CN108503564A - A kind of Mivacurium Chloride intermediate and the method using intermediate synthesis Mivacurium Chloride - Google Patents
A kind of Mivacurium Chloride intermediate and the method using intermediate synthesis Mivacurium Chloride Download PDFInfo
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- CN108503564A CN108503564A CN201711010252.2A CN201711010252A CN108503564A CN 108503564 A CN108503564 A CN 108503564A CN 201711010252 A CN201711010252 A CN 201711010252A CN 108503564 A CN108503564 A CN 108503564A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
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Abstract
The invention belongs to the synthesis technical fields of medical compounds, specifically disclose a kind of improved Mivacurium Chloride intermediate suitable for industrialized production and the method using intermediate synthesis Micoud chloramines.This method is that Mivacurium Chloride is prepared by two-step reaction in starting material with pungent 4 alkene, 1,8 diacid of E and (R) (+) 5' methoxyl group laudanosines.This method starting material is cheap and easy to get, is extracted by liquid separation after first step reaction and the simple post-processing steps such as concentration, second step can obtain the product of 98% or more purity by simple extraction or mashing.The technological reaction and post-processing operation are simple, and acquired product quality is high, and requirement can be met by being not required to be further purified.The invented technology is simple and practical, is extremely suitable for industrial production.
Description
Technical field
The invention belongs to the synthesis technical fields of medical compounds, in particular it relates to which a kind of being suitable for industrial metaplasia
The Mivacurium Chloride intermediate of production and the method for synthesizing Mivacurium Chloride using the intermediate.
Background technology
Mivacurium Chloride is by Abbott lab exploitations, in a kind of short-acting benzylisoquinoline in U.S.'s Initial Public Offering in 1992
Class nondepolarizer, clinically mainly as general anesthesia adjuvant, flesh pine is rapid-action (2 minutes) after intravenous, the duration
Short (15 minutes), with dosage increase and work it is rapid, but acting duration extend it is few, when usual amounts to cardiovascular system without
It influences, promotes histamine release effect smaller, on intracranial pressure and intraocular pressure without influence, for trachea cannula and maintain flesh pine, drug
Using rapid-action, action time is short, restores rapid, no cumulative effect is few to vegetative nerve and cardiovascular adverse reaction.Micoud
Oronain belongs to benzyl isoquinoline compound, and chemical structural formula is as follows：
The preparation method of Mivacurium Chloride is it is known in the art that such as EP0181055A1 discloses 6,7- dimethoxys -2-
Methyl-1-(3,4,5- trimethoxyphenyls)-1,2,3,4- tetrahydroisoquinolines are obtained by fractionation, quaternization and three steps of esterification
Mivacurium Chloride, reaction equation are as follows：
Mivacurium Chloride is the mixture and E- for the isomers 6A ︰ 6B=3 ︰ 1 of compound shown in formula 6 by ratio in the technique
Octyl- 4- alkene -1,8- diacid reactants obtain Mivacurium Chloride, and final product Mivacurium Chloride includes three isomers, respectively (1R, 1'R,
2S, 2'S)-Mivacurium Chloride 5A, (1R, 1'R, 2R, 2'S)-Mivacurium Chloride 5B and (1R, 1'R, 2R, 2'R)-Mivacurium Chloride 5C,
Middle Isomers content must satisfy：The content of 5C accounts for the 4%-8% of three isomers (5A, 5B and 5C) total contents；5A and 5B
The sum of content accounts for the 92%-96% of three isomers (5A, 5B and 5C) total contents.The isomers of compound shown in intermediate formula 6
The ratio of 6A and 6B determines the active ingredient ratio of Mivacurium Chloride, also determines the impurity composition of technique.
Since compound shown in intermediate formula 6 is quaternary ammonium salt, it is easy to the moisture absorption and goes bad, it is very bad in industrial processes
It preserves and weighs, and due to being a mixture (the isomers 6A and 6B of compound shown in formula 6), conventional recrystallization and excessively column
Equal way of purification are all not applicable, can only be beaten solvent and be purified with by way of extracting and washing, produced eventually to a step below
The purifying of object Mivacurium Chloride is brought a lot of trouble.
In compound shown in second step formula 6 and E- octyl- 4- alkene -1,8- diacid reactants, in the prior art by E- octyl- 4- alkene -
1,8- diacid becomes acyl chloride reaction, has used thionyl chloride, it is desirable that reaction is stringent anhydrous, equipment and operation are required it is high, and
And post-reaction treatment purifies also troublesome complexity.
The second step process is improved in technical solution disclosed in WO2013021398A2, using N, N'- dicyclohexyls carbon two
The mode being condensed under the conditions of acid imide DCC/4- dimethylamino naphthyridines DMAP is reacted, and the method is instead of reagents such as thionyl chlorides
It uses, keeps reaction condition more safety mild.Wherein N, N'- dicyclohexylcarbodiimide and 4-dimethylaminopyridine structural formula
It is as follows：
But genotoxicity impurity 4-dimethylaminopyridine and N, bis- rings of N'- are introduced in the synthesis of final step final product
Hexyl carbon imidodicarbonic diamide.And genotoxicity impurity limit in bulk pharmaceutical chemicals quality analysis is extremely low, which post-processes band to product
Come very big drawback, while by-product N, the N'- dicyclohexylurea (DCU) of N, N'- dicyclohexylcarbodiimide extremely easy to produce it is residual
It stays, it is very difficult to remove.
The applicant is the study found that the preparation method of Mivacurium Chloride seldom has been reported that both at home and abroad, for depositing in the prior art
Deficiency, new be suitable for industrialized production, economical and practical preparation method the present invention is intended to provide a kind of.
Invention content
High, the mild suitable industry easy to operate of reaction condition that the purpose of the present invention is to provide a kind of finished product purity and yields
The Mivacurium Chloride key intermediate of production and the method for synthesizing Micoud chloramines using the intermediate.Present invention firstly provides one kind
Mivacurium Chloride key intermediate, is bis- propyl propionate of compound E- octyl- 4- alkene -1,8- shown in formula 3, and structural formula is as follows：
In formula 3, X F, Cl, Br, I, methanesulfonyloxy group OMs or tolysulfonyl oxygroup OTos, preferably Cl or methane
Sulfonyloxy；Wherein methanesulfonyloxy group and tolysulfonyl oxygroup structural formula is as follows：
Further, the present invention provides the preparation methods of bis- propyl propionate of the alkene -1,8- of compound E- octyl- 4- shown in formula 3：With E-
2 compound of octyl- 4- alkene -1,8- diacid and formula (3 halogenated or the substitution of class halogen propyl alcohol) is raw material, carries out condensation reaction generation
Ester, reaction route are as follows：
The E- octyl- 4- alkene -1,8- diacid (1 compound of formula) in non-protonic solvent, condensing agent effect under with formula 2
React is condensed into ester to compound (propanol compound of halogenated or class halogen substitution), controls temperature of reaction system 0~100
DEG C, monitoring raw material disappears to get to the system containing product E-bis- propyl propionate of octyl- 4- alkene -1,8-, is then washed by simple extraction
Or mashing, it is concentrated to give bis- propyl propionate crude product of E- octyl- 4- alkene -1,8-；
Alternatively, not using condensing agent in above-mentioned reaction, but first E- octyl- 4- alkene -1,8- diacid is reacted with thionyl chloride
Become carrying out condensation reaction with 2 compound of formula again after acyl chlorides；
The condensing agent is selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides EDCl, N, bis- rings of N'-
In hexyl carbon imidodicarbonic diamide DCC and N, N'- diisopropylcarbodiimides DIC any one or it is two or more：
The aprotic solvent is selected from ether, ethyl acetate, tetrahydrofuran, dimethyl-tetrahydrofuran, dioxane, methyl
Tertbutyl ether, glycol dimethyl ether, glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, dichloromethane and three chloromethanes
One or more of alkane；
The aprotic solvent is preferably one or more of dichloromethane, ethyl acetate and tetrahydrofuran；
Compound shown in the formula 2 is selected from 3- chloropropyl alcohols, 3- iodine propyl alcohol, 3- bromopropyl alcohols, p-methyl benzenesulfonic acid 3- hydroxypropyl acrylates
One or more of with Loprazolam 3- hydroxypropyl acrylates；
Compound shown in the formula 2 is preferably 3- chloropropyl alcohols and/or Loprazolam 3- hydroxypropyl acrylates；
E- octyl-s 4- alkene -1,8- diacid and 2 compound mole ratio of formula is 1 ︰ 2~1 ︰ 6, preferably 1: 2.2~1: 4；Instead
Answer temperature control at 0~100 DEG C, preferably 0~30 DEG C；Reaction time is 0.5~24 hour, preferably 0.5~8 hour.
Further, the present invention also provides synthesized using above-mentioned bis- propyl propionate of E- octyl-s 4- alkene -1,8- (3 compound of formula)
The method of Mivacurium Chloride, steps are as follows：
Bis- propyl propionate of E- octyl- 4- alkene -1,8- and (R)-(+) -5'- methoxyl group laudanosines in reaction dissolvent, temperature control 50~
After 100 DEG C are stirred 1~24 hour, HPLC monitors reaction raw materials and disappears, cold filtration, and resin anion (R.A.) (717 chlorine are added in filtrate
Type), agitation and filtration, filtrate is spin-dried for obtaining crude compound shown in formula 5, and then by extracting concentration, i.e. obtaining purity reaches 98%
Above Mivacurium Chloride.
When the X in 3 compound of formula is F, Cl, Br or methanesulfonyloxy group, sodium iodide is added and promotes reaction；
The reaction dissolvent is selected from least one of acetonitrile, propionitrile, dioxane, 2- butanone and acetone, preferably
Acetonitrile.
Two propyl propionates of E- octyl- 4- alkene -1,8- are 1: 2~1 with (R)-(+) -5'- methoxyl group laudanosine molar ratios:
6, preferably 1: 2~1: 4；Reaction temperature is preferably 60~90 DEG C；Mixing time is preferably 8~16 hours.
The route that technical solution of the present invention synthesizes Mivacurium Chloride is as follows：
Compared to the prior art, it is with advantageous effect the advantages of technical solution provided by the invention：
1, the preparation method of Mivacurium Chloride provided by the invention, specifically with E- octyl-s 4- alkene -1,8- diacid and 3 it is halogenated or
The propyl alcohol of person's class halogen substitution is that starting material obtains compound shown in intermediate formula 3 by condensation reaction, by simple purification,
Compound shown in the formula 3 of high-purity just can be obtained, then flowing back under the conditions of acetonitrile equal solvent with compound shown in formula 4 can obtain
To target product, by-product easily can be obtained qualification due to differing larger with product characteristics by simple extraction washing
Bulk pharmaceutical chemicals.
2, the raw material of bis- propyl propionates of compound E- octyl- 4- alkene -1,8- shown in formula 3 of the present invention is easy to get, it is only necessary to simple
Extracting and washing or distillation may be used in next step, and without severe toxicity, pollution is few for reaction；It reacts and easy to operate, low energy consumption, technique
It is environmentally protective.
3, the present invention prepares the method starting material stabilization of Mivacurium Chloride, quality controllable, easy to maintain, is all single chemical combination
Object.Ground without original be difficult to purify in technique and preserve, the intermediate mixture of the easy moisture absorption.
4, the method for Mivacurium Chloride prepared according to the methods of the invention, three reacted in the final product Mivacurium Chloride of gained are different
Structure body (5A, 5B and 5C) component ratio meets the drug original and grinds requirement to bulk pharmaceutical chemicals：The content of 5C account for three isomers (5A,
5B and 5C) total content 4%-8%；The sum of 5A and 5B contents account for the 92%- of three isomers (5A, 5B and 5C) total contents
96%, the final product of stable quality can be obtained.
In short, technical solution provided by the invention does not use compound shown in formula 6, and directly use propyl ester and laudanosine
(4 compound of formula 3 and formula) is reacted, and post-processing is routine operation, and unexpectedly has the technical effect that in final product three kinds
The content of isomers meets original than relationship and grinds requirement.
The additional aspect and advantage of the present invention are set forth in part in the description, and will partly become from following describe
Obviously, or through the invention practice is recognized.
Description of the drawings
Fig. 1：The HNMR collection of illustrative plates of two -3- chlorine propyl ester of E- octyl- 4- alkene -1,8- diacid obtained by 1 step 1 of embodiment.
Fig. 2：The HNMR collection of illustrative plates of Mivacurium Chloride obtained by 1 step 2-1 of embodiment.
Specific implementation mode
Applicant will be described in the embodiment of the present invention below, it should be noted that the embodiments described below is example
Property, it is only used for explaining the present invention, and be not considered as limiting the invention.In addition, if do not clearly stated, below
Embodiment employed in all reagents be commercially available in the market, or be referred to document or known method and close
At, also it is what those skilled in the art were easy to get for the reaction condition that do not list.
In embodiment, the preparation method of Loprazolam 3- hydroxypropyl acrylates is as follows：
Add into the there-necked flask equipped with 1,3-PD (5g, 65.71mmol) and triethylamine (13.8mL, 98.56mmol)
Enter 100mL dichloromethane, in N2It is cooled to 0 DEG C under protection, methane sulfonyl chloride (6.1mL, 31.03mmol) is added dropwise, is stirred at 0 DEG C
1 hour, after TLC contact plates show that the reaction was complete, water is added and is quenched, then three times with dichloromethane extraction (3 × 10mL), have
Machine mutually uses anhydrous Na2SO4It is spin-dried for obtaining crude product after drying, in use, direct plungeing into reaction.
The preparation method of p-methyl benzenesulfonic acid 3- hydroxypropyl acrylates is as follows：
100mL triethylamines, N are added into 76g (1.0mol) 1,3-PDs and 150mL dichloromethane2The lower cooling of protection
It to 0 DEG C, is added dropwise in paratoluensulfonyl chloride 95g (0.50mol) to above-mentioned solution, is stirred overnight at room temperature, the display of TLC contact plates has been reacted
Quan Hou, decompression are spin-dried for, and the dissolving of 800mL dichloromethane is added, and organic phase uses 150mL water, 1mol/L dilute hydrochloric acid 150mL to wash successively
It washs.After organic phase anhydrous Na2SO4It is spin-dried for obtaining crude product after drying, in use, direct plungeing into reaction.
A kind of synthetic method of 1 Mivacurium Chloride of embodiment, includes the following steps：
Step 1：Condensation reaction
5.0g E- octyl- 4- alkene -1,8- diacid is added in 25mL thionyl chlorides, is heated to reflux 3 hours, reaction finishes
It is cooled to room temperature, is dissolved, be then slowly dropped at 0 DEG C or so dissolved with 5.6g 3- chloropropyl alcohols with 50mL dichloromethane after being spin-dried for
60mL dichloromethane in, reacted 10 hours at 25 DEG C after being added dropwise.Contact plate detects, and reaction finishes, and 50mL 1M hydrogen-oxygens are added
Change sodium and reaction is quenched, after liquid separation, organic phase is dried with anhydrous sodium sulfate, is spin-dried for obtaining compound E- octyl- 4- alkene -1,8- diacid
Two -3- chlorine propyl ester 8.3g (yield 86%) pale yellowish oil liquid, purity 95.6%.
HNMR(CDCl3)δ5.41(2H,m),4.16(4H,m),3.56(4H,m),2.31(4H,m),2.25(4H,m),
2.03(4H,m).
MS(ESI)m/z 326.2.3(M+1)。
Step 2-1：The synthesis (acetonitrile as solvents) of Mivacurium Chloride
By 4.1g (R)-(+) -5'- methoxyl groups laudanosine, 1.5g sodium iodides and 1.7g E- octyl- 4- alkene -1,8- diacid two -
3- chlorine propyl ester is added in 50mL acetonitriles, is heated to 60 DEG C and is flowed back 16 hours, and the reaction was complete for HPLC detections, is cooled to room temperature, mistake
Filter, filter cake are washed with 5mL acetonitriles.Filtrate is dissolved after being spin-dried for 200mL methanol, and resin anion (R.A.) (717 chlorine type) 41g is added, stirs
It mixes 3 hours.Filter out resin.Filtrate is spin-dried for obtaining yellow foam crude product 5.3g.50mL water and 50mL bis- are added into crude product
Chloromethanes stirs liquid separation, and product enters water phase, and water phase is washed three times with dichloromethane (25mL × 3), and 18g NaCl are then added,
Be added dichloromethane (100mL × 2) be extracted twice, dichloromethane mutually use 5m/v% (5g/100mL) NaCl solution (30mL ×
2) it washes twice, is spin-dried for obtaining 4.5g (yield 79%) colourless foam sterling, product purity amounts to 98.98%.
MS(ESI)m/z 514.3(M/2)。
Step 2-1 products are detected through nuclear-magnetism.
Step 2-2：The synthesis of Mivacurium Chloride (2- butanone makees solvent)
By 4.1g (R)-(+) -5'- methoxyl groups laudanosine, 1.5g sodium iodides and 1.7g E- octyl- 4- alkene -1,8- diacid two -
3- chlorine propyl ester is added in 50mL 2- butanone, is heated to 60 DEG C and is flowed back 16 hours, and HPLC detections have 6.2% (R)-(+) -5'-
Methoxyl group laudanosine raw material remains, and is cooled to room temperature, and filters, and filter cake is washed with 50mL 2- butanone.Merging filtrate adds after being spin-dried for
Enter the dissolving of 200mL methanol.Then resin anion (R.A.) (717 chlorine type) 41g is added, stirs 3 hours, filters out resin, filtrate is spin-dried for
Obtain yellow foam crude product 3.2g.50mL water and 50mL dichloromethane are added into crude product, stirs liquid separation, product enters water
Phase, water phase are washed three times with dichloromethane (25mL × 3), and 18g NaCl are then added, and dichloromethane (100mL × 2) is added and extracts
Twice, dichloromethane is mutually washed twice with the NaCl solution (30mL × 2) of 5m/v% (5g/100mL), is spin-dried for obtaining 2.3g (receipts
Rate 40.3%) colourless foam sterling, product purity amounts to 98.47%.
MS(ESI)m/z 514.3(M/2)。
Step 2-2 products are detected through nuclear-magnetism.
Isomers content in above-mentioned steps 2-1 and step 2-2 products therefroms is measured and (uses HPLC, similarly hereinafter),
And compared with bulk pharmaceutical chemicals ingredient in former triturate, and former triturate Comparative result is as follows：
The prior art is studies have shown that the ingredient with medicine effect is trans- trans isomer 5A and cis- in Mivacurium Chloride drug
Trans isomer 5B, three kinds of isomers each component contents are most when testing result comparison finds that reaction dissolvent is acetonitrile, in products therefrom
It is ground close to original, drug quality is best, and the result is most important to the quality of Mivacurium Chloride bulk pharmaceutical chemicals.
A kind of synthetic method of 2 Mivacurium Chloride of embodiment, includes the following steps：
Step 1：Condensation reaction
5g E- octyl- 4- alkene -1,8- diacid is added in 25mL thionyl chlorides, is heated to reflux 3 hours, reaction finishes cold
But it to room temperature, is dissolved, is then slowly dropped at 0 DEG C or so dissolved with 33.5g 3- iodine propyl alcohol with 50mL dichloromethane after being spin-dried for
In 100mL tetrahydrofurans, reacted 24 hours at 0 DEG C after being added dropwise.The reaction was complete for HPLC detections, and 50mL 1M hydroxides are added
Reaction is quenched in sodium.After liquid separation, organic phase is dried with anhydrous sodium sulfate.It is spin-dried for obtaining compound E- octyl- 4- alkene -1,8- diacid two -
3- iodine propyl ester 12.1g (yield 81.6%) pale yellowish oil liquid, purity 95.3%.
HNMR(CDCl3)δ5.41(2H,m),4.11(4H,m),3.19(4H,m),2.34(4H,m),2.28(4H,m),
2.10(4H,m)
MS(ESI)m/z 509.2(M+1)。
Step 2：The synthesis of Mivacurium Chloride
Two -3- iodine propyl ester of 4g E- octyl- 4- alkene -1,8- diacid, 23.2g (R)-(+) -5'- methoxyl group laudanosines are added to
It in 300mL propionitrile, is heated to 90 DEG C and flows back 8 hours, the reaction was complete for HPLC detections, is cooled to room temperature, and filters, filter cake 30mL third
Nitrile washs.Resin anion (R.A.) (717 chlorine type) 40g is added into filtrate, stirs 5 hours, filters out resin, filtrate is spin-dried for obtaining Huang
Color foam-like crude product 8.4g.50mL water and 50mL dichloromethane are added into crude product, stirs liquid separation, water phase dichloromethane
(25mL × 3) are washed three times, and chloroform (10mL × 1) is washed once, and 18g NaCl are then added, and dichloromethane (100mL × 2) is added and extracts
It takes twice, dichloromethane extract liquor merges, and is spin-dried for obtaining 6.5g (yield 75%) white foam sterling, purity 98.7%.
MS(ESI)m/z 514.3(M/2)。
Step 2 product is detected through nuclear-magnetism.
Isomers content in step 2 products therefrom is measured, and former triturate Comparative result is as follows：
A kind of synthetic method of 3 Mivacurium Chloride of embodiment, includes the following steps：
Step 1：Condensation reaction
5g E- octyl-s 4- alkene -1,8- diacid and 12.3g 3- iodine propyl alcohol are added in 60mL dichloromethane, are then added
12g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and 3.5g 4-dimethylaminopyridine are reacted at 100 DEG C
0.5 hour, the reaction was complete for HPLC detections, 50mL 1mol/L dilute hydrochloric acid is added, reaction is quenched.After liquid separation, organic phase is eaten with saturation
Brine (50mL × 2) washes twice, anhydrous sodium sulfate drying.It is spin-dried for obtaining two -3- iodine of compound E- octyl- 4- alkene -1,8- diacid
Propyl ester 10.6g (yield 71.8%) pale yellowish oil liquid, purity 94.5%.
MS(ESI)m/z 509.2(M+1)。
Step 1 product is detected through nuclear-magnetism and is confirmed.Step 2：The synthesis of Mivacurium Chloride
Two -3- iodine propyl ester of 4g E- octyl- 4- alkene -1,8- diacid, 15.5g (R)-(+) -5'- methoxyl group laudanosines are added to
It in 200mL acetonitriles, is heated to 50 DEG C and flows back 24 hours, the reaction was complete for HPLC detections, is cooled to room temperature, and filters, filter cake 40mL
Acetonitrile washs.Resin anion (R.A.) (717 chlorine type) 40g is added into filtrate, stirs 5 hours.Filter out resin.Filtrate is spin-dried for obtaining
Yellow foam crude product 10.5g.100mL water and 50mL dichloromethane are added into crude product, stirs liquid separation, water phase uses dichloro successively
Methane (25mL × 2) is washed twice, and chloroform (10mL × 1) is washed once, then addition 27g NaCl, addition dichloromethane (100mL ×
2) it is extracted twice, dichloromethane extract liquor merges, and is spin-dried for obtaining 7.1g (yield 82%) white foam sterling, purity
99.1%, 1- (3- dimethylamino-propyls) -3- ethyl carbamide contents are less than 6 μ g/mg.
MS(ESI)m/z 514.3(M/2)。
Step 2 product is detected through nuclear-magnetism.
Isomers content in 2 products therefrom of above-mentioned steps is measured, and former triturate Comparative result is as follows：
A kind of synthetic method of 4 Mivacurium Chloride of embodiment, includes the following steps：
Step 1：Condensation reaction
3.0g E- octyl- 4- alkene -1,8- diacid and 5.9g Loprazolam 3- hydroxypropyl acrylates are added to 100mL methyl tertbutyls
In ether, 7.8g N, N'- dicyclohexylcarbodiimides and 1.05g 4-dimethylaminopyridine is then added, reaction 8 is small at 30 DEG C
When, the reaction was complete for HPLC detections, 50mL 1mol/L dilute hydrochloric acid is added, reaction is quenched.After liquid separation, organic phase saturated salt solution
(50mL × 2) wash twice, anhydrous sodium sulfate drying.It is spin-dried for obtaining compound E- octyl- 4- alkene -1,8- two-sulfonyl methanes of diacid
Methyl tertiary butyl ether(MTBE) 100mL mashing is added in propyl ester crude product 6.4g, is filtered to remove N, N'- dicyclohexylurea (DCU)s.It is spin-dried for obtaining compound
E- octyl- 4- alkene -1,8- diacid two-sulfonyl methane propyl ester 4.9g (yield 63.6%), pale yellowish oil liquid, purity 95.3%.
MS(ESI)m/z 445.5(M+1)。
Step 1 product is detected through nuclear-magnetism and is confirmed.
Step 2：The synthesis of Mivacurium Chloride
By 4.4g E- octyl- 4- alkene -1,8- two-sulfonyl methanes of diacid propyl ester, 4.95g sodium iodides and 8.5g (R)-(+) -5'-
Methoxyl group laudanosine is added in 100mL acetone, is heated to 50 DEG C and is flowed back 10 hours, and the reaction was complete for HPLC detections, is cooled to room
Temperature, filtering, filter cake are washed with 20mL acetone.Resin anion (R.A.) (717 chlorine type) 50g is added into filtrate, stirs 5 hours.Filtering
Fall resin.Filtrate is spin-dried for obtaining yellow foam crude product 10.5g.50mL water and 50mL dichloromethane, stirring are added into crude product
Liquid separation, water phase are washed three times with dichloromethane (25mL × 3) successively, and chloroform (10mL × 1) is washed once.Then 18g NaCl are added,
Dichloromethane (100mL × 2) is added to be extracted twice.Dichloromethane extract liquor merges, and is spin-dried for obtaining 6.1g (yield 55%) whites
Foam-like sterling, purity 98.6%, N, N- dicyclohexylurea (DCU) contents are less than 6 μ g/mg.
MS(ESI)m/z 514.3(M/2)。
Step 2 product is detected through nuclear-magnetism.
Isomers content in 2 products therefrom of above-mentioned steps is measured, and former triturate Comparative result is as follows：
A kind of synthetic method of 5 Mivacurium Chloride of embodiment, includes the following steps：
Step 1：Condensation reaction
1.0g E- octyl- 4- alkene -1,8- diacid and 5.3g p-methyl benzenesulfonic acid 3- hydroxypropyl acrylates are added to 50mL ethylene glycol diethyls
In ether, 1.7g N, N'- diisopropylcarbodiimides and 1.2g 4-dimethylaminopyridine is then added, reaction 12 is small at 60 DEG C
When, the reaction was complete for HPLC detections, 20mL 1mol/L dilute hydrochloric acid is added, reaction is quenched.After liquid separation, organic phase saturated salt solution
(50mL × 2) wash twice, anhydrous sodium sulfate drying.It is spin-dried for obtaining compound E- octyl- 4- alkene -1,8- diacid two-to toluene sulphur
Acyl propyl ester 2.8g (yield 80%) pale yellowish oil liquid, purity 94.2%.
MS(ESI)m/z 597.5(M+1)。
Step 1 product is detected through nuclear-magnetism and is confirmed.
Step 2：The synthesis of Mivacurium Chloride
By 2.0g E- octyl- 4- alkene -1,8- two-tolysulfonyl of diacid propyl ester, 3.5g (R)-(+) -5'- methoxyl group laudanums
Element is added in 100mL dioxane, is heated to 100 DEG C and is flowed back 1 hour, and the reaction was complete for HPLC detections, is cooled to room temperature, mistake
Filter, filter cake are washed with 20mL methanol.Resin anion (R.A.) (717 chlorine type) 50g is added into filtrate, stirs 5 hours, filters out tree
Fat, filtrate are spin-dried for obtaining yellow foam crude product 4.3g.50mL water and 50mL dichloromethane are added into crude product, stirs liquid separation,
Water phase is washed three times with dichloromethane (25mL × 3) successively, and chloroform (10mL × 1) is washed once, and 18g NaCl are then added, and is added two
Chloromethanes (100mL × 2) is extracted twice.Dichloromethane extract liquor merges, and is spin-dried for obtaining 2.1g (yield 57%) white foam
Sterling, purity 98.7%, N, N'- diisopropyl urea contents are less than 6 μ g/mg.
MS(ESI)m/z 514.3(M/2)。
Step 2 product is detected through nuclear-magnetism.
Isomers content in 2 products therefrom of above-mentioned steps is measured, and former triturate Comparative result is as follows：
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective
In the case of the above embodiments can be changed within the scope of the invention, change, replace and modification.
Claims (10)
1. a kind of Mivacurium Chloride intermediate, which is characterized in that it is bis- propyl propionate of compound E- octyl- 4- alkene -1,8- shown in formula 3,
Structural formula is as follows：
In formula 3, X F, Cl, Br, I, methanesulfonyloxy group OMs or tolysulfonyl oxygroup OTos.
2. Mivacurium Chloride intermediate according to claim 1, it is characterised in that：X is Cl or methanesulfonyloxy group.
3. a kind of preparation method of Mivacurium Chloride intermediate as claimed in claim 1 or 2：With E- octyl- 4- alkene -1,8- diacid and formula
2 compoundsFor raw material, condensation reaction generation is carried out, specifically A or B with the following method：
Method A：The E- octyl- 4- alkene -1,8- diacid is sent out in non-protonic solvent, under condensing agent effect with 2 compound of formula
Raw reaction is condensed into ester, controls 0~100 DEG C of temperature of reaction system, after reaction, passes through extracting and washing or mashing, concentration
Obtain Mivacurium Chloride crude intermediate；
Method B：Reference method A, difference lies in without using condensing agent, but first by E- octyl-s 4- alkene -1,8- diacid and thionyl chloride
Reaction becomes carrying out condensation reaction with 2 compound of formula again after acyl chlorides.
4. preparation method according to claim 3, it is characterised in that：The condensing agent is selected from 1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides EDCl, N, N'- dicyclohexylcarbodiimide DCC and N, two acyl of N'- diisopropyls carbon
In imines DIC any one or it is two or more；
The aprotic solvent is selected from ether, ethyl acetate, tetrahydrofuran, dimethyl-tetrahydrofuran, dioxane, methyl- tert fourth
In base ether, glycol dimethyl ether, glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether, dichloromethane and chloroform
One or more；
Compound shown in the formula 2 is selected from 3- chloropropyl alcohols, 3- iodine propyl alcohol, 3- bromopropyl alcohols, p-methyl benzenesulfonic acid 3- hydroxypropyl acrylates and first
One or more of alkyl sulfonic acid 3- hydroxypropyl acrylates.
5. preparation method according to claim 4, it is characterised in that：The aprotic solvent is dichloromethane, acetic acid second
One or more of ester and tetrahydrofuran；
2 compound of formula is 3- chloropropyl alcohols and/or Loprazolam 3- hydroxypropyl acrylates.
6. preparation method according to claim 4 or 5, it is characterised in that：The E- octyl- 4- alkene -1,8- diacid and formula 2
Compound mole ratio is 1 ︰, 2~1 ︰ 6；Reaction temperature is controlled at 0~30 DEG C；Reaction time is 0.5~24 hour.
7. a kind of method that Mivacurium Chloride intermediate using described in claims 1 or 22 synthesizes Mivacurium Chloride, steps are as follows：
Mivacurium Chloride intermediate and (R)-(+) -5'- methoxyl group laudanosines in reaction dissolvent, 50~100 DEG C of stirrings 1 of temperature control~
24 hours, after reaction, Chioro-anion exchange resin, agitation and filtration was added in filtrate in cold filtration, and filtrate is spin-dried for obtaining
Then crude product obtains Mivacurium Chloride of the purity 98% or more by extracting concentration；
The reaction dissolvent is selected from least one of acetonitrile, propionitrile, dioxane, 2- butanone and acetone.
8. according to the method described in claim 7, it is characterized in that：When the X in 3 compound of Mivacurium Chloride intermediate formula be F,
Cl, Br or when methanesulfonyloxy group, are added sodium iodide and promote reaction.
9. method according to claim 7 or 8, it is characterised in that：The reaction dissolvent is acetonitrile.
10. method according to claim 7 or 8, it is characterised in that：The Mivacurium Chloride intermediate and (R)-(+)-
5'- methoxyl group laudanosine molar ratios are 1:2~1:6；The temperature of the temperature control is 60~90 DEG C；Mixing time is 8~16 hours.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109232222A (en) * | 2018-10-19 | 2019-01-18 | 武汉嘉诺康医药技术有限公司 | A kind of preparation method of (E)-octyl- 4- alkene -1,8- diacid |
| CN109942490A (en) * | 2019-04-11 | 2019-06-28 | 海南斯达制药有限公司 | A kind of reference substance of Mivacurium Chloride and preparation method thereof |
| CN110698398A (en) * | 2019-10-31 | 2020-01-17 | 武汉嘉诺康医药技术有限公司 | Purification method of mikui ammonium chloride |
| CN111471013A (en) * | 2020-05-26 | 2020-07-31 | 朗天药业(湖北)有限公司 | Mickura ammonium chloride and preparation method of injection thereof |
| CN112778200A (en) * | 2021-01-20 | 2021-05-11 | 江苏诚信药业有限公司 | Preparation method and application of cisatracurium besilate |
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| US7872137B2 (en) * | 2006-06-20 | 2011-01-18 | Farmabios S.P.A. | Process for the preparation of mivacurium chloride |
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| EP0181055A1 (en) * | 1984-07-18 | 1986-05-14 | The Wellcome Foundation Limited | Bis-dimethoxymethyl (trimethoxybenzyl)isoquinolinium salts, their preparation and pharmaceutical compositions containing them |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232222A (en) * | 2018-10-19 | 2019-01-18 | 武汉嘉诺康医药技术有限公司 | A kind of preparation method of (E)-octyl- 4- alkene -1,8- diacid |
| CN109232222B (en) * | 2018-10-19 | 2021-03-23 | 武汉嘉诺康医药技术有限公司 | Preparation method of (E) -octyl-4-ene-1, 8-diacid |
| CN109942490A (en) * | 2019-04-11 | 2019-06-28 | 海南斯达制药有限公司 | A kind of reference substance of Mivacurium Chloride and preparation method thereof |
| CN110698398A (en) * | 2019-10-31 | 2020-01-17 | 武汉嘉诺康医药技术有限公司 | Purification method of mikui ammonium chloride |
| CN111471013A (en) * | 2020-05-26 | 2020-07-31 | 朗天药业(湖北)有限公司 | Mickura ammonium chloride and preparation method of injection thereof |
| CN112778200A (en) * | 2021-01-20 | 2021-05-11 | 江苏诚信药业有限公司 | Preparation method and application of cisatracurium besilate |
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