CN100475773C - Synthesis method of naphthalene disulfonic acid aclatonium and similar compound thereof - Google Patents

Synthesis method of naphthalene disulfonic acid aclatonium and similar compound thereof Download PDF

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CN100475773C
CN100475773C CNB2006101456958A CN200610145695A CN100475773C CN 100475773 C CN100475773 C CN 100475773C CN B2006101456958 A CNB2006101456958 A CN B2006101456958A CN 200610145695 A CN200610145695 A CN 200610145695A CN 100475773 C CN100475773 C CN 100475773C
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carry out
organic solvent
naphthalene disulfonic
disulfonic acid
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CN1948271A (en
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徐自奥
李德刚
刘宏亮
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Chongqing Juqinuomei Pharmaceutical Co., Ltd.
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李晓祥
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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
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton

Abstract

The present invention provides a method for synthesizing cholinergic aclatonium napadisilate by using lactic acid as raw material. Said invention also provides the chemical structure formula of said product cholinergic aclatonium napadisilate.

Description

The synthetic method of naphthalene disulfonic acid aclatonium and similar compound thereof
Technical field
The present invention relates to a kind of synthetic method of formula V compound down, especially adopt the method for " one kettle way " synthetic compound V.The invention still further relates to the synthetic method of choline bases active constituents of medicine naphthalene disulfonic acid aclatonium and the method for similar compound, the especially naphthalene disulfonic acid aclatonium of a kind of synthetic following formula (I).Belong to the pharmaceutical chemistry field.
Figure C20061014569500041
Wherein, R1～R8 is identical or different, is selected from hydrogen, C respectively 1～4Alkyl; N is selected from 1～4 integer.
Background technology
Choline bases active constituents of medicine naphthalene disulfonic acid aclatonium and similar compound thereof, be that a kind of unstriated muscle and gastrointestinal motor function strengthen medicine, stomach, intestines and biliary tract are had excitation, the strongest to acting as of stomach pylorus vestibular position, to the effect at other positions of digestive tube than stomach a little less than.In addition, can also make the terminal motion of biliary tract hyperfunction, intrabiliary pressure raises, and promotes bile to discharge to duodenum.The low state of motion function due to cut-out vagus nerve and the morphine also there is enhancement.No matter to healthy people, chronic gastritis or operation back patient, the gastric content of promotion discharge effect is arranged all.Be used for the unusual treatment of tract function as nauseating, vomiting, poor appetite, abdominal distension, chronic gastritis, biliary dyskinesia, digestive tube postoperative etc.At present, the medicine of Ying Yonging mainly contains naphthalene disulfonic acid aclatonium clinically, and chemical structural formula is as shown in the formula (Ia):
Figure C20061014569500042
Figure C20061014569500051
Summary of the invention
In the naphthalene disulfonic acid aclatonium of prior art and the synthetic method of similar compound thereof, raw materials used difficult acquisition, the synthetic difficulty of raw material is also bigger, the separation of intermediate and purification ratio be difficulty, processing unit requires high, and production cost is also higher, is unfavorable for large-scale industrial production.
Purport of the present invention is to provide a kind of production method of naphthalene disulfonic acid aclatonium and similar compound thereof of suitable suitability for industrialized production.For realizing this goal of the invention, technical scheme of the present invention is as follows:
The invention provides a kind of method for preparing compound V, prepare by the method for Compound I I through comprising following steps:
(1) Compound I I and acyl chlorides a carry out esterification, obtain compound III;
Figure C20061014569500052
(2) compound III and sulfur oxychloride (SOCl 2) carry out acylation reaction, obtain compound IV;
Figure C20061014569500053
(3) compound IV and amino alcohol b carry out esterification in the presence of organic solvent and acid binding agent, obtain compound V.
Figure C20061014569500054
Wherein, R1～R7 is identical or different, is selected from hydrogen, C respectively 1～4Alkyl; N is selected from 1～4 integer.
As preferred version of the present invention, above-mentioned described method adopts " one kettle way " (or " one still process ") to carry out, and the process of step (1)～(3) is to carry out in same reaction vessel.
As on the other hand, the present invention also provides a kind of method for preparing Compound I, is prepared by the method for Compound I I through comprising following steps:
(1) Compound I I and acyl chlorides a carry out esterification, obtain compound III;
Figure C20061014569500061
(2) compound III and sulfur oxychloride (SOCl 2) carry out acylation reaction, obtain compound IV;
Figure C20061014569500062
(3) compound IV and amino alcohol b carry out esterification in the presence of organic solvent and acid binding agent, obtain compound V;
Figure C20061014569500063
(4) compound V and 1,5-naphthalene disulfonic acid dialkyl c reacts in the presence of organic solvent, obtains Compound I.
Figure C20061014569500064
Wherein, R1～R8 is identical or different, is selected from hydrogen, C respectively 1～4Alkyl; N is selected from 1～4 integer.
As preferred version of the present invention, the above-mentioned described method for preparing Compound I adopts " one kettle way " (or " one still process ") to carry out, and the process of step (1)～(3) is to carry out in same reaction vessel.Prepared compound V is again with 1, and the reaction of 5-naphthalene disulfonic acid dialkyl obtains Compound I.
Wherein, in the above-mentioned described method, step (1) and (2) can be carried out in the presence of solvent-free, also can carry out in the presence of organic solvent.Described organic solvent is preferably non-polar solvent, for example one or more in benzene, toluene or the ether solvent (as ether) etc.Wherein, carry out in the presence of solvent-free preferred steps of the present invention (1) and (2).
Wherein, the reaction times and the temperature of step (1) and (2), not restriction especially.For example, carry out under 1～8 hour the condition of common 0～100 ℃ of reaction of the esterification of step (1), carry out under 2～6 hours the condition of common 20～80 ℃ of reactions of the acylation reaction of step (2).
Wherein, in the above-mentioned described method, the organic solvent described in the step (3) is preferably used in acetonitrile, ether, benzene, acetone, the trichloromethane etc. one or more.Wherein, described acid binding agent is preferably tertiary amine, for example triethylamine, N, one or more in dinethylformamide, N,N-dimethylacetamide, the pyridine etc.
Wherein, the esterification of step (3) is preferable over-10～30 ℃ of reactions 0.5～6 hour.After reaction finished, product obtained the higher compound V of purity through extraction, separation, drying with after concentrating.
Wherein, in the above-mentioned described method, the organic solvent described in the step (4) is preferably in ethanol, Virahol, acetonitrile, ether, acetone, benzene and the toluene etc. one or more.Wherein, preferred reaction is to carry out 0.5～3 hour under 20～100 ℃ of temperature.
As a specific embodiment of the present invention, in the above-mentioned described method, wherein, R1, R6, R7 are hydrogen, and R2, R3, R4, R5, R8 are methyl, and n is 2, and described Compound I is the Compound I a of following formula structure:
Compare with the naphthalene disulfonic acid aclatonium of prior art and the synthetic method of similar compound thereof, reaction raw materials of the present invention, cheap and easy to get, the reaction raw materials lactic acid of synthesizing aclatonium napadisilate especially of the present invention and similar compound thereof, abundant raw material, cheap and easy to get especially.The advantage that the present invention is more outstanding, also show the building-up process of from raw material (Compound I I) to intermediate (compound V), can adopt " one kettle way " or " one still process " to carry out, whole process is carried out in same reaction vessel, separating step and conversion unit have been reduced, improve yield, greatly reduced production cost.In addition, synthetic method of the present invention, entire reaction course reaction conditions gentleness is easy to control, and is easy and simple to handle, is particularly suitable for large-scale industrial production.
Embodiment
Further specify the present invention below by embodiment.Described embodiment should not be understood that it is to the perhaps qualification of purport in the present invention.
The preparation of embodiment 1:2-acetoxyl group propionic acid (dimethylamino) ethyl ester (compound Va)
Figure C20061014569500081
200g (90%) lactic acid (2.0mol) is joined in the reaction flask, under agitation condition, drip 282g (3.6mol) Acetyl Chloride 98Min., after dripping off, in 20～30 ℃ of reactions 4 hours, after reaction finishes, with the reaction solution underpressure distillation, steam excessive Acetyl Chloride 98Min., after having steamed, get α-acetoxyl group propionic acid, Dropwise 35 7g (3.0mol) sulfur oxychloride, be warming up to backflow after dropwising, reacted 4 hours, reaction finishes, and decompression steams excessive sulfur oxychloride, get 2-acetoxyl group propionyl chloride, under cooling conditions, with 134g (1.5mol) N, N-dimethylaminoethanol, 152g (1.5mol) triethylamine and 1000ml ether join in the above-mentioned reaction flask, in 5～10 ℃ of stirring reactions 2 hours, after reaction finishes, filter, filtrate is used the 1%NaOH solution washing, washing, the organic layer anhydrous sodium sulfate drying filters, after distilling out ether layer, underpressure distillation obtains compound Va (244g that weighs, yield: 60.0%).
The preparation of embodiment 2:2-acetoxyl group propionic acid (dimethylamino) ethyl ester (compound Va)
200g (90%) lactic acid (2.0mol) is joined in the reaction flask, under agitation condition, drip 282g (3.6mol) Acetyl Chloride 98Min., after dripping off, in 20～30 ℃ of reactions 4 hours, after reaction finishes, with the reaction solution underpressure distillation, steam excessive Acetyl Chloride 98Min., after having steamed, get α-acetoxyl group propionic acid, Dropwise 35 7g (3.0mol) sulfur oxychloride, be warming up to backflow after dropwising, reacted 4 hours, reaction finishes, and decompression steams excessive sulfur oxychloride, get 2-acetoxyl group propionyl chloride, under cooling conditions, with 134g (1.5mol) N, N-dimethylaminoethanol, 110g (1.5mol) dimethyl formamide and 1000ml benzene join in the above-mentioned reaction flask, in 5～10 ℃ of stirring reactions 2 hours, after reaction finishes, filter, filtrate is used the 1%NaOH solution washing, washing, the organic layer anhydrous sodium sulfate drying filters, after distilling out the benzene layer, underpressure distillation obtains compound Va (236g that weighs, yield: 58.1%).
The preparation of embodiment 3:2-acetoxyl group propionic acid (dimethylamino) ethyl ester (compound Va)
According to the identical method of embodiment 1, wherein, with 119g (1.5mol) pyridine, 1000ml chloroform, corresponding triethylamine, ether in the alternative embodiment 1 make compound V a (229g that weighs, yield: 56.3%) respectively.
(Compound I preparation a) of embodiment 4 naphthalene disulfonic acid aclatoniums
With 100g (0.316mol) 1,5-naphthalene disulfonic acid dimethyl ester and 800ml Virahol join in the reaction flask, stir and adding 130g (0.634mol) 2-acetoxyl group propionic acid (dimethylamino) ethyl ester (compound Va), be warming up to 50～60 ℃ after adding, stirring reaction 1 hour is after reaction finishes, cooling, filtration obtain the 170g naphthalene disulfonic acid aclatonium (Compound I a), yield: 74.5%, fusing point: 191～192 ℃.Ultimate analysis (C 30H 46N 2O 14S 2): theoretical value (%): C49.85, H6.42, N3.88; Measured value (%): C49.84, H6.44, N3.88; 1H-NMR (D 2O): 1.350 (3H, d, CHC H 3), 2.046 (3H, s, COC H 3), 3.011 (3H, s, NC H 3), 3.547 (2H, t, NC H 2CH 2), 4.412 (2H, t, NCH 2C H 2), 4.976 (1H, q, C HCH 3), 7.675～8.798 (Ar- H). 13C-NMR(D 2O)：15.865(CH CH 3)，20.101(CO CH 3)，53.750(N CH 3)，59.258(NCH 2 CH 2)，64.397(N CH 2CH 2)，69.448( CHCH 3)，126.348～139.251(- C＝)，172.025(O COCHCH3)，173.440(O COCH3)。IR(cm -1)：3036，2984，1758，1733，1491，1456，1380，1247，1201，1106，1033，803。MS(EI)m/z：222，127，115，58，42。
(Compound I preparation a) of embodiment 5 naphthalene disulfonic acid aclatoniums
With 100g (0.316mol) 1,5-naphthalene disulfonic acid methyl esters and 900ml acetone join in the reaction flask, stir and adding 130g (0.634mol) 2-acetoxyl group propionic acid (dimethylamino) ethyl ester (compound Va), be warming up to 50～60 ℃ after adding, stirring reaction 1 hour is after reaction finishes, cooling, filtration obtain the 167g naphthalene disulfonic acid aclatonium (Compound I a), yield: 73.1%, fusing point: 191～192 ℃.
The preparation of embodiment 6:2-propionyloxy propionic acid (dimethylamino) ethyl ester (compound Vb)
200g (90%) lactic acid (2.0mol) is joined in the reaction flask, under agitation condition, drip 332.8g (3.6mol) propionyl chloride, after dripping off, in 20～30 ℃ of reactions 4 hours, after reaction finishes, with the reaction solution underpressure distillation, steam excessive propionyl chloride, after having steamed, get α-propionyloxy propionic acid, Dropwise 35 7g (3.0mol) sulfur oxychloride, be warming up to backflow after dropwising, reacted 4 hours, reaction finishes, and decompression steams excessive sulfur oxychloride, get 2-propionyloxy propionyl chloride, under cooling conditions, with 134g (1.5mol) N, N-dimethylaminoethanol, 152g (1.5mol) triethylamine and 1000ml ether join in the above-mentioned reaction flask, in 5～10 ℃ of stirring reactions 2 hours, after reaction finishes, filter, filtrate is used the 1%NaOH solution washing, washing, the organic layer anhydrous sodium sulfate drying filters, after distilling out ether layer, underpressure distillation obtains compound Va (265g that weighs, yield: 61.0%).
The preparation of the embodiment 7 naphthalene disulfonic acids third newborn courage ammonium (compounds ib)
With 100g (0.316mol) 1,5-naphthalene disulfonic acid dimethyl ester and 800ml Virahol join in the reaction flask, stir and adding 138g (0.634mol) 2-propionyloxy propionic acid (dimethylamino) ethyl ester (compound Vb), be warming up to 50～60 ℃ after adding, stirring reaction 1 hour is after reaction finishes, cooling, filtration obtains the 176g naphthalene disulfonic acid third newborn courage ammonium (Compound I b), yield: 75.6%, and fusing point: 120～122 ℃.Ultimate analysis (C 31H 48N 2O 14S 2): theoretical value (%): C50.53, H6.57, N3.80; Measured value (%): C50.46, H6.49, N3.72.
Embodiment 8: the preparation of naphthalene disulfonic acid fourth breast courage ammonium (Compound I c)
According to the preparation method of the foregoing description, butyryl chloride is replaced Acetyl Chloride 98Min. or propionyl chloride in the above-mentioned example respectively, operation can obtain naphthalene disulfonic acid butyryl courage ammonium (Compound I c) in accordance with the law.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.

Claims (9)

1. method for preparing Compound I is characterized in that being prepared by the method for Compound I I through comprising following steps:
(1) Compound I I and acyl chlorides a carry out esterification, obtain compound III;
Figure C2006101456950002C1
(2) compound III and sulfur oxychloride carry out acylation reaction, obtain compound IV;
(3) compound IV and amino alcohol b carry out esterification in the presence of organic solvent and acid binding agent, obtain compound V;
Figure C2006101456950002C3
(4) compound V and 1,5-naphthalene disulfonic acid dialkyl c reacts in the presence of organic solvent, obtains Compound I,
Figure C2006101456950002C4
Wherein, R1～R8 is identical or different, is selected from hydrogen, C respectively 1～4Alkyl; N is selected from 1～4 integer, and described method adopts " one kettle way " to carry out, and the process of step (1)～(3) is to carry out in same reaction vessel.
2. method according to claim 1, wherein step (1) and (2) are to carry out in the presence of solvent-free or organic solvent.
3. method according to claim 2, wherein step (1) and (2) are to carry out in the presence of solvent-free.
4. method according to claim 2, wherein said organic solvent are non-polar solvent.
5. method according to claim 4, wherein said organic solvent is selected from one or more in benzene, toluene, the ether solvent.
6. method according to claim 1, wherein the organic solvent described in the step (3) is selected from one or more in acetonitrile, ether, benzene, acetone, the trichloromethane.
7. method according to claim 1, wherein the acid binding agent described in the step (3) is selected from triethylamine, N, one or more in dinethylformamide, N,N-dimethylacetamide, the pyridine.
8. method according to claim 1, wherein the organic solvent described in the step (4) is selected from one or more in ethanol, Virahol, acetonitrile, ether, acetone, benzene, the toluene.
9. method according to claim 1, wherein, R1, R6, R7 are hydrogen, and R2, R3, R4, R5, R8 are methyl, and n is 2.
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CNB2006101456958A CN100475773C (en) 2006-11-24 2006-11-24 Synthesis method of naphthalene disulfonic acid aclatonium and similar compound thereof
PCT/CN2007/070948 WO2008061466A1 (en) 2006-11-24 2007-10-24 Synthetic methods of aclatonium napadisilate and analogs thereof
JP2008551635A JP5007309B2 (en) 2006-11-24 2007-10-24 Method for the synthesis of acratonium napadisylate and its analogues

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CN100475773C (en) * 2006-11-24 2009-04-08 李晓祥 Synthesis method of naphthalene disulfonic acid aclatonium and similar compound thereof
CN110386878B (en) * 2018-04-20 2022-04-22 扬子江药业集团有限公司 Industrial preparation method of diethyl cholamine napadisylate

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