CN103159672A

CN103159672A - Preparation method of tropine amide

Info

Publication number: CN103159672A
Application number: CN2012102453399A
Authority: CN
Inventors: 陈芳军
Original assignee: HUNAN IVEN BIO-TECHNOLOGY Co Ltd
Current assignee: HUNAN IVEN BIO-TECHNOLOGY Co Ltd
Priority date: 2012-07-16
Filing date: 2012-07-16
Publication date: 2013-06-19

Abstract

The invention relates to the field of medicinal chemistry, and provides a preparation method of tropine amide. The preparation method of the tropine amide comprises that phenyl group malonic acid diethyl ester is used as raw materials and the tropine amide is obtained after hydrolyzation, condensation and reduction. According to the preparation method of the tropine amide, diester is hydrolyzed into a monoester compound in a first step, follow-up reaction procedures are mild in condition, aftertreatment is simple, yield coefficient is good, and the preparation method of the tropine amide is a process line suitbale for industrialization.

Description

A kind of preparation method of mydriacyl

Technical field

The present invention relates to a kind of preparation method of chemicals, specifically relate to the preparation method of compound mydriacyl.

Background technology

Mydriacyl, English name Tropicamide, chemical name N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl) propanamide, CAS:1508-75-4, structural formula is:

This product is anticholinergic drug, and mydriasis effect and ciliary muscle anesthetic action are arranged, and its effect is fast, and the time is short, is ophthalmology mydriasis drug of first choice, is used for mydriasis and checks the eyeground, and mirror is joined in optometry, and the rainbow membranous body is scorching.

At present, the synthetic method of disclosed mydriacyl only has one, and namely the method for Silvia Dei etc. (Life Sciences, Vol. 58, No. 23, pp. 2147-2153) report is as follows:

This route successively obtains mydriacyl through overprotection hydroxyl, acidylate, condensation, hydrolysis take tropic acid as raw material.The intermediate 2 of this route is extremely unstable, causes the subsequent step reaction impurities a lot, is difficult to purifying, and total recovery is very low.

Summary of the invention

Technical problem to be solved by this invention is to overcome above-mentioned weak point, the more favourable industrialized production mydriacyl preparation method of research and design.

A kind of method for preparing mydriacyl is the process hydrolysis take phenyl ethyl malonate as raw material, acidylate, and condensation, reduction makes mydriacyl.Synthetic route is as follows:

Described method concrete steps are as follows:

1) take phenyl ethyl malonate as raw material, issue the reaction of unboiled water solution at alkaline condition, then use rare acid for adjusting pH value, obtain 2;

2) under sulfur oxychloride exists, acylation reaction occuring with 2 obtains 3;

3) 3 obtain 4 with N-ethyl-4-picoline amine generation condensation reaction;

4) 4 under the reductive agent effect, and ester group is reduced into hydroxyl, obtains mydriacyl.

Described step 1) is reacted in solvent with mineral alkali take phenyl ethyl malonate as raw material, and temperature of reaction is-5 ~ 40 ℃, and the reaction times is 0.25 ~ 10 hour.The mol ratio of phenyl ethyl malonate and mineral alkali is 1:1 ~ 1.5, and mineral alkali used can be salt of wormwood, potassium hydroxide, and sodium hydroxide, solvent can be the first alcohol and waters, the second alcohol and water, solvent is 200:1 ~ 10:1 with the ratio of substrate.

Described step 2) with 2 and solvent, add sulfur oxychloride, make solvent with methylene dichloride or tetrahydrofuran (THF), or solvent-free reaction, temperature of reaction is 0 ~ 70 ℃, the reaction times is 1 ~ 24 hour.Wherein, compound 2 is 1:1.5 ~ 10 with the mol ratio of sulfur oxychloride.

Described step 3) is dissolved in N-ethyl-4-picoline amine in methylene dichloride or tetrahydrofuran (THF), and the mol ratio that is added dropwise to 3, N-ethyl-4-picoline amine and 3 is 1:1 ~ 1.3, and temperature of reaction is 0 ~ 25 ℃, 0.5 ~ 24 hour reaction times.

Described step 4) is dissolved in methyl alcohol or ethanol with 4, adds reductive agent, and temperature of reaction is-10 ~ 80 ℃, and the reaction times is 1 ~ 24 hour.After reaction is completed, add in dilute hydrochloric acid, add ethyl acetate extraction, collect water layer, then transfer pH=12 with sodium hydroxide, add ethyl acetate, collected organic layer, drying, concentrated, obtain compound 5, i.e. mydriacyl.

The invention discloses a kind of novel method for preparing mydriacyl, than disclosed preparation method, the method to have overcome original method intermediate unstable, subsequent step impurity is many, difficult purifying, the shortcoming that yield is low, present method reaction conditions is gentle, greatly improve yield, reduced production cost.

Embodiment

The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, within still belonging to protection scope of the present invention.

Embodiment one

The 500g phenyl ethyl malonate is joined in 35L water, then add 5L methyl alcohol, stir, be cooled to 0 ℃, then drip the potassium hydroxide aqueous solution of 10L 0.25M, reacted 5 hours.After reaction is completed, add ethyl acetate extraction, organic phase is collected in layering, and drying is concentrated, obtains the light yellow solid thing 2. of 418g

IR（KBr）(cm ^-1):?3614,?2960,?2850,?2840,?1770，1740,?1568,?1220,?750,?700,?650。

Embodiment two

410g compound 2 is dissolved in the 4L methylene dichloride, then adds the 470g sulfur oxychloride, under room temperature, reaction is 20 hours, and after reaction was completed, methylene dichloride and unnecessary sulfur oxychloride were removed in decompression, and residuum 3 is directly used in next step reaction.

Embodiment three

239g N-ethyl-4-picoline amine is dissolved in the 5L methylene dichloride, adds the 363g Anhydrous potassium carbonate, more slowly be added dropwise to 3, stirring at room 2 hours, add 3L water, then add dilute hydrochloric acid, collect water layer, add 0.1M NaOH to transfer pH=10, use again ethyl acetate extraction, collect organic phase, drying, concentrated, obtain 568g compound 4.

IR（KBr）(cm ^-1):?3612,?2958,?2930,?2850,?2838,?1768，1738,?1660，1565,?1219,?748,?697,?649。

Embodiment four

560g compound 4 is dissolved in 7L methyl alcohol, is cooled to 0 ℃, slowly add 391 g sodium borohydrides in batches, after adding, reacted 8 hours, after reaction was completed, methyl alcohol was removed in decompression, adds dilute hydrochloric acid and ethyl acetate, extraction, separatory, collect organic phase, drying, concentrated, obtain compound 5, i.e. mydriacyl.

IR（KBr）(cm ^-1):?3611,?3300,?2956,?2917,?2848,?1765,?1737,?1660，?1218,?750,?698,?650。

Claims

1. a method for preparing mydriacyl, is characterized in that, is take phenyl ethyl malonate as raw material, through hydrolysis, and acidylate, condensation, reduction reaction makes mydriacyl.

2. method according to claim 1, is characterized in that, described method concrete steps are as follows:

1) take phenyl ethyl malonate as raw material, hydrolysis reaction occurs, obtain 2;

2) with 2 under the sulfur oxychloride condition acidylate obtain 3;

3) 3 obtain 4 with N-ethyl-4-picoline amine generation condensation reaction under alkaline condition;

4) 4 under the reductive agent effect, and ester changes alcohol into, obtains mydriacyl.

3. method according to claim 1 and 2, is characterized in that, described step 1) is reacted in solvent with mineral alkali take phenyl ethyl malonate as starting raw material, and temperature of reaction is-5 ~ 40 ℃, and the reaction times is 0.25 ~ 10 hour.

4. method according to claim 1 and 2, is characterized in that, described step 2) with 2 and solvent, add sulfur oxychloride, temperature of reaction is 0 ~ 25 ℃, the reaction times is 10 ~ 24 hours.

5. method according to claim 1 and 2, is characterized in that, described step 3) is N-ethyl-4-picoline amine and solvent, is added dropwise to 3 in reaction system, and temperature of reaction is 0 ~ 25 ℃, 0.5 ~ 6 hour reaction times.

6. method according to claim 1 and 2, is characterized in that, described step 4) is dissolved in methyl alcohol with 4, adds sodium borohydride or POTASSIUM BOROHYDRIDE, and temperature of reaction is 0 ~ 60 ℃, and the reaction times is 2 ~ 24 hours.