CN110386878A - A kind of industrialized process for preparing of aclatonium napadisilate - Google Patents
A kind of industrialized process for preparing of aclatonium napadisilate Download PDFInfo
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Abstract
The invention discloses a kind of industrialized process for preparing of aclatonium napadisilate, include the following steps: by lactic acid successively with acetic anhydride, chloro-formate, N, the reaction of N- dimethylethanolamine, acetyl lactoyl choline is made, acid adding after salt at separating, and it is reacted with 1,5- naphthalenedisulfonic acid dimethyl ester and aclatonium napadisilate is made.The present invention has the advantages that preparing acetyl lactoyl choline using " mixed acid anhydride strategy ", the use of high volatility corrosion reagent can avoid；The preparation of intermediate can make solvent with water, can avoid or reduce the dosage of organic solvent；" one kettle way " can be used and prepare intermediate, reduce unit operation；Prepared by finished product can be added the direct crystallization of solvent in last handling process, improve product purity；Reaction scale can be amplified to ten kilograms or more.
Description
Technical field
The invention belongs to field of medicinal chemistry, in particular to a kind of preparation of industrialization of aclatonium napadisilate
Method.
Background technique
Aclatonium napadisilate (chemical entitled 2- [2- (acetoxyl group) -1- oxygen propoxyl group]-N, N, N- trimethyl second
Ammonium -1,5- napadisilate, the entitled Aclatonium Napadisilate of English) be it is a kind of it is artificial synthesized to smooth muscle and
Gastrointestinal motor function has the choline drug of humidification, is developed by Toyama Chemical Co., Ltd. and on 1981
There is excitation in city to stomach, intestines and biliary tract, is suitable for digestive tract function exception, chronic gastritis, biliary dyskinesia, alimentary canal
Postoperative equal treatment.Its chemical structure is as follows:
United States Patent (USP) US 3903137 reports the synthetic method of two kinds of aclatonium napadisilates, and first method is with 2-
[2- (acetoxyl group) propionyloxy]-N, N- dimethyl amine (i.e. acetyl lactoyl choline) are raw material and 1,5- naphthalenedisulfonic acid diformazan
Ester reacts in acetonitrile is made aclatonium napadisilate, and second method is with 1,5- naphthalenedisulfonic acid dimethyl ester and N, N- dimethyl
Ethanol amine reacts 2- hydroxy-n obtained, N, and naphthalene is made in N- trimethyl second ammonium -1,5- napadisilate and acetolactic acid anhydride reactant
Disulfonic acid aclatonium；Chinese patent CN 1948271A is reported using lactic acid as raw material, through chloroacetic chloride, thionyl chloride, N, N- bis-
After acetyl lactoyl choline is made in methylethanolamine one pot reaction, then is reacted with 1,5- naphthalenedisulfonic acid dimethyl ester and synthesize naphthalenedisulfonic acid
Aclatonium；101407468 A of Chinese patent CN of the applicant discloses another synthetic method: using lactic acid as raw material,
Through with N, N- dimethylethanolamine at ester, acetylation be made acetyl lactoyl choline, then with 1,5- naphthalenedisulfonic acid dimethyl ester react, system
Obtain aclatonium napadisilate.
The synthetic method of reported aclatonium napadisilate or its analog there are the problem of, comprising: original used
Material (acetolactic acid acid anhydride) is not easy to obtain, using reagent (such as acetyl largely to the disagreeableness volatility of environment, strong corrosive
Chlorine, thionyl chloride) and the catalyst (such as solid super-strong acid) of higher cost, high (such as high-temperature pressure-reduction distillation of process equipment requirement
Deng), the stability of intermediate it is poor, cause production cost higher, so that synthetic method is difficult to realize good industrialized production.By
It is domestic not yet to realize putting into serial production for aclatonium napadisilate in the factors such as raw material or synthesis technology.
Summary of the invention
Inventor developed one kind using lactic acid as raw material, through " method of fractional steps " or (and) " one kettle way ", successively through acetylation
At mixed acid anhydride and N, at ester and acid, at salt, acetyl lactoyl is made in N- dimethylethanolamine for reaction and chloro-formate
The salt of choline reacts the method that aclatonium napadisilate is made with methylating reagent later.Method provided by the invention can be real
The feather weight industrialization of existing aclatonium napadisilate.
The present invention is to be realized by the following technical programs, and the present invention provides a kind of aclatonium napadisilates
Industrialized process for preparing, here, the chemical structure of the aclatonium napadisilate (compound I) are as follows:
The preparation method the following steps are included:
1) lactic acid (compound II) and acetic anhydride are added into reaction vessel, after acetic acid is distilled off, be made
Acetolactic acid (compound III)；
2) acetolactic acid (compound III) for obtaining step 1) is with chloro-formate (compound IV) in the presence of a base anti-
It answers and is reacted in solvent 1, is made mixed acid anhydride (compound V)；
3) mixed acid anhydride (compound V) and N obtained step 2), N- dimethylethanolamine (compound VI) reaction, system
After obtaining acetyl lactoyl choline, sour HX is added, at salt in reaction dissolvent 2, Crystallization Separation obtains acetyl lactoyl choline salt (chemical combination
Object VII)；
4) the acetyl lactoyl choline salt (compound VII) for obtaining step 3) and 1,5- naphthalenedisulfonic acid dimethyl ester (compound
VIII it) reacts, is made aclatonium napadisilate (compound I) in organic solvent 1；
Wherein, compound IV is identical with the R in compound V, is both selected from C1-C6Alkyl, aromatic radical (such as phenyl) and benzyl
One of base；Preferably, R is methyl, ethyl or benzyl.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein method of fractional steps progress or step 1) can be used in three steps of step 1), step 2) and step 3) and step 2) uses
" one kettle way " carry out making after step 3) or step 1) again step 2) and step 3) to carry out using " one kettle way " after carrying out,
Or step 1) is carried out to step 3) using " one kettle way "；The operation of " one kettle way " is wherein preferably comprised, it is highly preferred that being step 1)
It is carried out to three steps of step 3) using " one kettle way ".
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein the reaction is optionally added into or is added without organic solvent 2, it is preferable that is added without organic solvent in step 1)
2；The reaction is optionally added into or is added without catalyst 1, it is preferable that catalyst 1 is added；Reaction temperature is -20~80 DEG C,
Preferably 0~30 DEG C, more preferably 10~20 DEG C.Here, the organic solvent 2 is selected from the carbon atom that alkanol and alkanoic acid are formed
Sum is the rouge of the ester of 3-10, the chain ether that the alkane of C1-C8 or halogenated alkane, the total number of carbon atoms are 4-8 or cyclic ethers, C3-C8
The mixture of one or more of the alkyl-substituted benzene of fat ketone, acetonitrile, benzene, C1-C4, it is preferable that organic solvent 2 is selected from acetic acid
The mixture of one of ethyl ester, methylene chloride or both；The catalyst 1 is selected from Bronsted acid or Lewis acid or two
The mixture of person；The Bronsted acid is selected from the mixture of one or more of hydrochloric acid, sulfuric acid, sulfonic acid, nitric acid, preferably selects
Select one of your hydrochloric acid, sulfuric acid, p-methyl benzenesulfonic acid；The Lewis acid is selected from boron trifluoride, alchlor, zinc chloride, tetrachloro
The mixture for changing one or more of titanium, tin tetrachloride, is preferably selected from one of alchlor, boron trifluoride.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein in step 2), the alkali is inorganic base or organic base or the mixture for both being, preferably inorganic base；Institute
The inorganic base stated be selected from MOH, MOR ', M2CO3、M3PO4、M2HPO4、MHCO3One or more of mixture, be preferably selected from
MOH、M2CO3、MHCO3One of；The organic base be selected from guanidine, amidine, the total number of carbon atoms 4-24 tetra-alkyl ammonium hydroxide
One or more of mixture.Wherein, MOH, MOR, M2CO3、M3PO4、M2HPO4、MHCO3In M be selected from Li, Na, K,
Rb、Cs、Mg1/2、Ca1/2、Sr1/2、Ba1/2One or more of mixture, be preferably selected from one of Na, K；Here,
R ' in MOR ' is selected from the alkyl of C1-C5.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein in step 2), the reaction dissolvent 1 be water or organic solvent 3, or both mixture, preferred reaction dissolvent
1 is water；Wherein, the organic solvent 3 is selected from the alkane that the total number of carbon atoms that alkanol and alkanoic acid are formed is the ester of 3-10, C1-C6
The mixture of alcohol, the alkane of C1-C8 or one or more of alkyl-substituted benzene, is preferably selected from ethyl acetate, methanol, second
The mixtures of the one or more of alcohol, acetone, methylene chloride, toluene.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein in step 3), the reaction be made the sour HX being added after acetyl lactoyl choline be selected from hydrogen halides, sulfuric acid, sulfonic acid,
The mixture of one or more of carboxylic acid；Wherein, the hydrogen halides is selected from one of hydrogen chloride, hydrogen bromide, hydrogen iodide
Or several mixtures, preferably hydrogen chloride；In alkyl or aryl sulfonic acid of the sulfonic acid selected from C1-C12, sulfamic acid
One or more of mixtures, is preferably selected from the mixture of one of methanesulfonic acid, p-methyl benzenesulfonic acid or both；The carboxylic acid
In citric acid, oxalic acid, malic acid, gluconic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid, substituted benzoic acid
One or more of mixtures, is preferably selected from one or more of citric acid, oxalic acid, maleic acid, fumaric acid or tartaric acid
Mixture.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein the reaction dissolvent 2 is organic solvent 4 in step 3)；It is added before acid HX is added into salt or acid is being added
HX is added at after salt, is preferably added after at salt；The reaction dissolvent 2 is organic solvent 4, and the organic solvent 4 is selected from
The alkane or halogenated alkane, the total number of carbon atoms of ester, C1-C8 that the total number of carbon atoms that alkanol and alkanoic acid are formed is 3-10 are 4-8's
The mixture of one or more of chain ether or cyclic ethers, the aliphatic ketone of C3-C8, acetonitrile, benzene, the alkyl-substituted benzene of C1-C4, it is excellent
Choosing is selected from one of ethyl acetate, methylene chloride or toluene.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein when selecting in the step 2) with organic solvent 3 as reaction dissolvent 1, as reaction dissolvent 2 organic solvent 4 with it is organic
Solvent 3 is identical；When selecting in step 2) using water as reaction dissolvent 1, the reaction dissolvent 2 in step 3) is organic solvent 4.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein the organic solvent 1 is selected from ester, the C1- that the total number of carbon atoms that alkanol and alkanoic acid are formed is 3-10 in step 4)
The alkanol of C6, the alkane of C1-C8 or halogenated alkane, the chain ether or cyclic ethers, the aliphatic ketone of C3-C8, second that the total number of carbon atoms is 4-8
One in the alkyl-substituted benzene of nitrile, benzene, C1-C4, amide solvent (such as N,N-dimethylformamide, N-Methyl pyrrolidone)
Kind or several mixtures, are preferably selected from ethyl acetate, isopropyl acetate, methylene chloride, chloroform, methanol, ethyl alcohol, first
The mixture of one or more of benzene, acetonitrile is more preferably used alone ethyl alcohol or acetonitrile or uses methylene chloride and first
The mixed solvent that alcohol is formed.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, wherein crystallization solvent can be precipitated crystal or be added directly cooling down after completion of the reaction in the post-reaction treatment of step 4),
It improves reaction yield and product purity, improve product characteristics.Here, the crystallization solvent of the addition be selected from C1-C4 alkanol,
The mixture of one or more of the aliphatic ketone of C3-C8, acetonitrile, is preferably selected from the fat of acetonitrile, the alkanol of C1-C4, C3-C6
One of ketone, more have choosing is selected from one of acetonitrile, methanol, ethyl alcohol, isopropanol.
In embodiments of the invention, the preparation of industrialization side of a kind of aclatonium napadisilate provided by the invention
Method, step 1) to step 4) reaction scale can be amplified to 10kg rank or more.
It compared with the prior art, can the advantage of the invention is that preparing acetyl lactoyl choline using " mixed acid anhydride strategy "
Avoid the use of high volatility corrosion reagent；The preparation of intermediate can make solvent with water, can avoid or reduce the use of organic solvent
Amount；" one kettle way " can be used and prepare intermediate, reduce unit operation；Finished product prepares and solvent can be added in last handling process directly analyses
Crystalline substance improves product purity；Reaction scale can be amplified to ten kilograms or more.
Specific embodiment
It will be helpful to understand the present invention by following embodiments, but do not limit the contents of the present invention.
Embodiment 1
Step 1): acetolactic a small amount of preparations of hydrochloric acid catalysis --- lactic acid 200g (85% is added into 1L there-necked flask
Aqueous solution, 1.00 equivalents), concentrated hydrochloric acid 5mL mechanical stirring, reaction is down to 0-10 DEG C, controls reaction temperature at 10~20 DEG C, drop
Add acetic anhydride 360g (1.90 equivalent), reaction solution is transferred in 1L single port bottle by used time 45min after being added dropwise, and is slowly heated up
Being concentrated under reduced pressure into residue weight to 90-100 DEG C is about 250g to get acetolactic acid, and yield about 100% is directly used in subsequent
Reaction.
Embodiment 2
Step 1): acetolactic a small amount of preparations of improved hydrochloric acid catalysis --- lactic acid 200g is added into 1L there-necked flask
(85% aqueous solution, 1.00 equivalents), are down to 0-10 DEG C for reaction, add chloroacetic chloride 1mL, continue to drip after stirring 5min after being added dropwise
Add acetic anhydride 360g (1.90 equivalent), controls reaction temperature at 10~20 DEG C, used time 25min, turn reaction solution after being added dropwise
It moves in 1L single port bottle, is to slowly warm up to 90-100 DEG C and is concentrated under reduced pressure into residue weight be about 250g to get acetolactic acid, receive
Rate about 100%, is directly used in subsequent reactions.
Embodiment 3
Step 1): acetolactic a small amount of preparations of sulfuric acid catalysis --- it is similar with embodiment 1, it is added into 1L there-necked flask
Reaction is down to 0~10 DEG C, acetic anhydride is added dropwise by lactic acid 200g (85% aqueous solution, 1.00 equivalents), concentrated sulfuric acid 5mL, mechanical stirring
Reaction solution is transferred in 1L single port bottle after being added dropwise, is to slowly warm up to 90-100 by 360g (1.90 equivalent), used time 30min
DEG C being concentrated under reduced pressure into residue weight is about 270g to get acetolactic acid (sulfur acid), and yield about 100% can be directly used for down
Subsequent reactions.
Embodiment 4
Step 1): acetolactic a small amount of preparations of Catalyzed by p-Toluenesulfonic Acid --- it is similar with embodiment 1, to 1L there-necked flask
Middle addition lactic acid 200g (85% aqueous solution, 1.00 equivalents), p-methyl benzenesulfonic acid 10g,
Reaction is down to 0~10 DEG C, is added dropwise acetic anhydride 360g (1.90 equivalent), used time 45min by mechanical stirring,
After the reaction was continued after being added dropwise 1h, be to slowly warm up to 90-100 DEG C and be concentrated under reduced pressure into residue weight be about
260g, yield about 100% can be directly used for lower subsequent reactions to get acetolactic acid (containing p-methyl benzenesulfonic acid).
Embodiment 5
Step 1): acetolactic a small amount of preparations of no catalysis --- lactic acid 200g is added in 1L single port bottle, and (85% is water-soluble
Liquid, 1.00 equivalents), acetic anhydride 360g (1.90 equivalent), reaction temperature is slowly increased to 70 DEG C after adding, will after heating reaction 5h
It is about 250g that reaction liquid, which is concentrated under reduced pressure into residue weight in 90-100 DEG C, and yield about 100% can be directly used for subsequent anti-
It answers.
Embodiment 6
It is prepared by " one kettle way " of step 1) and step 2) --- lactic acid 1.00kg the first stage: is added into 5L there-necked flask
Reaction temperature is down to 10~20 DEG C, acetic anhydride is added dropwise by (85% aqueous solution, 1.00 equivalents), concentrated hydrochloric acid 20mL, logical cooling medium
1.80kg (1.90 equivalent), used time 1.5h are concentrated under reduced pressure after being added dropwise and remove acetic acid (being to slowly warm up to 95-105 DEG C) to evaporating
Object significantly reduces out, obtains acetolactic acid；Second stage: being reduced to 0-10 DEG C for reaction temperature, is successively added dropwise and pre-cools to 0-
10 DEG C of 15%NaOH aqueous solution 1.69kg (1.00 equivalents, used time 100min), benzyl chloroformate 1.62kg (use by 1.00 equivalents
When 50min), reaction temperature is risen to 30-40 DEG C after being added dropwise, the reaction was continued 2.5h, stopping stirring, by reaction solution with 5L points
Liquid funnel liquid separation, upper organic phase are the mixed acid anhydride that acetolactic acid and benzyloxy formic acid are formed, and colourless transparent liquid is directly used in
It reacts in next step.
Embodiment 7
" one kettle way " of step 2) and step 3) prepares (acetyl lactoyl choline oxalic acid hydrochlorate) --- the first stage: anti-to 5L
Answer and acetolactic acid 1.20kg well prepared in advance be added in kettle, reaction temperature is reduced to 0-10 DEG C, successively be added dropwise pre-cool to
0-10 DEG C of 15%NaOH aqueous solution 2.42kg (1.00 equivalents, used time 130min), ethyl chloroformate 0.99kg (1.00 equivalents,
Used time 70min), reaction temperature is risen to 20~30 DEG C after being added dropwise, liquid separation after the reaction was continued 1.0h removes lower layer's water phase；
Second stage: ethyl acetate 2L is added into reaction kettle, N, N- dimethylethanolamine 0.80kg (1.00 equivalent) are stirred to react 6h
Oxalic acid 0.82kg (1.00 equivalent) is added in backward reaction kettle, reaction temperature is reduced to 0-10 DEG C by stirring 1h, is taken out after stirring 2h
Filter, filter cake and 50-60 DEG C of vacuum drying 5h, obtain acetyl lactoyl choline oxalates 1.57kg；Total recovery 59%.
Embodiment 8
Step 1) to step 3) " one kettle way preparation ": acetyl lactoyl choline benzoate " one kettle way " method preparation ---
First stage: to be added in 2L there-necked flask (bottom has the function of liquid separation, and interlayer can lead to medium) lactic acid 200g (85% aqueous solution,
1.00 equivalents), concentrated hydrochloric acid 5mL, methylene chloride 400mL, mechanical stirring, control in temperature be 10~20 DEG C, be added dropwise acetic anhydride 360g
After being added dropwise (being to slowly warm up in 90-100 DEG C) is concentrated under reduced pressure to being concentrated into reaction solution by (1.90 equivalents, used time 45min)
Distillate speed obviously slows down, and stops concentration, obtains acetolactic acid；Second stage: reaction temperature is reduced to 0-10 DEG C, is successively dripped
Add 15%NaOH aqueous solution 337g (1.00 equivalents, used time 30min), the methylchloroformate 210g pre-cooled to 0-10 DEG C
(1.00 equivalents, used time 30min) stirs 1h, stops stirring after being added dropwise, liquid separation discards lower layer's water phase, and upper organic phase is
The mixed acid anhydride that acetolactic acid and methoxyl group formic acid are formed；Second stage: ethyl acetate 500mL, N, N- are added into reaction flask
Reaction temperature is risen to 50-60 DEG C after adding by dimethylethanolamine 167g (0.99 equivalent), and benzoic acid 231g is added after stirring 2h
(1.00 equivalent), normal heptane 500mL are cooled to 10~20 DEG C of stirring 5h, filter, and filter cake obtains second in 50-60 DEG C of vacuum drying 7h
Acyl lactoyl choline benzoate 382g, white solid, yield 62%.
Embodiment 9
Step 1) to step 3) " one kettle way preparation " (10 feather weight acetyl lactoyl choline list oxalates) --- the first rank
Section: lactic acid 5.00kg (85% aqueous solution, 1.00 equivalents), concentrated sulfuric acid 50mL being added into 50L double-layer glass reaction kettle, and machinery stirs
It mixes, controlling interior temperature is 10~20 DEG C, is added dropwise acetic anhydride 9.15kg (1.90 equivalent), used time 2h, is added dropwise and continues to stir 1h, subtracts
(being to slowly warm up to 90-100 DEG C) is concentrated in pressure, stops concentration after 3.5h, cools the temperature to room temperature；Second stage: continue to reaction
In kettle plus NaHCO is added portionwise at 0-20 DEG C in water 20kg, control reaction temperature34.09kg (1.05 equivalent), control reaction temperature
Degree at 0-20 DEG C, after stirring no longer generates gas to system after dropwise addition ethyl chloroformate 5.29kg (1.05 equivalents, used time
2.5h), liquid separation is stood after stirring 3h after adding, discards lower layer's water phase, upper organic phase is mixed acid anhydride；Phase III: continue
N, N- dimethylethanolamine 3.93kg (0.95 equivalent), used time 1.5h are added dropwise into obtained mixed acid anhydride, it will after being added dropwise
Reaction temperature rises to 50-60 DEG C, and ethyl acetate 32kg, oxalic acid 4.18kg (1.00 equivalent) is added after reacting 2h, will be anti-after adding
It answers temperature to be slowly dropped to 10~20 DEG C of stirring 8h, filters, filter cake obtains acetyl lactoyl choline oxalic acid in 50-60 DEG C of forced air drying 12h
Salt 10.2kg, white powdery solids；Total recovery 75%.
Embodiment 10
The preparation of aclatonium napadisilate: acetyl lactoyl choline list oxalates is added into 100L double-layer glass reaction kettle
9.00kg (1.00 equivalent), ethyl alcohol 30kg, 1,5- naphthalenedisulfonic acid dimethyl ester (4.85kg, 0.50 equivalent), heating reflux reaction
12h continues that ethyl alcohol 40kg, active carbon 200g are added into reaction system, filters out deactivation charcoal after stirring 1h, cool the filtrate to
It is filtered after 10~20 DEG C of stirring and crystallizing 3h, filter cake obtains aclatonium napadisilate 9.3kg in 70-80 DEG C of vacuum drying 5h, white
Crystalline solid, yield 84%, 189-191 DEG C of fusing point, purity 99.95% (HPLC method).
1H-NMR(D2O, 500MHz): 8.93 (d, J=8.70Hz, 2H), 8.27 (d, J=7.30Hz, 2H), 7.80-7.78
(m, 2H), 5.07 (q, J=7.05Hz, 2H), 4.69-4.49 (m, 4H), 3.62 (d, J=3.6Hz 4H), 3.08 (s, 18H),
2.14 (s, 6H), 1.44 (d, J=7.10Hz, 6H)；13C-NMR(D2O,125MHz):173.3,171.9,139.6,129.5,
129.1,126.6,126.3,69.4,64.4,59.2,53.80,53.77,53.74,20.1,15.9；IR(KBr):ν3088,
3034,3011,2986,2955,2944,1759,1732,1493,1458,1427,1379,1352,1312,1250,1219,
1202,1138,1106,1083,1055,1033,965,951,914,878,805,763,697,670,650,611,563,
526,509,464,446,421cm-1；HRMS:218.13852(+ESI,MeOH),504.09940(-ESI,MeOH).
Claims (10)
1. a kind of industrialized process for preparing of aclatonium napadisilate, here, the aclatonium napadisilate, that is, chemical combination
The chemical structure of object I is as follows:
The preparation method the following steps are included:
1) lactic acid, that is, compound II and acetic anhydride are added into reaction vessel, after acetic acid is distilled off, acetyl is made
Lactic acid；
2) the acetolactic acid i.e. compound III that step 1) obtains is being reacted molten in the presence of a base with chloro-formate i.e. compound IV
It is reacted in agent 1, mixed acid anhydride, that is, compound V is made；
3) mixed acid anhydride for obtaining step 2) i.e. compound V and N, N- dimethylethanolamine, that is, compound VI reaction, are made second
After acyl lactoyl choline, sour HX is added, at salt in reaction dissolvent 2, Crystallization Separation obtains acetyl lactoyl choline salt i.e. compound
VII；
4) the acetyl lactoyl choline salt i.e. compound VII for obtaining step 3) and 1,5- naphthalenedisulfonic acid dimethyl ester i.e. compound VIII
It is reacted in organic solvent 1, aclatonium napadisilate, that is, compound I is made；
Wherein, compound IV is identical with the R in compound V, is both selected from one of C1-C6 alkyl, aromatic radical and benzyl；It is excellent
Selection of land, R are methyl, ethyl or benzyl.
2. preparation method as described in claim 1, wherein three steps of step 1), step 2) and step 3) use the method for fractional steps
Progress or step 1) and step 2) carry out making step 2) and step after step 3 or step 1) after carrying out using " one kettle way " again
It is rapid 3) to be carried out to three steps of step 3) using " one kettle way " using " one kettle way " progress or step 1)；Preferably, contain " one
The operation of pot method " is more electedly that step 1) is carried out to three steps of step 3) using " one kettle way ".
3. preparation method as described in claim 1, wherein the reaction is optionally added into or has been added without in step 1)
Solvent 2, it is preferable that be added without organic solvent 2；The organic solvent 2 is selected from the total number of carbon atoms that alkanol and alkanoic acid are formed
For the ester of 3-10, the alkane of C1-C8 or halogenated alkane, the total number of carbon atoms be 4-8 chain ether or cyclic ethers, C3-C8 aliphatic ketone,
The mixture of one or more of the alkyl-substituted benzene of acetonitrile, benzene, C1-C4, it is preferable that organic solvent 2 be selected from ethyl acetate,
The mixture of one of methylene chloride or both；The reaction is optionally added into or is added without catalyst 1, it is preferable that is added
Catalyst 1；The catalyst 1 is selected from the mixture of Bronsted acid or Lewis acid or both；The Bronsted acid is selected from
The mixture of one or more of hydrochloric acid, sulfuric acid, sulfonic acid, nitric acid is preferably selected from hydrochloric acid, sulfuric acid, one in p-methyl benzenesulfonic acid
Kind；The Lewis acid is selected from one or more of boron trifluoride, alchlor, zinc chloride, titanium tetrachloride, tin tetrachloride
Mixture is preferably selected from one of alchlor, boron trifluoride.
4. preparation method as described in claim 1, wherein the temperature of the reaction is -20~80 DEG C, preferably in step 1)
It is 0~30 DEG C, more preferably 10~20 DEG C.
5. preparation method as described in claim 1, wherein the alkali is inorganic base or organic base or two in step 2)
The mixture of person, preferably inorganic base；Wherein, the inorganic base be selected from MOH, MOR ', M2CO3、M3PO4、M2HPO4、MHCO3
One or more of mixture, be preferably selected from MOH, M2CO3、MHCO3One of；The organic base be selected from guanidine, amidine,
Mixture of the total number of carbon atoms in one or more of the tetra-alkyl ammonium hydroxide of 4-24；MOH,MOR',M2CO3、M3PO4、
M2HPO4、MHCO3Middle M is selected from Li, Na, K, Rb, Cs, Mg1/2、Ca1/2、Sr1/2、Ba1/2One or more of mixture, it is excellent
Choosing is selected from one of Na, K；Here, the R ' in MOR ' is selected from the alkyl of C1-C5.
6. preparation method as described in claim 1, wherein the reaction dissolvent 1 is water or is organic molten in step 2)
Agent 3, or both mixture, preferably water；Wherein, it is total to be selected from the carbon atom that alkanol and alkanoic acid are formed for the organic solvent 3
Number is the ester of 3-10, the alkanol of C1-C6, the alkane of C1-C8 or halogenated alkane, tetrahydrofuran, 2- methyltetrahydrofuran, C3-C8
Aliphatic ketone, acetonitrile, benzene, one or more of the alkyl-substituted benzene of C1-C4 mixture, be preferably selected from ethyl acetate, first
The mixture of one or more of alcohol, ethyl alcohol, acetone, methylene chloride, toluene.
7. preparation method as described in claim 1, wherein the sour HX is selected from hydrogen halides, sulfuric acid, sulphur in step 3)
The mixture of one or more of acid, carboxylic acid；Wherein, the hydrogen halides in hydrogen chloride, hydrogen bromide, hydrogen iodide one
Kind or several mixtures, preferably hydrogen chloride；In alkyl or aryl sulfonic acid of the sulfonic acid selected from C1-C12, sulfamic acid
One or more of mixtures, be preferably selected from the mixture of one of methanesulfonic acid, p-methyl benzenesulfonic acid or both；The carboxylic
Acid is in citric acid, oxalic acid, malic acid, gluconic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid, substituted benzoic acid
One or more of mixtures, be preferably selected from one or more of citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid
Mixture.
8. preparation method as described in claim 1, wherein in step 3), the reaction dissolvent 2 be added acid HX at salt it
Preceding addition is added after acid HX is added into salt, is preferably added after at salt；The reaction dissolvent 2 is organic solvent 4,
The organic solvent 4 be selected from the total number of carbon atoms that alkanol and alkanoic acid are formed be the ester of 3-10, the alkane of C1-C8 or halogenated alkane,
The total number of carbon atoms is one of chain ether or cyclic ethers, the aliphatic ketone of C3-C8, acetonitrile, benzene, the alkyl-substituted benzene of C1-C4 of 4-8
Or several mixtures, it is preferably selected from one of ethyl acetate, methylene chloride or toluene.
9. preparation method as described in claim 1, wherein the organic solvent 1 is selected from alkanol and alkanoic acid in step 4)
The alkanol of ester, C1-C6, the alkane of C1-C8 or halogenated alkane that the total number of carbon atoms of formation is 3-10, the total number of carbon atoms 4-8
Chain ether or one of cyclic ethers, the aliphatic ketone of C3-C8, acetonitrile, benzene, the alkyl-substituted benzene of C1-C4, amide solvent or several
The mixture of kind, is preferably selected from ethyl acetate, isopropyl acetate, methylene chloride, chloroform, methanol, ethyl alcohol, toluene, acetonitrile
One or more of mixture, more preferably exclusive use ethyl alcohol or acetonitrile or formed using methylene chloride and methanol
Mixed solvent.
10. preparation method as described in claim 1 further includes wherein post-reaction treatment in step 4): after completion of the reaction directly
Cooling precipitates crystal or is added crystallization solvent；Here, the crystallization solvent of the addition is selected from the rouge of the alkanol of C1-C4, C3-C8
The mixture of one or more of fat ketone, acetonitrile, one be preferably selected from the aliphatic ketone of acetonitrile, the alkanol of C1-C4, C3-C6
Kind, it is highly preferred that for one of acetonitrile, methanol, ethyl alcohol or isopropanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3903137A (en) * | 1973-06-12 | 1975-09-02 | Toyama Chemical Co Ltd | Choline sulfonate derivatives |
| CN1948271A (en) * | 2006-11-24 | 2007-04-18 | 李晓祥 | Synthesis method of naphthalene disulfonic acid aclatonium and its similar compound |
| CN101407468A (en) * | 2008-11-18 | 2009-04-15 | 扬子江药业集团有限公司 | Novel method for synthesizing aclatonium napadisilate |
-
2018
- 2018-04-20 CN CN201810361248.9A patent/CN110386878B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3903137A (en) * | 1973-06-12 | 1975-09-02 | Toyama Chemical Co Ltd | Choline sulfonate derivatives |
| CN1948271A (en) * | 2006-11-24 | 2007-04-18 | 李晓祥 | Synthesis method of naphthalene disulfonic acid aclatonium and its similar compound |
| CN101407468A (en) * | 2008-11-18 | 2009-04-15 | 扬子江药业集团有限公司 | Novel method for synthesizing aclatonium napadisilate |
Non-Patent Citations (3)
| Title |
|---|
| K. HIDEG，等: "Synthesis of spin-labeled procaine and its derivatives", 《SYNTHETIC COMMUNICATIONS》 * |
| KOJI MIURA，等: "Acyloxyalkanoylcholine derivatives. Synthesis and contracting activity on smooth muscle", 《YAKUGAKU ZASSHI》 * |
| 倪文杰: "《简明物资词典》", 30 April 1988 * |
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