阅读说明：本技术 一种改进的丁苯酞的制备方法 (A kind of preparation method of improved butylphenyl phthaleine ) 是由 刘云涛 王晓波 陈伟 于 2019-08-16 设计创作，主要内容包括：本发明属于化学制药技术领域,涉及一种改进的丁苯酞的制备方法。所述的制备方法包括如下步骤：(1)2-(2-(乙氧羰基)戊酰基)苯甲酸合成；(2)2-戊酰基苯甲酸合成；(3)丁苯酞合成：(4)丁苯酞纯化。利用本发明的改进的丁苯酞的制备方法,能够操作简单、成本低、纯度高的制备丁苯酞。(The invention belongs to chemical pharmaceutical technology fields, are related to a kind of preparation method of improved butylphenyl phthaleine.The preparation method includes the following steps: that (1) 2- (2- (carbethoxyl group) valeryl) benzoic acid synthesizes；(2) 2- valeryl yl benzoic acid synthesizes；(3) butylphenyl phthaleine synthesizes: the purifying of (4) butylphenyl phthaleine.Using the preparation method of improved butylphenyl phthaleine of the invention, can be easy to operate, at low cost, with high purity prepare butylphenyl phthaleine.)

1. a kind of preparation method of improved butylphenyl phthaleine, which is characterized in that the preparation method includes the following steps:

(1) 2- (2- (carbethoxyl group) valeryl) benzoic acid synthesizes: in the presence of solvent and alkali, phthalic anhydride and valeric acid second The reaction as shown in following formula (a) occurs for ester, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction is added, extraction gained is organic Phase desolventizing obtains 2- (2- (carbethoxyl group) valeryl) benzoic acid；

(2) 2- valeryl yl benzoic acid synthesizes: 2- (2- (carbethoxyl group) valeryl) benzoic acid, inorganic base are stirred in aqueous solution The reaction as shown in following formula (b) occurs to reflux, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction, extraction gained is added Organic phase desolventizing obtains 2- valeryl yl benzoic acid；

(3) butylphenyl phthaleine synthesizes: in the presence of solvent and alkali, reducing agent and 2- valeryl yl benzoic acid occur as shown in following formula (c) instead It answers, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction is added, it is thick that extraction gained organic phase desolventizing obtains butylphenyl phthaleine Product；

(4) butylphenyl phthaleine purifies: butylphenyl phthaleine crude product purifies to obtain butylphenyl phthaleine sterling through molecular distillation.

2. preparation method according to claim 1, it is characterised in that: in step (1), the solvent is N, N- dimethyl Formamide, dimethyl sulfoxide and/or tetrahydrofuran.

3. preparation method according to claim 1, it is characterised in that: in step (1), the alkali be sodium tert-butoxide and/ Or potassium tert-butoxide.

4. preparation method according to claim 1, it is characterised in that: in step (2), the inorganic base is hydroxide Lithium, sodium hydroxide and/or potassium hydroxide.

5. preparation method according to claim 1, it is characterised in that: in step (3), the solvent be methanol, ethyl alcohol, Normal propyl alcohol and/or isopropanol.

6. preparation method according to claim 1, it is characterised in that: in step (3), the alkali is lithium hydroxide, hydrogen Sodium oxide molybdena and/or potassium hydroxide.

7. preparation method according to claim 1, it is characterised in that: in step (3), the reducing agent is sodium borohydride And/or potassium borohydride.

8. preparation method according to claim 1, it is characterised in that: step (1), (2), in (3), adjusting pH to acidity is It the use of the hydrochloric acid of 2~10mol/L, sulfuric acid and/or phosphorus acid for adjusting pH is 2~5.

9. preparation method according to claim 1, it is characterised in that: in step (4), the steaming of the molecular distillation purifying Evaporating temperature is 130~150 DEG C, and distillation pressure is 10~20Pa.

10. preparation method according to claim 1, it is characterised in that: in step (4), the molecular distillation purifying exists It is carried out in wiped film molecular distillation equipment, preheating temperature is 65~75 DEG C, and blade applicator revolving speed is 300~350rpm, feed rate For 100~150g/h.

Technical field

The invention belongs to chemical pharmaceutical technology fields, are related to a kind of preparation method of improved butylphenyl phthaleine.

Background technique

N butylphthalide (n-butylphthalide), entitled -1 (the 3H)-isobenzofuranone of 3- butyl of chemistry, abbreviation fourth Phthalide, also known as Butylphthalide are a kind new medicines of China's independent research, are that first, the whole world is with " cerebral arterial thrombosis treatment " The completely new chemicals of principal indication.

Butylphenyl phthaleine is by improving cerebrovascular endothelial NO and PGI₂Level, reduce intracellular calcium concentration, inhibit glutamic acid release It puts, reduces arachidonic acid content, inhibit oxygen radical and improve the machining functions such as activities of antioxidant enzymes caused by cerebral ischemia Multiple pathology links.Animal pharmacodynamics is studies have shown that butylphenyl phthaleine can pass through multiple target spots and play reconstruction with multiple pharmacological effect Microcirculation increases ischemic region perfusion, protection mitochondria and the effect for reducing nerve cell death.

2 months 2005, butylphenyl phthaleine soft capsule (Shi Yao group) listing；In April, 2010, butylphenyl phthaleine sodium chloride injection (stone Medicine group) listing.

The chemical structural formula of butylphenyl phthaleine are as follows:

The existing technique for preparing butylphenyl phthaleine and problem are as follows:

1, (Lanzhou University is learned for Chinese patent application CN201710606003.3, CN201710606891.9 and document Report, 1990 (1): 118-119) using phthalic anhydride and valeric anhydride as starting material, pyroreaction (190 DEG C or 300 DEG C), this The high requirements on the equipment is unfavorable for industrial production.

2, it is prepared using metal alkyl reagent

As Chinese patent application CN201810176976.2, CN201010514433.0, CN201510659708.2, CN201510027695.7 and document Bioorg.Med.Chem.Lett.21 (2011) 4210-4214 etc. are tried using grignard Agent normal-butyl magnesium bromide participates in reaction.Furthermore Chinese patent application CN201810176976.2 also uses more active normal-butyl Lithium.Since metal alkyl reagent needs low temperature, control anhydrous and oxygen-free reaction, therefore the requirement to Workshop Production equipment is very high, no Conducive to amplification production.

Typical reaction is (CN201010514433.0) as follows.

Chinese patent application CN201710158206.0 discloses a kind of without Grignard Reagent, more mild butylphenyl phthaleine system Preparation Method, but the first step reaction time is long, and phthalic monoester and 90~100 DEG C of valerate reactions are monitored more than 48h, TLC Still there is raw material unreacted complete, and impurity is more.

Summary of the invention

The object of the present invention is to provide a kind of preparation method of improved butylphenyl phthaleine, with can be easy to operate, at low cost, pure It spends and high prepares butylphenyl phthaleine.

In order to achieve this, the present invention provides a kind of preparation method of improved butylphenyl phthaleine in the embodiment on basis, The preparation method includes the following steps:

(1) 2- (2- (carbethoxyl group) valeryl) benzoic acid synthesizes: in the presence of solvent and alkali, phthalic anhydride and penta The reaction as shown in following formula (a) occurs for acetoacetic ester, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction, extraction gained is added Organic phase desolventizing obtains 2- (2- (carbethoxyl group) valeryl) benzoic acid；

(2) 2- valeryl yl benzoic acid synthesizes: in aqueous solution by 2- (2- (carbethoxyl group) valeryl) benzoic acid, inorganic base The reaction as shown in following formula (b) occurs for stirring to reflux, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction, extraction is added Gained organic phase desolventizing obtains 2- valeryl yl benzoic acid；

(3) butylphenyl phthaleine synthesizes: in the presence of solvent and alkali, reducing agent and 2- valeryl yl benzoic acid occur such as following formula (c) institute Show reaction, adjusts pH after the reaction was completed to acidity, ethyl acetate extraction is added, extraction gained organic phase desolventizing obtains butylphenyl phthaleine Crude product；

(4) butylphenyl phthaleine purifies: butylphenyl phthaleine crude product purifies to obtain butylphenyl phthaleine sterling through molecular distillation.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (1) in, the solvent is n,N-Dimethylformamide, dimethyl sulfoxide and/or tetrahydrofuran.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (1) in, the alkali is sodium tert-butoxide and/or potassium tert-butoxide.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (2) in, the inorganic base is lithium hydroxide, sodium hydroxide and/or potassium hydroxide.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (3) in, the solvent is methanol, ethyl alcohol, normal propyl alcohol and/or isopropanol.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (3) in, the alkali is lithium hydroxide, sodium hydroxide and/or potassium hydroxide.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (3) in, the reducing agent is sodium borohydride and/or potassium borohydride.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (1), (2), in (3), adjust pH to acidity the use of the hydrochloric acid of 2~10mol/L, sulfuric acid and/or phosphorus acid for adjusting pH to be 2~5.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (4) in, the vapo(u)rizing temperature of the molecular distillation purifying is 130~150 DEG C, and distillation pressure is 10~20Pa.

In a preferred embodiment, the present invention provides a kind of preparation method of improved butylphenyl phthaleine, wherein step (4) in, the molecular distillation purifying carries out in wiped film molecular distillation equipment, and preheating temperature is 65~75 DEG C, blade applicator Revolving speed is 300~350rpm, and feed rate is 100~150g/h.

The beneficial effects of the present invention are, using the preparation method of improved butylphenyl phthaleine of the invention, can it is easy to operate, At low cost, with high purity prepares butylphenyl phthaleine.

One aspect of the present invention single step reaction prepares 2- (2- (carbethoxyl group) valeryl) benzoic acid (phthalic anhydride and penta Acid esters reacts preparation 2- (2- (carbethoxyl group) valeryl) benzoic acid in a solvent, which is with sodium tert-butoxide (potassium) Alkali avoids 2- (2- (carbethoxyl group) valeryl) benzoic acid that high-purity can be prepared using sodium hydrogen；And In the method for CN201710158206.0,2- (2- (carbethoxyl group) valeryl) benzoic acid is prepared by two-step reaction: adjacent first Phthalate anhydride 40-80 DEG C of reaction 2-6h in the solution, prepares phthalic monoester；Secondly phthalic monoester and valeric acid 90~100 DEG C of reactions of ester prepare 2- (2- (carbethoxyl group) valeryl) benzoic acid, and this method prepares 2- (2- (ethoxy carbonyl in two steps Base) valeryl) benzoic acid, and found in actual mechanical process, phthalic monoester and 90-100 DEG C of valerate reaction are super Crossing 48h still has raw material unreacted completely (TLC monitoring), while impure point is larger)；On the other hand, 2- valeryl yl benzoic acid is added to In alcoholic solvent, reinforcing body inorganic base rather than the aqueous solution of alkali, then plus sodium borohydride, 20-30 DEG C of room temperature reaction, such impurity Few, (method of CN201710158206.0 takes water as a solvent, and with sodium hydroxide solution alkali tune, the reaction time is about for fully reacting 20h still has starting material left).

Detailed description of the invention

Fig. 1 is the high performance liquid chromatography detection map of butylphenyl phthaleine prepared by embodiment 1.

Fig. 2 is the high performance liquid chromatography detection map of butylphenyl phthaleine prepared by embodiment 2.

Specific embodiment

A specific embodiment of the invention is further illustrated with reference to embodiments.