WO2008061466A1 - Procédés de synthèse du napadisilate d'aclatonium et d'analogues de celui-ci - Google Patents

Procédés de synthèse du napadisilate d'aclatonium et d'analogues de celui-ci Download PDF

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Publication number
WO2008061466A1
WO2008061466A1 PCT/CN2007/070948 CN2007070948W WO2008061466A1 WO 2008061466 A1 WO2008061466 A1 WO 2008061466A1 CN 2007070948 W CN2007070948 W CN 2007070948W WO 2008061466 A1 WO2008061466 A1 WO 2008061466A1
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WIPO (PCT)
Prior art keywords
compound
oocr3
organic solvent
carried out
acid
Prior art date
Application number
PCT/CN2007/070948
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English (en)
Chinese (zh)
Inventor
Ziao Xu
Degang Li
Hongliang Liu
Original Assignee
Li, Xiaoxiang
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Li, Xiaoxiang filed Critical Li, Xiaoxiang
Priority to JP2008551635A priority Critical patent/JP5007309B2/ja
Publication of WO2008061466A1 publication Critical patent/WO2008061466A1/fr

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Classifications

    • 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

Definitions

  • the present invention relates to a process for the synthesis of a compound of the formula (V), in particular a process for the synthesis of a compound V by a "one-pot process".
  • the present invention also relates to a method for synthesizing a choline-based active ingredient of the following formula (I), a method for synthesizing a choline ammonium naphthalate, and a compound thereof, in particular, a method for synthesizing naphthyldisulfonic acid.
  • a method for synthesizing a choline-based active ingredient of the following formula (I) a method for synthesizing a choline ammonium naphthalate, and a compound thereof, in particular, a method for synthesizing naphthyldisulfonic acid.
  • R1 to R8 are the same or different and are respectively selected from hydrogen and an alkyl group of 4 ; and n is selected from an integer of 1 to 4.
  • the active component of choline drugs, naphthyl disulfonate and its analog compounds is a smooth muscle and digestive tract motor enhancement drug, which has an excitatory effect on the stomach, intestines and biliary tract, and has the most effect on the pyloric part of the stomach. Strong, the effect on other parts of the digestive tract is weaker than the stomach. In addition, it can also make the end of the biliary tract move, the internal pressure of the gallbladder rises, and promote the discharge of bile to the duodenum. It also enhances the low motor function caused by the vagus nerve and morphine. Whether it is for healthy people, chronic gastritis or post-operative patients, it promotes the discharge of gastric contents.
  • the drugs used in clinical practice mainly include ethyl gallate diammonium sulfonate, and the structural formula is as follows
  • the main idea of the present invention is to provide a process for producing industrially produced naphthyl disulfonium naphthalate and similar compounds.
  • the technical solution of the present invention is as follows: The present invention provides a process for producing a compound V, which is prepared from the compound II by the method comprising the following steps:
  • R1 to R7 are the same or different and are respectively selected from hydrogen, 4 alkyl groups; n is selected from 1 to 4 as a preferred embodiment of the present invention, and the above-mentioned method is a "one-pot method" (or “one” The process of steps (1) to (3) is carried out in the same reaction vessel.
  • the present invention also provides a process for the preparation of Compound I, which is prepared from a compound ⁇ by a process comprising the following steps:
  • R1 to R8 are the same or different and are respectively selected from hydrogen and an alkyl group of 4; and n is selected from an integer of 1 to 4.
  • the above-mentioned method for preparing the compound I is carried out by "one-pot method” (or “one-pot method"), and the processes of the steps (1) to (3) are in the same reaction.
  • the obtained compound V is further reacted with 1,2-naphthalenedisulfonic acid dialkyl ester to obtain a compound I.
  • the steps (1) and (2) may be carried out in the absence of a solvent or in the presence of an organic solvent.
  • the organic solvent is preferably a non-polar solvent such as one or more of benzene, toluene or an ether solvent such as diethyl ether.
  • preferred steps (1) and (2) of the present invention are carried out in the absence of a solvent.
  • the reaction time and temperature of the steps (1) and (2) are not particularly limited.
  • the esterification reaction of the step (1) is usually carried out at 0 to 100 ° C for 1 to 8 hours
  • the acylation reaction of the step ( 2 ) is usually carried out at 20 to 80 ° C for 2 to 6 hours.
  • the organic solvent described in the step (3) is preferably one or more selected from the group consisting of acetonitrile, diethyl ether, benzene, acetone, and chloroform.
  • the acid binding agent is preferably a tertiary amine such as one or more of triethylamine, N, N-dimethylformamide, N, N-dimethylacetamide, pyridine or the like.
  • the esterification reaction of the step (3) is preferably carried out at -10 to 30 ° C for 0.5 to 6 hours. After the reaction is completed, the product is extracted, separated, dried and concentrated to obtain a compound of higher purity.
  • the organic solvent described in the step (4) is preferably one or more selected from the group consisting of ethanol, isopropanol, acetonitrile, diethyl ether, acetone, benzene, and toluene. Among them, preferred It should be carried out at a temperature of 20 ⁇ 100 °C for 0.5 ⁇ 3 hours.
  • the reaction raw material of the invention is cheap and easy to obtain, especially the synthetic naphthyl disulfonate and the like of the present invention.
  • the raw material of the compound is lactic acid, which is rich in raw materials and is cheap and easy to obtain.
  • the more prominent advantages of the present invention are also manifested in the synthesis process from the starting material (compound II) to the intermediate (compound V), which can be carried out by "one-pot method” or "one-pot method", and the whole process is carried out in the same reaction vessel. In progress, the separation step and reaction equipment are reduced, the yield is increased, and the production cost is greatly reduced.
  • the synthesis method of the invention has mild reaction conditions, is easy to control, and is easy to operate, and is particularly suitable for large-scale industrial production. detailed description
  • Example 1 Preparation of 2-acetoxypropionic acid (dimethylamino)ethyl ester (Compound Va) 200 g (90%) (2.0 mol) of lactic acid was added to the reaction flask, and 282 g (3.6 mol) of acetyl chloride was added dropwise under stirring, and after the completion of the dropwise addition, the reaction was carried out at 20 to 30 ° C for 4 hours. The reaction liquid was distilled under reduced pressure, and excess acetyl chloride was distilled off.
  • Example 4 Preparation of naphthyldisulfonic acid ethyl urethane ammonium (compound la)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des procédés de synthèse de composés de formule (V) : dans laquelle formule R1-R7 sont identiques ou différents et sont chacun sélectionnés parmi un hydrogène et un alkyle en C1-4; et n est un nombre entier de 1-4. Lesdits procédés peuvent être mis en œuvre sous forme de procédés effectués dans un seul réacteur. L'invention concerne également des procédés de synthèse du napadisilate d'aclatonium cholinergique et d'analogues de celui-ci.
PCT/CN2007/070948 2006-11-24 2007-10-24 Procédés de synthèse du napadisilate d'aclatonium et d'analogues de celui-ci WO2008061466A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008551635A JP5007309B2 (ja) 2006-11-24 2007-10-24 アクラトニウムナパジシル酸塩及びその類似化合物の合成方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2006101456958A CN100475773C (zh) 2006-11-24 2006-11-24 萘二磺酸乙乳胆铵及其类似化合物的合成方法
CN200610145695.8 2006-11-24

Publications (1)

Publication Number Publication Date
WO2008061466A1 true WO2008061466A1 (fr) 2008-05-29

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/070948 WO2008061466A1 (fr) 2006-11-24 2007-10-24 Procédés de synthèse du napadisilate d'aclatonium et d'analogues de celui-ci

Country Status (3)

Country Link
JP (1) JP5007309B2 (fr)
CN (1) CN100475773C (fr)
WO (1) WO2008061466A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100475773C (zh) * 2006-11-24 2009-04-08 李晓祥 萘二磺酸乙乳胆铵及其类似化合物的合成方法
CN110386878B (zh) * 2018-04-20 2022-04-22 扬子江药业集团有限公司 一种萘二磺酸乙乳胆铵的工业化制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3903137A (en) * 1973-06-12 1975-09-02 Toyama Chemical Co Ltd Choline sulfonate derivatives
JPS5414092B1 (fr) * 1970-12-28 1979-06-05
US5011973A (en) * 1982-04-19 1991-04-30 Toyama Chemical Co., Ltd. Novel process for producing bischoline-disulfonate derivatives
CN1948271A (zh) * 2006-11-24 2007-04-18 李晓祥 萘二磺酸乙乳胆铵及其类似化合物的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS551251B2 (fr) * 1973-06-20 1980-01-12
DE2546845A1 (de) * 1975-10-18 1977-04-28 Basf Ag Substituierte 2-(chinolyl-xy)- und 2-(isochinolyl-oxy)-carbonsaeurederivate
US4937367A (en) * 1987-07-15 1990-06-26 Zambon Group S.P.A. Process for the preparation of intermediates for the synthesis of fosfomycin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5414092B1 (fr) * 1970-12-28 1979-06-05
US3903137A (en) * 1973-06-12 1975-09-02 Toyama Chemical Co Ltd Choline sulfonate derivatives
US5011973A (en) * 1982-04-19 1991-04-30 Toyama Chemical Co., Ltd. Novel process for producing bischoline-disulfonate derivatives
CN1948271A (zh) * 2006-11-24 2007-04-18 李晓祥 萘二磺酸乙乳胆铵及其类似化合物的合成方法

Also Published As

Publication number Publication date
JP2009524606A (ja) 2009-07-02
JP5007309B2 (ja) 2012-08-22
CN100475773C (zh) 2009-04-08
CN1948271A (zh) 2007-04-18

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