
2 phenyl ethoxies) quinuclidine hydrochloride is to obtain within 1999 National Drug Administration's approval (military medicine science
Institute), after rather produced with trade name length support by Chengdu Lisite Pharmaceutical Co., Ltd., for organophosphorus poison (pesticide)
Later stage or the aging rear maintenance atropinization of acetylcholine esterase (ChE) are treated and be poisoned to poisoning first-aid.Chemical structural formula is as shown in (1).
This strain new selective anticholinergic agent, can be combined with M, N cholinoceptor, cholinergic innervation after suppressing to save
Smooth muscle and body of gland physiological function, the muscarinic and nicotinic action to anti-acetylcholine and other quinoline drugs can be thoroughly
Blood brain barrier is crossed, therefore while there is stronger, more comprehensive maincenter and periphery cholinolytic effect.This product has substantially choosing to m receptor
Selecting property, i.e., main selection is in M1、M3Receptor, and to M2The effect of receptor is weaker or obvious, does not block presynaptic membrane M2Receive
Body regulation and control teleneuron discharges the function of ACh, stable heart-rate.Meanwhile, this product is to N1、N2Receptor also has certain effect.This product can be compared with
The good effect to anti-acetylcholine, releases and discharges acetylcholine because a large amount of in vivo, caused by causing vagus nerve fever
Smooth muscle spasm；The acute microcirculation dysfunction that releasing lung, the lasting spasm of cerebral microvascular cause.Meanwhile, can be preferably short of money
The maincenter poisoning symptom that anti-organophosphorus poison (pesticide) poisoning causes, such as convulsions, maincenter respiratory and circulatory failure and dysphoria etc.；
Also can the muscarinic poisoning symptom that causes of antagonism organophosphorus poison (pesticide) poisoning strongly, such as bronchial smooth muscle in periphery
Spasm and secretions increase, perspiration, sialorrhea, myosis and gastrointestinal smooth muscle spasm and contraction etc..It can also increase respiratory frequency
And respiratory flow.
The salivation effect of this product anti-mouse and rabbit is strong than atropine, and the ED of rabbit50Only 0.03mg/kg,
It is stronger than atropine about 17 times；This product can substantially suppress mouse salivary secretion and tracheal mucus secretion (p<0.001) action intensity will
It is better than isodose atropine injection；After intramuscular injection this product, stomach, small intestinal, colon to Anaesthetic Rabbits and Conscious Rabbit, gallbladder convulsion
The relaxation effect that contraction is shunk (P strong compared with atropine<0.05) atropic is significantly stronger than to the relaxation effect that cystospasm is shunk,
Product (P<0.01).
Long term toxicity test shows：This product 0.68,3.38,13.50mg/kg (be respectively equivalent to people clinic usual amounts 40,
199th, 794 times) in rat, this product 0.015,0.9mg/kg (is respectively equivalent to 0.9,53 times of people's clinic usual amounts) for difference intramuscular injection
Intramuscular injection once a day, is administered, in addition to some common cholinolytics occur and reacting, has no other exceptions in Canis familiaris L. for continuous 12 weeks respectively；One
As reproductive toxicity test show：This product 2.5,12.5,62.5ppm (being respectively equivalent to 15,75,375 times of people's consumption) difference mouth
Take in male Mus successive administration 60 days, raettin successive administration 14 days, in addition to high dose group has certain toxicity to mice, this product is to little
After the generation of Mus gamete, potency concipiendi, childbirth and birth, F1 generation filial mice growth promoter has no and significantly affects, and mutagenicity test is the moon
Property, has no teratogenesis and fetal toxicity in equivalent to 300 times of people's consumption.
Jing is retrieved, and the synthesis of amyl ethyl quin ether hydrochloride mainly has two lines：
Route one：As shown in (2), with α-cyclopenta mandelic acid as initiation material, Jing reduce α-phenyl-α-cyclopenta-
Alpha-hydroxy ethanol, α-phenyl-α-cyclopenta-Alpha-hydroxy ethanol Jing sulfonic acid esterification obtains α-phenyl-α-cyclopenta-Alpha-hydroxy to first
Ethyl benzenesulfonat, sulfonate intermediate prepared α-phenyl-α-cyclopenta -1,2- epoxies Jing after cyclisation under Anhydrous potassium carbonate effect
Ethane, obtains amyl ethyl quin ether free alkali with the reaction of 3- quinuclidinols, finally obtains amyl ethyl quin ether hydrochloride into after salt with hydrogen chloride.
Route two：As shown in (3), with Benzenecarbonyl chloride. as starting material, and cyclopentenes react to obtain α-phenyl-α-cyclopenta first
Ketone, then prepared α-phenyl-α-cyclopenta -1 of cyclization, 2- oxirane, obtain amyl ethyl quin ether free alkali with the reaction of 3- quinuclidinols, most
Amyl ethyl quin ether hydrochloride is obtained into after salt with hydrogen chloride afterwards.
Two lines produce a kind of major impurity (4)：3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -
2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochloride.
At present, document report 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) are had no
Ethyoxyl] quinuclidine hydrochloride preparation method, and exploitation amyl ethyl quin ether hydrochloride during, it is found that this impurity is α-benzene
Base-α-cyclopenta -1,2- oxirane is produced during preparing amyl ethyl quin ether free alkali with 3- quinuclidinol reactions, is measured little and is divided
From complex operation.
In drug discovery process, miscellaneous Quality Research is an important link, while the foundation needs of quality standard are a certain amount of
Standard substance.Based on this, to the major impurity in amyl ethyl quin ether hydrochloride：3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2-
Hydroxyl -2- Phenyl-ethoxies) ethyoxyl] preparation of quinuclidine hydrochloride has great importance, and it can be used for hydrochloric acid penta
The quality research such as Qualitative and quantitative analysis of impurity in the synthesis of second Kui ether, so as to be favorably improved the quality of amyl ethyl quin ether hydrochloride,
And the drug risk for reducing amyl ethyl quin ether hydrochloride provides important directive significance.
The content of the invention
It is an object of the invention to provide a kind of preparation method of the impurity in amyl ethyl quin ether hydrochloride.
Impurity preparation process of the present invention is as follows：
α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate and 3- quinuclidinols react a timing in the basic conditions
Between, it is post-treated to obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinine
Cycloalkanes free alkali, obtains 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) with hydrogen chloride into salt
Ethyoxyl] quinuclidine hydrochloride.
Synthetic route (5) is as follows：
The preparation method of impurity of the present invention, comprises the following steps：
(1) 3- quinuclidinols are added in dimethyl sulfoxide, add alkali reaction to obtain 3- quinine alkoxide after stirring and dissolving；Deca α-benzene
The dimethyl sulphoxide solution of base-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate, Deca purified water after stirring reaction, acetic acid second
Ester is extracted；
(2) acidic aqueous solution extraction organic faciess, divide and go organic faciess, and it is 8～9 that water alkali adjusts pH, ethyl acetate extraction,
Organic faciess purification water washing, anhydrous sodium sulfate drying, filter and be concentrated to give dope；
(3) dope Jing column chromatography for separation obtained by obtains 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- benzene
Base-ethyoxyl) ethyoxyl] quinuclidine free alkali；
(4) free alkali is dissolved in mixed solvent, under temperature control, Deca contains the solution of hydrogen chloride, it is 2～3 to adjust pH；
(5) cooling crystallize, filters to obtain crude product；
(6) crude product mixed solvent recrystallization, obtains 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- benzene
Base-ethyoxyl) ethyoxyl] quinuclidine hydrochloride finished product.
Further, the alkali for adding in step (1) is sodium hydride, potassium tert-butoxide, the one kind in Feldalat NM, preferably hydrogen
Change sodium.
Further, α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate described in step (1) and 3- Kuis
The mol ratio of thujol is 1～5:1, preferably 1～3:1.
Further, in step (1) stirring reaction temperature be 40～100 DEG C, preferably 60～80 DEG C, the response time be
1～10 hour, preferably 6～8 hours.
Further, in step (2), acid solution is hydrochloric acid, citric acid, maleic acid, the one kind in sulphuric acid, preferably
Citric acid.
Further, in step (3) the step of column chromatography it is：
A, mix sample：Dope is dissolved in dichloromethane, plus mixes sample silica gel in right amount, be evaporated and mix sample, wherein dope and silicon
The mass ratio of glue is 1:1～5, preferably 1:1～2；
B, dress post：Weigh silica gel, add dichloromethane homogenate, pour in glass column and settle, wherein fixing phase silica gel and viscous
The mass ratio of thick thing is 10～50:1, preferably 10～30:1；
C, eluting：The mixed solution eluting of dichloromethane and methanol is added, product point, wherein dichloromethane and methanol is collected
Volume ratio be 10～50:1, preferably 10～30:1.
Further, in step (4), the mixed solvent of dissolving free alkali is isopropanol-ethyl acetate, Ethanol-Acetic Acid
Ethyl ester, methanol-ethyl acetate, preferably isopropanol-ethyl acetate.
Further, t-butyl methyl ether solution, chlorine of the solution of the hydrogen chloride described in step (4) for hydrogen chloride
One kind in the petroleum ether solution of change hydrogen, the ethyl acetate solution of hydrogen chloride, the preferably ethyl acetate solution of hydrogen chloride.
Further, in step (5), recrystallization temperature is -10～10 DEG C, preferably -5～5 DEG C.
Further, mixed solvent described in step (6) is ethanol and ethyl acetate, ethanol and methyl tertbutyl
Ether, isopropanol and ethyl acetate, isopropanol and methyl tertiary butyl ether(MTBE), the preferably one kind in acetoneand ethyl acetate, isopropanol-second
Acetoacetic ester.
Present invention has the advantages that：
The invention provides a kind of preparation method of the impurity in amyl ethyl quin ether hydrochloride, can significantly improve miscellaneous in preparation process
The content of matter, reduces complex operation degree, it is adaptable to extensive to prepare, and is obtained with reaching quality using new preparation technology
High-purity 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine of requirement
Heptane hydrochloride salt, HPLC detections 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl]
Quinuclidine hydrochloride purity reaches 100%.
Description of the drawings
Fig. 1 is 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinine
Cycloalkanes hydrochlorate proton nmr spectra (1H-NMR)；
Fig. 2 is 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinine
Cycloalkanes hydrochlorate ES-API Positive are composed；
Fig. 3 is 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinine
Cycloalkanes hydrochlorate efficient liquid phase (HPLC) collection of illustrative plates.
Specific embodiment
The present invention is described in detail below in conjunction with specific embodiments and the drawings, it is therefore an objective to make advantages of the present invention fuller and more accurate, and
The unrestricted present invention.It should be appreciated by those skilled in the art that the present invention is not limited to these embodiments and the preparation side for using
Method, it is any that the present invention is carried out to replace on an equal basis, combine, improve or modify, it is both contained in the present invention.
α used in the present invention-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate, is purchased from commercially available prod,
Also can be obtained by prior art synthesis.
Embodiment 1
In a kind of amyl ethyl quin ether hydrochloride, the preparation method of impurity, comprises the following steps：
(1) in 1L reaction bulbs 100ml dimethyl sulfoxide, 20g 3- quinuclidinols, stirring is added to make solid dissolving, add by several times
Enter 7.5g sodium hydrides (60%), stirring and evenly mixing is warming up to 60 DEG C and stirs 1 hour, obtains 3- quinine sodium alkoxides.70 DEG C are warming up to, are mixed
The dimethyl sulphoxide solution (100ml) of Deca 113.4g α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate in compound,
Maintain temperature stirring reaction 6 hours, be cooled to less than 10 DEG C, Deca 150ml purified water, drop finish, add 300ml ethyl acetate,
After stirring, a point liquid is stood.
(2) organic faciess are extracted with 10% aqueous citric acid solutions of 300ml, are divided and are gone organic faciess, and water is mutually molten with saturated sodium bicarbonate
Liquid adjusts sour aqueous pH values to 8～9, adds 100ml ethyl acetate, and point liquid, organic faciess are washed twice with 100ml purified water, had
Machine mutually uses anhydrous sodium sulfate drying, filters, and filtrate decompression is evaporated, and obtains yellow oil 87g.
(3) filtrate is dissolved with 400ml dichloromethane, adds 200～300 mesh column chromatography silica gel 100g, evaporated under reduced pressure mix
All product.200～300 mesh column chromatography silica gels of 2kg are added into 10L dichloromethane, is stirring evenly and then adding into glass and is chromatographed
In post, pillar is compacted by sedimentation, pressurization, and the sample mixed is added into glass column, dichloromethane is used：Methanol=20:1 it is mixed
Bonding solvent carries out eluting, collects impact point evaporated under reduced pressure, obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -
2- Phenyl-ethoxies) ethyoxyl] quinuclidine pale yellow oil 15.4g.
(4) grease is dissolved in 45ml isopropanols and 450ml ethyl acetate mixed solvents, and Deca contains 2mol/L hydrogen chloride
Ethyl acetate solution, adjusts pH to 2～3.
(5) it is cooled to 0～5 DEG C of crystallize 2 hours, filters, dry off-white powder 3- [2- cyclopenta -2- phenyl -2-
(2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 11.4g.
(6) above-mentioned solid is added in 60ml isopropanols and 600ml ethyl acetate mixed solvents, is heated to 40～50 DEG C,
Filter, be cooled to 0～5 DEG C of crystallize 2 hours, filter, 40～50 DEG C of drying under reduced pressure obtain 3- [2- cyclopenta -2- phenyl -2- (2- rings
Amyl group -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 8.7g, purity 100%.
ES-API Positive：504.4
1H-NMR(400MHz,CDCl3):δ7.13-7.38(m,2H),7.36-7.29(m,2H),7.26-7.17(m,
4H),7.07-7.05(m,1.3H),6.87-6.85(m,0.7H),3.91(t,0.4H),3.86-3.85(m,0.3H),3.83-
3.78(m,1.3H),3.75-3.73(m,0.7H),3.71-3.69(m,0.7H),3.62-3.61(m,0.3H),3.56-3.55
(m,0.6H),3.52-3.47(m,1H),3.45-3.41(m,0.3H),3.24-3.18(m,2.5H),3.16-3.08(m,2H),
3.07-2.94(m,1H),2.38-2.34(m,1H),2.27-2.16(m,2H),2.03-1.93(m,2H),1.85-1.68(m,
2H),1.67-1.56(m,3H),1.55-1.42(m,3H),1.40-1.33(m,5H),1.29-1.12(m,5H)。
Embodiment 2
In a kind of amyl ethyl quin ether hydrochloride, the preparation method of impurity, comprises the following steps：
(1) in 2L reaction bulbs 120ml dimethyl sulfoxide, 24g3- quinuclidinols, stirring is added to make solid dissolving, add by several times
Enter 9.8g sodium hydrides (60%), stirring and evenly mixing is warming up to 50 DEG C and stirs 1 hour, obtains 3- quinine sodium alkoxides.70 DEG C are warming up to, are mixed
The dimethyl sulphoxide solution (200ml) of Deca 204.2g α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate in compound,
Maintain temperature stirring reaction 8 hours, be cooled to less than 10 DEG C, Deca 300ml purified water, drop finish, add 400ml ethyl acetate,
After stirring, a point liquid is stood.
(2) organic faciess are extracted with 10% aqueous citric acid solutions of 370ml, are divided and are gone organic faciess.Water is mutually molten with saturated sodium bicarbonate
Liquid adjusts sour aqueous pH values to 8～9, adds 120ml ethyl acetate, and point liquid, organic faciess are washed twice with 120ml purified water, had
Machine mutually uses anhydrous sodium sulfate drying, filters, obtains yellow oil 104g.
(3) filtrate is dissolved with 500ml dichloromethane, adds 200～300 mesh column chromatography silica gel 150g, evaporated under reduced pressure mix
All product.200～300 mesh column chromatography silica gels of 2.5kg are added into 11L dichloromethane, is stirring evenly and then adding into glassy layer
In analysis post, pillar is compacted by sedimentation, pressurization, the sample mixed is added into glass column, dichloromethane：Methanol=20:1 it is mixed
Bonding solvent carries out eluting, collects impact point evaporated under reduced pressure, obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -
2- Phenyl-ethoxies) ethyoxyl] quinuclidine pale yellow oil 20.8g.
(4) during grease is dissolved in 60ml isopropanols and in 600ml ethyl acetate mixed solvents, Deca 2mol/L hydrogen chloride second
Acetate solution, adjusts pH to 2～3.
(5) it is cooled to 0～5 DEG C of crystallize 2 hours, filters, dry off-white powder 3- [2- cyclopenta -2- phenyl -2-
(2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 16.5g.
(6) above-mentioned solid is added in 100ml isopropanols and 1L ethyl acetate mixed solvents, is heated to 40～50 DEG C, mistake
Filter, is cooled to 0～5 DEG C of crystallize 3 hours, filters, and 40～50 DEG C of drying under reduced pressure obtain 3- [2- cyclopenta -2- phenyl -2- (2- rings penta
Base -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 13.2g, purity 100%.
Embodiment 3
In a kind of amyl ethyl quin ether hydrochloride, the preparation method of impurity, comprises the following steps：
(1) in 1L reaction bulbs 60ml dimethyl sulfoxide, 12.7g3- quinine cyclols, stirring is added to make solid dissolving, by several times
5g sodium hydrides (60%), stirring and evenly mixing is added to be warming up to 50 DEG C and stir 1 hour, obtain 3- quinine sodium alkoxides.80 DEG C are warming up to, are dripped
Plus the dimethyl sulphoxide solution (90ml) of 90g α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate, maintain temperature stirring
Reaction 7 hours.Less than 10 DEG C are cooled to, Deca 100ml purified water, drop finish, add 200ml ethyl acetate, it is after stirring, quiet
Put a point liquid.
(2) organic layer is extracted with 10% aqueous citric acid solutions of 230ml, is divided and is removed organic layer.Water layer is molten with saturated sodium bicarbonate
Liquid adjusts sour water layer pH value to 8～9, adds 100ml ethyl acetate, point liquid, and organic faciess are washed twice with 50ml purified water, organic
Anhydrous sodium sulfate drying is mutually used, is filtered, is obtained yellow oil 56g.
(3) filtrate is dissolved with 300ml dichloromethane, adds 200～300 mesh column chromatography silica gel 80g, evaporated under reduced pressure mix
All product.200～300 mesh column chromatography silica gels of 1.2kg are added into 6L dichloromethane, is stirring evenly and then adding into glassy layer
In analysis post, pillar is compacted by sedimentation, pressurization, the sample mixed is added into glass column, dichloromethane：Methanol=20:1 it is mixed
Bonding solvent carries out eluting, collects impact point evaporated under reduced pressure, obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -
2- Phenyl-ethoxies) ethyoxyl] quinuclidine pale yellow oil 10.9g.
(4) grease is dissolved in 30ml isopropanols and 300ml ethyl acetate mixed solvents, Deca 2mol/L chlorination hydroacetic acid
Ethyl ester solution, adjusts pH to 2～3.
(5) it is cooled to 0～5 DEG C of crystallize 2 hours, filtration drying obtains off-white powder 3- [2- cyclopenta -2- phenyl -2- (2-
Cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 8.1g.
(6) above-mentioned solid is added in 50ml isopropanols and 500ml ethyl acetate mixed solvents, is heated to 40～50 DEG C,
Filter, be cooled to 0～5 DEG C of crystallize 3 hours, filter, 40～50 DEG C of drying under reduced pressure obtain 3- [2- cyclopenta -2- phenyl -2- (2- rings
Amyl group -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 6.6g, purity 100%.
Embodiment 4
In a kind of amyl ethyl quin ether hydrochloride, the preparation method of impurity, comprises the following steps：
(1) in 1L reaction bulbs 120ml dimethyl sulfoxide, 25.4g3- quinine cyclols, stirring is added to make solid dissolving, point
Secondary addition 10g sodium hydrides (60%), stirring and evenly mixing are warming up to 50 DEG C and stir 1 hour, obtain 3- quinine sodium alkoxides.75 DEG C are warming up to,
The dimethyl sulphoxide solution (180ml) of Deca 180g α-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate, maintains temperature
Stirring reaction 7.5 hours.Less than 10 DEG C are cooled to, Deca 200ml purified water, drop finish, add 400ml ethyl acetate, stirring is equal
After even, a point liquid is stood.
(2) organic layer is extracted with 10% aqueous citric acid solutions of 460ml, is divided and is removed organic layer.Water layer is molten with saturated sodium bicarbonate
Liquid adjusts sour water layer pH value to 8～9, adds 200ml ethyl acetate, and point liquid, organic faciess are washed twice with 100ml purified water, had
Machine mutually uses anhydrous sodium sulfate drying, filters, obtains yellow oil 110g.
(3) filtrate is dissolved with 500ml dichloromethane, adds 200～300 mesh column chromatography silica gel 130g, evaporated under reduced pressure mix
All product.200～300 mesh column chromatography silica gels of 2.4kg are added into 10L dichloromethane, is stirring evenly and then adding into glassy layer
In analysis post, pillar is compacted by sedimentation, pressurization, the sample mixed is added into glass column, dichloromethane：Methanol=20:1 it is mixed
Bonding solvent carries out eluting, collects impact point evaporated under reduced pressure, obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -
2- Phenyl-ethoxies) ethyoxyl] quinuclidine pale yellow oil 22.6g.
(4) grease is dissolved in 60ml isopropanols and 600ml ethyl acetate mixed solvents, Deca 2mol/L chlorination hydroacetic acid
Ethyl ester solution, adjusts pH to 2～3.
(5) it is cooled to 0～5 DEG C of crystallize 2 hours, filtration drying obtains off-white powder 3- [2- cyclopenta -2- phenyl -2- (2-
Cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 16.7g.
(6) above-mentioned solid is added in 100ml isopropanols and 1L ethyl acetate mixed solvents, is heated to 40～50 DEG C, mistake
Filter, is cooled to 0～5 DEG C of crystallize 3 hours, filters, and 40～50 DEG C of drying under reduced pressure obtain 3- [2- cyclopenta -2- phenyl -2- (2- rings penta
Base -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine hydrochlorate 12.7g, purity 100%.
3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxies) ethyoxyl] quinuclidine salt
The HPLC detection methods of hydrochlorate：
Inspection method：2015 editions two annex high performance liquid chromatography of Chinese Pharmacopoeia
Experimental condition：C18 post (models：Long 150mm, internal diameter 4.6mm, 3 μm of inserts particle diameter)
Detector：UV detectors
Detection wavelength：230nm
Column temperature：25℃
Flow velocity：1.0ml/min
Mobile phase A：0.02mol/L potassium dihydrogen phosphates (containing 0.5% triethylamine, adjust pH to 4.5) with phosphoric acid
Mobile phase B：Acetonitrile
Linear gradient elution is as shown in table 1 below：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 73 | 27 |
| 5.0 | 73 | 27 |
| 20.0 | 50 | 50 |
| 30.0 | 40 | 60 |
| 50.0 | 40 | 60 |
| 55.0 | 73 | 27 |
| 65.0 | 73 | 27 |
Wherein precision measures 20 μ l of test sample (embodiment 1) solution, injects chromatograph of liquid, records chromatogram.Test sample
If any impurity peaks in solution chromatogram, calculate by areas of peak normalization method, as a result see accompanying drawing 3, purity is 100%.
Claims (10)
1. in a kind of amyl ethyl quin ether hydrochloride impurity preparation method, it is characterised in that comprise the following steps：
(1) 3- quinuclidinols are added in dimethyl sulfoxide solvent, add alkali reaction to obtain 3- quinine alkoxide after stirring and dissolving；Deca α-benzene
The dimethyl sulphoxide solution of base-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate, Deca purified water after stirring reaction, acetic acid second
Ester is extracted；
(2) acidic aqueous solution extraction organic faciess, divide and go organic faciess, and it is 8～9 that water alkali adjusts pH, and ethyl acetate extraction is organic
With purification water washing, anhydrous sodium sulfate drying, filter and be concentrated to give dope；
(3) dope Jing column chromatography for separation obtained by obtain 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- phenyl -
Ethyoxyl) ethyoxyl] quinuclidine free alkali；
(4) free alkali is dissolved in mixed solvent, under temperature control, Deca contains the solution of hydrogen chloride, it is 2～3 to adjust pH；
(5) cooling crystallize, filters to obtain crude product；
(6) crude product mixed solvent recrystallization, obtains 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyls -2- phenyl-second
Epoxide) ethyoxyl] quinuclidine hydrochloride finished product.
2. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(1) alkali added in is sodium hydride, potassium tert-butoxide, the one kind in Feldalat NM.
3. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(1) α described in-phenyl-α-cyclopenta-Alpha-hydroxy ethyl p-toluenesulfonate is 1～5 with the mol ratio of 3- quinuclidinols:1.
4. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(1) in stirring reaction temperature be 40～100 DEG C, the response time be 1～10 hour.
5. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(2) in, acidic aqueous solution is hydrochloric acid, citric acid, maleic acid, the one kind in sulphuric acid；
6. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(3) in the step of column chromatography it is：
A, mix sample：Dope is dissolved in dichloromethane, plus mixes sample silica gel in right amount, be evaporated and mix sample, wherein dope and silica gel
Mass ratio is 1:1～5；
B, dress post：Silica gel is weighed, dichloromethane homogenate is added, is poured in glass column and settle, wherein fixing phase silica gel and dope
Mass ratio be 10～50:1；
C, eluting：The mixed solution eluting of dichloromethane and methanol is added, product point, the wherein body of dichloromethane and methanol is collected
Product is than being 10～50:1.
7. in a kind of amyl ethyl quin ether hydrochloride according to claim 6 impurity preparation method, it is characterised in that the step
(4) in, the mixed solvent of dissolving free alkali is isopropanol-ethyl acetate, EtOH-EtOAc, methanol-ethyl acetate.
8. in a kind of amyl ethyl quin ether hydrochloride according to claim 6 impurity preparation method, it is characterised in that the step
(4) solution of the hydrogen chloride described in is the t-butyl methyl ether solution of hydrogen chloride, the petroleum ether solution of hydrogen chloride, hydrogen chloride
One kind in ethyl acetate solution.
9. in a kind of amyl ethyl quin ether hydrochloride according to claim 1 impurity preparation method, it is characterised in that the step
(5) in, recrystallization temperature is -10～10 DEG C.
10. in a kind of amyl ethyl quin ether hydrochloride according to claim 6 impurity preparation method, it is characterised in that the step
Suddenly mixed solvent described in (6) is ethanol and ethyl acetate, ethanol and methyl tertiary butyl ether(MTBE), isopropanol and ethyl acetate, isopropyl
Alcohol and methyl tertiary butyl ether(MTBE), the one kind in acetoneand ethyl acetate.
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| CN109824661A (en) * | 2019-03-30 | 2019-05-31 | 山东博洛德生物科技有限公司 | The preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride |
| CN109851615A (en) * | 2019-04-22 | 2019-06-07 | 上海旭东海普药业有限公司 | The method for purifying amyl ethyl quin ether |
| CN110003198A (en) * | 2019-04-22 | 2019-07-12 | 上海旭东海普药业有限公司 | The purification process of amyl ethyl quin ether |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109824662A (en) * | 2019-03-30 | 2019-05-31 | 山东博洛德生物科技有限公司 | A kind of quinine class compound and preparation method thereof |
| CN109824661A (en) * | 2019-03-30 | 2019-05-31 | 山东博洛德生物科技有限公司 | The preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride |
| CN109824661B (en) * | 2019-03-30 | 2020-06-05 | 山东博洛德生物科技有限公司 | Preparation method of impurities in penehyclidine hydrochloride |
| CN109851615A (en) * | 2019-04-22 | 2019-06-07 | 上海旭东海普药业有限公司 | The method for purifying amyl ethyl quin ether |
| CN110003198A (en) * | 2019-04-22 | 2019-07-12 | 上海旭东海普药业有限公司 | The purification process of amyl ethyl quin ether |
| CN109851615B (en) * | 2019-04-22 | 2021-06-08 | 上海旭东海普药业有限公司 | Process for purifying penehyclidine |
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