CN105037186A - Preparation method of aminomethylbenzoic acid - Google Patents
Preparation method of aminomethylbenzoic acid Download PDFInfo
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- CN105037186A CN105037186A CN201510338012.XA CN201510338012A CN105037186A CN 105037186 A CN105037186 A CN 105037186A CN 201510338012 A CN201510338012 A CN 201510338012A CN 105037186 A CN105037186 A CN 105037186A
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Abstract
The invention discloses a preparation method of aminomethylbenzoic acid. Specifically, p-cyanobenzyl chloride (particularly 4-cyanobenzyl chloride) is taken as a raw material, and then 4-cyanobenzyl chloride is subjected to ammonolysis reaction under the catalysis of urotropine, so that the intermediate 4-cyanobenzylamine is obtained, and acid hydrolysis is carried out to obtain the end product aminomethylbenzoic acid. According to the preparation method of aminomethylbenzoic acid, provided by the invention, the synthetic procedures are short, the raw materials are easy to get, the yield is high, the cost is low, the quality is good, the pollution is less, the operation is simple and convenient and large-scale industrial production is facilitated.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of preparation method of Aminomethylbenzoic Acid.
Background technology
The relevant information of Aminomethylbenzoic Acid is as described below:
Chinese: Aminomethylbenzoic Acid;
English name: AminomethylbenzoicAcid;
Chemical name: Aminomethylbenzoic Acid;
CAS：56-91-7；
Structural formula:
;
Molecular formula: C
8h
9nO
2;
Molecular weight: 151.16;
Proterties: the crystallization of white flakes shape or crystalline powder, be slightly dissolved in cold water, dissolves in hot water, is dissolved in ethanol, chloroform hardly;
Fusing point: about 345 DEG C.
Aminomethylbenzoic Acid is a kind of conventional potent haemostatic medicament, there is antifibrinolytic anastalsis, its mechanism of action is identical with hexosamine, but comparatively the latter is strong 4 ~ 5 times, haemostatic effect is remarkable, and toxic side effect is slight, drug safety is high, be applicable to the treatment of polytype bleeding, obviously can reduce the hemorrhage harm that human body is caused, even can save the life of hemorrhage.Meanwhile, it be again the another kind of application of preparation wider hemostatic drug---the key intermediate of tranexamic acid, market demand is larger.
In the prior art, relevant Aminomethylbenzoic Acid has five kinds of synthetic methods, and its detailed synthetic route as shown in Figure 1.
One method (see " national bulk drug technique compilation " 506th ~ 509 pages) employing p-nitrobenzoic acid is raw material, para-amino benzoic acid is obtained through iron powder and hydrochloric acid reduction, then Sodium Nitrite is utilized to carry out diazotization reaction, react with sodium cyanide again and generate paracyanobenzoic acid, finally under raney ni catalysis, obtain product Aminomethylbenzoic Acid through hydrogen reducing, but this synthetic route step is long, pollutes large, use again the sodium cyanide of severe toxicity, production exists larger potential safety hazard.
Two methods take p-Xylol as raw material, obtain product through catalyzed oxidation, chlorination and ammonification three-step reaction, but chlorination reaction restriction is many, and by product is many, and yield is lower.
Three methods and two methods similar, but raw material cymene is not easy to obtain, and now bromine price is higher, causes production cost to increase thereupon.
Four methods (see CN102718673A) with to cyano group benzyl chloride for raw material, obtain product through acid hydrolysis, ammonification, although this method route is short, produce hydrolysising by-product---benzyl chloride during hydrolysis, and product crystal structure is variant.
Five methods are the existing technique of current industrial use, and it take p-chloromethyl benzoic acid as raw material, through ammonification, acidifying, removal impurity, obtain product with after ammonia neutralization, but this process byproducts is many, and yield is lower.
Summary of the invention
For above-mentioned situation, the invention provides a kind of preparation method of Aminomethylbenzoic Acid.The method adopt can supply in a large number and cheap and easy to get be raw material to cyano group benzyl chloride, obtain, to cyano group benzylamine, then namely obtaining Aminomethylbenzoic Acid through acid hydrolysis through ammonia solution.
Specifically, the preparation method of a kind of Aminomethylbenzoic Acid provided in the present invention, it comprises the steps:
(1) to the ammonolysis reaction carried out between cyano group halogen benzyl and ammonia:
In reaction vessel, add organic solvent and to cyano group halogen benzyl, stirring at room temperature makes dissolving, obtain cyano group halogen benzyl solution; Urotropine (urotropin) and water is added in another reaction vessel, stirring at room temperature makes dissolving, cryosel bath cooling, ammoniacal liquor is added after interior temperature drop to 5 DEG C, then drip described to cyano group halogen benzyl solution wherein, in controlling in dropping process, temperature is no more than 15 DEG C, in 10 ~ 80 DEG C of stirring reactions 5 ~ 6 hours after dropwising; After completion of the reaction, be cooled to room temperature, separatory after stratification, ammoniacal liquor layer is waited until down to criticize and is applied mechanically, containing directly dropping into next step acid hydrolytic reaction to the organic solvent layer of cyano group benzylamine:
(2) to the acid hydrolytic reaction carried out between cyano group benzylamine and acid:
Water is added in reaction vessel, drip acid under agitation condition, then add the organic solvent layer contained cyano group benzylamine obtained in step (1), be heated to 80 DEG C, stop stirring, separatory after stratification, the organic solvent layer on upper strata returns in step (1) to be applied mechanically, and the sour water layer of lower floor joins in another reaction vessel, under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; After backflow terminates, be cooled to 90 DEG C, add water, be cooled to room temperature, then stir 1h, filter the solid of separating out, sour water layer is waited until down to criticize and is applied mechanically, and is added to the water by filtration gained solid, stirs lh, is neutralized to neutrality, be cooled to-5 DEG C, filter, washing is drained, and obtains Aminomethylbenzoic Acid.
Preferably, described in step (1), organic solvent is selected from any one in the aromatic solvents such as toluene, dimethylbenzene, chlorobenzene, preferred toluene.
Preferably, be to cyano group benzyl chloride or to cyano-benzyl bromide to cyano group halogen benzyl described in step (1), preferably to cyano group benzyl chloride.
Preferably, described when feeding intake in step (1) is 1g:4 ~ 6mL to the weightmeasurement ratio between cyano group halogen benzyl and organic solvent.
Preferably, weight ratio when feeding intake in step (1) between described urotropine and water is 1:8 ~ 10.
Preferably, in ammoniacal liquor described in step (1), the mass concentration of ammonia is 25% ~ 28%.
Preferably, be 1:5 ~ 10:0.5 ~ 1 to cyano group halogen benzyl, mol ratio between ammonia and urotropine described in step (1).
Preferably, described in step (1), stirring reaction carries out at 15 ~ 75 DEG C.
Preferably, described in step (1), ammoniacal liquor layer is applied mechanically in the following manner: in described ammoniacal liquor layer, pass into liquefied ammonia, until the mass concentration of ammonia is 9% ~ 10%, add urotropine, be cooled to 5 DEG C, drip cyano group halogen benzyl dissolving solution in organic solvent, subsequent operations is identical with step (1); Preferred, after described ammoniacal liquor layer applies mechanically 2 batches, steam ammoniacal liquor and reclaim, remaining liquid Distillation recovery ammonium chloride.
Preferably, acid described in step (2) is selected from any one in the strong acid such as sulfuric acid, phosphoric acid, nitric acid, preferably sulfuric acid.
Preferably, weight ratio when feeding intake in step (2) between described acid and water is 1:1 ~ 2.
Preferably, described in step (2) acid and be 2 ~ 5:1 to the mol ratio between cyano group halogen benzyl.
Preferably, described in step (2), sour water layer is applied mechanically in the following manner: join in reaction vessel by described sour water layer, the organic solvent layer contained cyano group benzylamine obtained in step (1) is added under agitation condition, be heated to 80 DEG C, stop stirring, stratification, the organic solvent layer on upper strata returns in step (1) to be applied mechanically, the sour water layer of lower floor joins in another reaction vessel, then adds acid, and subsequent operations is identical with step (2); Preferred, after described sour water layer applies mechanically 5 batches, steam Water Sproading ammonium sulfate, remaining liquid continues to apply mechanically.
Preferably, described in step (2), Aminomethylbenzoic Acid is refined in the following manner: by described Aminomethylbenzoic Acid 2.5% ammonia solvent, add gac, stirs, be heated to 75 DEG C, insulation reaction 2h, filtered while hot, filtrate reduced in volume, filter, dry, obtain the Aminomethylbenzoic Acid refined; Described refining need be carried out once, the purity of Aminomethylbenzoic Acid can be made to reach 99.94%.
Preferably, any one in purified water, distilled water, deionized water of wet concentration described in step (1) and (2), preferred purified water.
In a preferred embodiment, the preparation method of a kind of Aminomethylbenzoic Acid of the present invention, it comprises the steps:
(1) to the ammonolysis reaction carried out between cyano group halogen benzyl and ammonia:
In 500mL four-hole bottle, add 300mL toluene and 60g to cyano group benzyl chloride, stirring at room temperature makes dissolving, obtains cyano group benzyl chloride toluene liquid, for subsequent use; 30g urotropine and 270mL purified water is added in 1000mL four-hole bottle, stirring at room temperature makes dissolving, add 135g28% ammoniacal liquor after cryosel bath is cooled to 5 DEG C, then start to drip wherein to cyano group benzyl chloride toluene liquid, in controlling in dropping process, temperature is no more than 15 DEG C, drip off recession deicing salt bath, make interior temperature at 15 ~ 30 DEG C of stirring reaction 3h, heating in water bath to 70 ~ 75 DEG C, insulation reaction 3h, liquid-phase chromatographic analysis, reacts completely to cyano group benzyl chloride; Be cooled to room temperature, stratification, lower batch of the ammonia mother liquid of lower floor is applied mechanically, containing to cyano group benzylamine in the toluene liquid on upper strata, for subsequent use;
(2) to the acid hydrolytic reaction carried out between cyano group benzylamine and acid:
240mL purified water is added in 1000mL four-hole bottle, stir and lower drip 120g sulfuric acid, then add in step (1) obtained to cyano group benzylamine toluene liquid, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step (1) to be applied mechanically, and the sulfuric acid layer of lower floor adds in 500mL four-hole bottle, under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; Until raw material complete reaction, be cooled to 90 DEG C, add 120mL purified water, be cooled to room temperature, then stir 1h, filter the solid of separating out, lower batch of sulfate liquor is applied mechanically; Join in 240mL purified water by the Aminomethylbenzoic Acid sulfate solid of gained, stir lh, drip ammonia neutralization to neutral, be cooled to-5 DEG C, filter, washing is drained, and obtains Aminomethylbenzoic Acid crude product; By described Aminomethylbenzoic Acid crude product 550g2.5% ammonia solvent, add 3g gac, stir, be heated to 75 DEG C, insulation reaction 2h, filtered while hot, after filtrate reduced in volume to about 200g, be cooled to 0 DEG C, filter, dry, obtain the Aminomethylbenzoic Acid that 50g is refining.
Preferably, described in step (1), ammonia mother liquid is applied mechanically in the following manner: in above-mentioned ammonia mother liquid, pass into liquefied ammonia, until the mass concentration of ammonia is 9 ~ 10%, add 30g urotropine, be cooled to 5 DEG C, drip 60g to cyano group benzyl chloride and 300mL toluene, subsequent operations is identical with step (1).
Preferably, described in step (2), sulfate liquor is applied mechanically in the following manner: added by sulfate liquor in 1000mL four-hole bottle, to add in step (1) obtained to cyano group benzylamine toluene liquid under agitation condition, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step (1) to be applied mechanically, the sulfuric acid layer of lower floor joins in 500mL four-hole bottle, then adds 120g50% sulfuric acid, and subsequent operations is identical with step (2).
Due to the utilization of technique scheme, the present invention compared with prior art tool has the following advantages:
1, the method reaction conditions in the present invention is gentle, and raw material is cheap and easy to get, and side reaction is few, easy and simple to handle, and yield is high, is applicable to carrying out large-scale industrial production;
2, under the existence of urotropine, ammonolysis reaction is carried out at a lower temperature smoothly, and product purity is improved, and decreases the generation of secondary amine, tertiary amine and hydroxylated by-products simultaneously, product is more easily refined, only needs a recrystallization can obtain highly purified Aminomethylbenzoic Acid;
3, the plurality of reagents used in method of the present invention all can be applied mechanically repeatedly, greatly saves production cost, has saved the operating time of reaction and aftertreatment, and has reduced production energy consumption.
Accompanying drawing explanation
Fig. 1 is five kinds of synthetic route charts of Aminomethylbenzoic Acid in prior art.
Fig. 2 ~ 4 are the XRD spectra of the Aminomethylbenzoic Acid prepared by different methods, wherein Fig. 2 is the XRD spectra of the Aminomethylbenzoic Acid prepared by five methods (existing technique), Fig. 3 is the XRD spectra of the Aminomethylbenzoic Acid prepared by method of the present invention, and Fig. 4 is the XRD spectra by the standby Aminomethylbenzoic Acid of four legal systems.
Embodiment
Below with reference to the drawings and specific embodiments, further detailed description is made to the present invention.
Embodiment one: the preparation of Aminomethylbenzoic Acid.
1, to the ammonia solution of cyano group benzyl chloride:
React according to the formula recorded in following synthetic route and table:
Synthetic route:
Formula:
Operation:
In 500mL four-hole bottle, add toluene (300mL) and to cyano group benzyl chloride (60g, 0.396mol), stirring at room temperature makes dissolving, obtain cyano group benzyl chloride toluene liquid, for subsequent use; In 1000mL four-hole bottle, add urotropine (30g, 0.214mol) and purified water (270mL), stirring at room temperature makes dissolving, 28% ammoniacal liquor (135g is added after cryosel bath is cooled to 5 DEG C, 2.223mol), then start to drip wherein to cyano group benzyl chloride toluene liquid, in controlling in dropping process, temperature is no more than 15 DEG C, drip off recession deicing salt bath, make interior temperature at 15 ~ 30 DEG C of stirring reaction 3h, heating in water bath to 70 ~ 75 DEG C, insulation reaction 3h, liquid-phase chromatographic analysis, reacts completely to cyano group benzyl chloride; Be cooled to room temperature, stratification, lower batch of the ammonia mother liquid of lower floor is applied mechanically, containing to cyano group benzylamine in the toluene liquid on upper strata, for subsequent use.
The using method of ammonia mother liquid:
In above-mentioned ammonia mother liquid, pass into liquefied ammonia, until the mass concentration of ammonia is 9 ~ 10%, adds urotropine (30g), be cooled to 5 DEG C, drip cyano group benzyl chloride (60g) and toluene (300mL), optional using criticizes Ethylene recov), operation is the same, and reaction is normal.Apply mechanically again once, steam ammoniacal liquor and reclaim, remaining liquid Distillation recovery ammonium chloride.
2, to the acid hydrolysis of cyano group benzylamine:
React according to the formula recorded in following synthetic route and table:
Synthetic route:
Formula:
Operation:
Water (240mL) is added in 1000mL four-hole bottle, drip sulfuric acid (120g) under stirring, then to add in step 1 obtained to cyano group benzylamine toluene liquid, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step 1 to be applied mechanically, and the sulfuric acid layer of lower floor adds in 500mL four-hole bottle, under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; Until raw material complete reaction, be cooled to 90 DEG C, add purified water (120mL), be cooled to room temperature, then stir 1h, filter the solid of separating out, lower batch of sulfate liquor is applied mechanically; Joined by the Aminomethylbenzoic Acid sulfate solid of gained in water (240mL), stir lh, drip ammonia neutralization to neutral, be cooled to-5 DEG C, filter, washing is drained, and obtains Aminomethylbenzoic Acid crude product, claims weight in wet base 84.5 grams, and HPLC detects purity and is about 99.7%; Dissolve with 2.5% ammoniacal liquor (550g), add gac (3g), stir, be heated to 75 DEG C, insulation reaction 2h, filtered while hot, is cooled to 0 DEG C after filtrate reduced in volume to about 200g, filter, dry, obtain 50g solid ammonia toluic acid, HPLC detects purity and is about 99.94%; Lower batch of filtrate is applied mechanically, and steams Water Sproading Aminomethylbenzoic Acid afterwards three times.
The using method of sulfate liquor:
Sulfate liquor is added in 1000mL four-hole bottle, to add in step 1 obtained to cyano group benzylamine toluene liquid under agitation condition, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step 1 to be applied mechanically, and the sulfuric acid layer of lower floor joins in 500mL four-hole bottle, then adds 50% sulfuric acid (120g), under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; Until raw material complete reaction, be cooled to 90 DEG C, add purified water (120mL), be cooled to room temperature, then stir 1h, filter the solid of separating out, lower batch of sulfate liquor is applied mechanically; Apply mechanically 5 batch reactions normal, but mother liquor volume increases, continue to apply mechanically after steaming Water Sproading ammonium sulfate, reaction is normal.
Known by the X-ray single crystal diffraction experiment spectrogram such as shown in Fig. 2 ~ 4, adopt the crystalline structure of the made Aminomethylbenzoic Acid of method of the present invention substantially identical with five methods (existing technique) made Aminomethylbenzoic Acid, method of the present invention can make the crystalline structure of product homogeneous and stable, is a kind of excellent process for the preparation of aminobenzoic acid; By the crystalline structure of the made Aminomethylbenzoic Acid of four methods then Aminomethylbenzoic Acid made with current technology differ very greatly, illustrates in its crystalline network or be doped with other composition, or crystalline network self there occurs change.Comparatively speaking, method of the present invention should be considered as and novel method that performance better completely different with four methods, but not the variant can known by inference easily by four methods.
Embodiment two: the preparation of Aminomethylbenzoic Acid.
Substituting toluene as solvent using dimethylbenzene, take urotropine as catalyzer, and as above ammonolysis reaction operates, and carry out mother liquor from amination and apply mechanically, situation and toluene are that the experimental result of solvent is identical.
Embodiment three: the preparation of Aminomethylbenzoic Acid.
Substituting toluene as solvent using chlorobenzene, take urotropine as catalyzer, and as above ammonolysis reaction operates, result is identical with embodiment two with embodiment one.
Embodiment four: the preparation of Aminomethylbenzoic Acid.
Dissolve cyano group benzyl chloride with toluene, do not add the urotropine as catalyzer, as above ammonolysis reaction operates.HPLC result shows, and being 22% to the content of cyano group benzyl chloride, is 53% to cyano group benzylamine, and secondary amine side products is 22%.
Embodiment five: the preparation of Aminomethylbenzoic Acid.
Dissolve cyano group benzyl chloride with toluene, add the urotropine 15g as catalyzer, as above ammonolysis reaction operates.HPLC result shows, and being 4% to the content of cyano group benzyl chloride, is 89% to cyano group benzylamine, and secondary amine side products is 5%.
Embodiment six: the preparation of Aminomethylbenzoic Acid.
Dissolve cyano group benzyl chloride with toluene, add the urotropine 45g as catalyzer, as above ammonolysis reaction operates, result is identical with embodiment one.
Embodiment seven: the preparation of Aminomethylbenzoic Acid
With 50% phosphoric acid (240g) as hydrating solution, as above acid hydrolytic reaction operates, obtain Aminomethylbenzoic Acid 49.5g, it is 99.92% that HPLC detects purity.
Claims (10)
1. a preparation method for Aminomethylbenzoic Acid, it comprises the steps:
1) to the ammonolysis reaction carried out between cyano group halogen benzyl and ammonia:
In reaction vessel, add organic solvent and to cyano group halogen benzyl, stirring at room temperature makes dissolving, obtain cyano group halogen benzyl solution; Urotropine and water is added in another reaction vessel, stirring at room temperature makes dissolving, cryosel bath cooling, ammoniacal liquor is added after interior temperature drop to 5 DEG C, then drip described to cyano group halogen benzyl solution wherein, in controlling in dropping process, temperature is no more than 15 DEG C, in 10 ~ 80 DEG C of stirring reactions 5 ~ 6 hours after dropwising; After completion of the reaction, be cooled to room temperature, separatory after stratification, ammoniacal liquor layer is waited until down to criticize and is applied mechanically, containing directly dropping into next step acid hydrolytic reaction to the organic solvent layer of cyano group benzylamine:
2) to the acid hydrolytic reaction carried out between cyano group benzylamine and acid:
Water is added in reaction vessel, drip acid under agitation condition, then add the organic solvent layer contained cyano group benzylamine obtained in step 1), be heated to 80 DEG C, stop stirring, separatory after stratification, the organic solvent layer on upper strata returns in step 1) to be applied mechanically, and the sour water layer of lower floor joins in another reaction vessel, under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; After backflow terminates, be cooled to 90 DEG C, add water, be cooled to room temperature, then stir 1h, filter the solid of separating out, sour water layer is waited until down to criticize and is applied mechanically, and is added to the water by filtration gained solid, stirs lh, is neutralized to neutrality, be cooled to-5 DEG C, filter, washing is drained, and obtains Aminomethylbenzoic Acid.
2. preparation method according to claim 1, is characterized in that:
Organic solvent described in step 1) be selected from toluene, dimethylbenzene, chlorobenzene any one;
Be to cyano group benzyl chloride or to cyano-benzyl bromide to cyano group halogen benzyl described in step 1);
Step 2) described in acid be selected from sulfuric acid, phosphoric acid, nitric acid any one;
Step 1) and 2) described in any one in purified water, distilled water, deionized water of wet concentration.
3. preparation method according to claim 2, is characterized in that:
Organic solvent described in step 1) is toluene;
Be to cyano group benzyl chloride to cyano group halogen benzyl described in step 1);
Step 2) described in acid be sulfuric acid;
Step 1) and 2) described in water be purified water.
4. preparation method according to claim 1, is characterized in that:
Described when feeding intake in step 1) is 1g:4 ~ 6mL to the weightmeasurement ratio between cyano group halogen benzyl and organic solvent;
Weight ratio when feeding intake in step 1) between described urotropine and water is 1:8 ~ 10;
In ammoniacal liquor described in step 1), the mass concentration of ammonia is 25% ~ 28%;
Be 1:5 ~ 10:0.5 ~ 1 to cyano group halogen benzyl, mol ratio between ammonia and urotropine described in step 1);
Step 2) in weight ratio when feeding intake between described acid and water be 1:1 ~ 2;
Step 2) described in acid and be 2 ~ 5:1 to the mol ratio between cyano group halogen benzyl.
5. preparation method according to claim 1, it is characterized in that: the layer of ammoniacal liquor described in step 1) is applied mechanically in the following manner: in described ammoniacal liquor layer, pass into liquefied ammonia, until the mass concentration of ammonia is 9% ~ 10%, add urotropine, be cooled to 5 DEG C, drip cyano group halogen benzyl dissolving solution in organic solvent, subsequent operations is identical with step 1).
6. preparation method according to claim 1, it is characterized in that: step 2) described in sour water layer apply mechanically in the following manner: described sour water layer is joined in reaction vessel, the organic solvent layer contained cyano group benzylamine obtained in step 1) is added under agitation condition, be heated to 80 DEG C, stop stirring, stratification, the organic solvent layer on upper strata returns in step 1) to be applied mechanically, the sour water layer of lower floor joins in another reaction vessel, then adds acid, subsequent operations and step 2) identical.
7. preparation method according to claim 1, it is characterized in that: step 2) described in Aminomethylbenzoic Acid refine in the following manner: by described Aminomethylbenzoic Acid 2.5% ammonia solvent, add gac, stir, be heated to 75 DEG C, insulation reaction 2h, filtered while hot, filtrate reduced in volume, filters, dry, obtain the Aminomethylbenzoic Acid refined.
8. preparation method according to claim 1, is characterized in that: described preparation method comprises the steps:
1) to the ammonolysis reaction carried out between cyano group halogen benzyl and ammonia:
In 500mL four-hole bottle, add 300mL toluene and 60g to cyano group benzyl chloride, stirring at room temperature makes dissolving, obtains cyano group benzyl chloride toluene liquid, for subsequent use; 30g urotropine and 270mL purified water is added in 1000mL four-hole bottle, stirring at room temperature makes dissolving, add 135g28% ammoniacal liquor after cryosel bath is cooled to 5 DEG C, then start to drip wherein to cyano group benzyl chloride toluene liquid, in controlling in dropping process, temperature is no more than 15 DEG C, drip off recession deicing salt bath, make interior temperature at 15 ~ 30 DEG C of stirring reaction 3h, heating in water bath to 70 ~ 75 DEG C, insulation reaction 3h, liquid-phase chromatographic analysis, reacts completely to cyano group benzyl chloride; Be cooled to room temperature, stratification, lower batch of the ammonia mother liquid of lower floor is applied mechanically, containing to cyano group benzylamine in the toluene liquid on upper strata, for subsequent use;
2) to the acid hydrolytic reaction carried out between cyano group benzylamine and acid:
240mL purified water is added in 1000mL four-hole bottle, stir and lower drip 120g sulfuric acid, then add in step 1) obtained to cyano group benzylamine toluene liquid, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step 1) to be applied mechanically, and the sulfuric acid layer of lower floor adds in 500mL four-hole bottle, under agitation condition, water is steamed in heating, treat that interior temperature arrives 120 DEG C, stop steaming water, insulation backflow 4h; Until raw material complete reaction, be cooled to 90 DEG C, add 120mL purified water, be cooled to room temperature, then stir 1h, filter the solid of separating out, lower batch of sulfate liquor is applied mechanically; Join in 240mL purified water by the Aminomethylbenzoic Acid sulfate solid of gained, stir lh, drip ammonia neutralization to neutral, be cooled to-5 DEG C, filter, washing is drained, and obtains Aminomethylbenzoic Acid crude product; By described Aminomethylbenzoic Acid crude product 550g2.5% ammonia solvent, add 3g gac, stir, be heated to 75 DEG C, insulation reaction 2h, filtered while hot, after filtrate reduced in volume to about 200g, be cooled to 0 DEG C, filter, dry, obtain the Aminomethylbenzoic Acid that 50g is refining.
9. preparation method according to claim 8, it is characterized in that: described in step 1), ammonia mother liquid is applied mechanically in the following manner: in above-mentioned ammonia mother liquid, pass into liquefied ammonia, until the mass concentration of ammonia is 9 ~ 10%, add 30g urotropine, be cooled to 5 DEG C, drip 60g to cyano group benzyl chloride and 300mL toluene, subsequent operations is identical with step 1).
10. preparation method according to claim 8, it is characterized in that: step 2) described in sulfate liquor apply mechanically in the following manner: sulfate liquor is added in 1000mL four-hole bottle, to add in step 1) obtained to cyano group benzylamine toluene liquid under agitation condition, be heated to 80 DEG C, stop stirring, stratification, the toluene layer on upper strata returns in step 1) to be applied mechanically, the sulfuric acid layer of lower floor joins in 500mL four-hole bottle, then adds 120g50% sulfuric acid, subsequent operations and step 2) identical.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105929098A (en) * | 2016-06-30 | 2016-09-07 | 湖南洞庭药业股份有限公司 | Aminomethylbenzoic acid and injection composition and quality control method thereof |
| CN108689870A (en) * | 2018-07-30 | 2018-10-23 | 周道平 | A kind of preparation method of tranexamic acid |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
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| CN108689870A (en) * | 2018-07-30 | 2018-10-23 | 周道平 | A kind of preparation method of tranexamic acid |
| CN108689870B (en) * | 2018-07-30 | 2020-12-18 | 周道平 | Preparation method of tranexamic acid |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
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