CN104418808A - Method for preparing intermediate Buzolic acid suitable for industrial production - Google Patents
Method for preparing intermediate Buzolic acid suitable for industrial production Download PDFInfo
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention relates to a method for preparing an intermediate Buzolic acid (2,3-dihydro-2-oxygen-1H-benzimidazole-1-butyric acid) suitable for industrial production. According to the method, with o-phenylenediamine and ethyl acetoacetate as initial raw materials, Buzolic acid is prepared by cyclization, condensation, saponification and deprotection reaction. The method is cheap and available in initial raw material, simple in technological operation, mild in reaction condition, and free of equipment for special reaction. A to-be-separated compound is not required in the preparation process; and a concentrated solvent is not required in condensation, saponification and deprotection reaction, or is replaced with other reaction solvents to be directly subjected to next step of reaction or operation, thus direct continuous feeding is achieved, and energy consumption is reduced. In addition, the yield and the purity of a reaction product in each step can be further improved through simple treatment such as devitrification, watering and pulping; high yield is achieved by through a low-cost solvent, namely water; and the method is environmentallyfriendly, economical, practical and very suitable for industrial production.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly, the present invention relates to a kind of preparation method being suitable for the intermediate B uzolicacid of suitability for industrialized production.
Background technology
Buzolic acid(CAS:3273-68-5), chemical name: 2-oxo-1-Benzimidazolinebutyric acid is the key intermediate of zilpaterol (Zilpaterol).
Zilpaterol (Zilpaterol) is β 2 adrenaline excitant with following structure:
CAS：117827-79-9
Beta 2-adrenergic agonist is the common growth stimulant of a class.When this type of material is used in animal cultivation, can feed conversion rate be increased, improve the ratio of muscle and fat in tissue.In the country such as Mexico and South Africa, the fodder additives that zilpaterol is allowed to as slaughtering phase ox uses.US Patent No. 4585770 discloses the Animal husbandry composition of the trans zilpaterol of racemize and salt thereof, and it may be used for increasing warm-blooded animal and comprises ox, the body weight of pig and poultry and meat quality.U.S. Patent Application Publication No. US2005/0284380 describes ionophore/macrolide/zilpaterol dosage regimen to be increased beef production, reducing feed picked-up, is maintaining beef production simultaneously and reduce the application in beef liver abscess sickness rate.
On the other hand, because zilpaterol can cause sympathomimetic nerve excited, the beta 2 receptor of the exciting respiratory tract of selectivity, causes lax bronchial smooth muscle, reduces vascular permeability, play antiasthmatic effect.The beta 2 receptor of the exciting cardiac muscle of all right selectivity, conducting system and sinus node, strengthens cardiac contractility, accelerates to conduct, accelerates heart rate, improve the excitability of cardiac muscle.Therefore clinical treatment asthma and heart trouble has been widely used in.
The preparation method of zilpaterol and salt thereof is well known in the art.Such as, describe in US Patent No. 4585770 and be characterized as 6-amino-7-hydroxyl-4,5,6,7-tetrahydro-imidazo also [4,5,1-jk] compound (and salt) that comprises of [1]-benzazepines-2 [1H]-one derivative and pharmaceutically acceptable acid salt kind thereof.
This derivative is structurally equivalent to:
r can be various substituting group herein, and wave-like line represents that bonding that is amino with 6-and 7-OH has transconfiguration.This type comprises the trans zilpaterol of racemize, and now R is sec.-propyl.
Applicant research finds, take O-Phenylene Diamine as starting raw material, to zilpaterol intermediate B uzolic acid [i.e. 4-(2-oxo-2,3-dihydrobenzo imidazoles-1-base) butyric acid] preparation method improve, obtain a kind of newly be suitable for suitability for industrialized production, environmental protection, economical and practical preparation method.
Summary of the invention
The present invention completes based on the following discovery of contriver:
It is the acid salt that HCl is mixed with zilpaterol that international monopoly WO2008119754 discusses by what use method well known in the art free alkali and mineral acid or organic acid to be enumerated especially.Buzolic acid is as key intermediate, participates in reaction.Its synthetic route is as follows:
US Patent No. 4585770 discloses Buzolic acid(and 2-oxo-1-Benzimidazolinebutyric acid) preparation method as follows:
(1) with 1,3-dihydro-1-(1-methyl ethylene)-2H-2-ketone benzimidaozole for starting raw material, synthetic compound 2,3-dihydro-3-(pseudoallyl)-2-oxygen-1H-benzoglyoxaline-1-ethyl butyrate, operational path is as follows:
(2) synthetic compound 2-oxo-1-Benzimidazolinebutyric acid ethyl ester, operational path is as follows:
(3) synthetic compound 2-oxo-1-Benzimidazolinebutyric acid, operational path is as follows:
The shortcoming of this method is: reactions steps is many, and the three wastes of generation are many, total recovery only 63%, uses sodium hydride in the first step reaction, because it can spontaneous combustion in damp atmosphere; Be heated or contact with moisture, acids and namely release heat and hydrogen, cause burning and blast; Can with oxygenant generation kickback, cause burning and blast; Meet the oxyhydroxide that moisture content is raw, be corrosive.Therefore very inconvenient for suitability for industrialized production, to equipment and operational requirement harshness, the easy contaminate environment of the three wastes.
Chinese patent CN102603650 is optimized based on this, with 1,3-dihydro-1-(1-methyl ethylene)-2H-2-ketone benzimidaozole is starting raw material, finished product is prepared through dehydration reaction, phase of point anhydrating, saponification reaction, aftertreatment, it is compared with technology before, got rid of sodium hydride, emphasis eliminates safe hidden trouble and three-waste pollution problem.Its synthetic route is as follows:
Often walk in the method after reaction terminates and need distillation and concentration, the reaction solvent more renewed.Distillation and concentration need increase production energy consumption, and the reaction solvent simultaneously more renewed, need increase the raw materials cost of technique.
The present invention is intended to solve one of above technical problem at least to a certain extent or at least provide a kind of useful business to select.
According to embodiments of the invention, the present invention proposes a kind of preparation method being suitable for the intermediate B uzolic acid of suitability for industrialized production newly.According to embodiments of the invention; this intermediate B uzolic acid(that is 2; 3-dihydro-2-oxygen-1H-benzoglyoxaline-1-butyric acid; represent with BUZ below) preparation method with O-Phenylene Diamine (representing with BUZ-A below) and methyl aceto acetate (representing with BUZ-B below) for starting raw material; through cyclization, condensation, saponification, deprotection reaction, prepare Buzolic acid.
Prepare the method for intermediate B uzolic acid according to an embodiment of the invention, provide the synthetic route and preparation method that are more suitable for suitability for industrialized production, this synthetic route has no bibliographical information.The starting raw material of the method is cheap and easy to get, and technological operation is simple, and reaction conditions is gentle, does not need the equipment of special reaction; Do not need the compound be separated in preparation process, condensation, saponification and deprotection reaction do not need concentrated solvent or are replaced by other reaction solvents and directly carry out next step reaction or operation, realize direct continuous dosing, reduce energy consumption.In addition, by crystallization, add water the simple process such as making beating, can further improve yield and the purity of each step reactor product, realize high yield by this low cost solvent of water, environmental protection, economical and practical, is very suitable for suitability for industrialized production.
According to embodiments of the invention, this method preparing Buzolic acid comprises the following steps:
BUZ-A and BUZ-B, through ring-closure reaction, obtains 1,3-dihydro-1-(1-methyl ethylene)-2H-2-ketone benzimidaozole (representing with BUZ-C);
BUZ-C and 4-bromobutyrate, through condensation reaction, obtains 2,3-dihydro-3-(pseudoallyl)-2-oxygen-1H-benzoglyoxaline-1-ethyl butyrate (representing with BUZ-D);
BUZ-D, through saponification reaction, obtains 2,3-dihydro-3-(pseudoallyl)-2-oxygen-1H-benzoglyoxaline-1-butyric acid (representing with BUZ-E);
BUZ-E sloughs pseudoallyl, finally obtains Buzolic acid(and 2-oxo-1-Benzimidazolinebutyric acid, represents with BUZ).
Particularly, Buzolic acid(BUZ of the present invention) synthetic route as follows:
With reference to this synthetic route, the method for synthesis Buzolic acid according to a particular embodiment of the invention comprises:
(1) ring-closure reaction
Stir in dimethylbenzene and add starting raw material O-Phenylene Diamine BUZ-A, heat temperature raising, methyl aceto acetate BUZ-B is dripped with molar ratio 1:1.0 ~ 1:5.0, time for adding is 2 ~ 5h, and dropwise and follow-up continuing be warmed up to 120 ~ 150 DEG C of reactions, the reaction times is 1 ~ 5h, reaction solution is concentrated, add non-polar solvent stirring and crystallizing, suction filtration, obtain BUZ-C;
(2) condensation reaction
In described BUZ-C, add the polar aprotic solvent of 1 ~ 4 times of volume, then add the mineral alkali of 0.5 ~ 2 mol ratio, be warming up to 100 ~ 150 DEG C, drip 4-bromobutyrate, BUZ-C and its mol ratio are 1:0.8 ~ 1:4.0, and time for adding is 2 ~ 20h, and reaction 0.5 ~ 8h obtains BUZ-D;
(3) saponification reaction
Without the need to aftertreatment after upper step reaction, the system containing described BUZ-D is lowered the temperature, drips mineral alkali/aqueous solution, carry out saponification reaction, obtain BUZ-E;
(4) deprotection reaction
System containing described BUZ-E is cooled to-10 ~ 25 DEG C, and the chemically acceptable acid of agitation and dropping 2 ~ 10 times of volumes, dropwises rear stirring 0.5 ~ 3h, then 15 ~ 50 DEG C of reaction 1 ~ 8h that rise again, and obtains BUZ.
In addition, according to embodiments of the invention, in above-mentioned step (1), O-Phenylene Diamine (BUZ-A) can be 1:1.0 ~ 1:5.0 with the molar ratio of methyl aceto acetate (BUZ-B), and time for adding can be 2 ~ 5h.After heating up, temperature of reaction can be 120 ~ 150 DEG C, and the reaction times can be 1 ~ 5h.The solvent of stirred crystallization can be non-polar solvent, as alkanes organic solvent.According to a particular embodiment of the invention, in above-mentioned step (1), described non-polar organic solvent is be selected from hexane, pentane, heptane, octane or its isomer alkane or contain the mixed alkanes of its composition, at least one of methyl tertiary butyl ether, and described non-polar organic solvent is preferably selected from least one in sherwood oil, hexane, heptane.
According to a particular embodiment of the invention, in above-mentioned step (1), reaction solution can be concentrated into 1.0 ~ 5.0 volumes of starting material O-Phenylene Diamine, non-polar solvent is its 2 ~ 10 times of volumes, whipping temp can be 10 ~ 30 DEG C, the crystallization time can be 0.5 ~ 4h, suction filtration, and filter cake can with the non-polar solvent drip washing of 0.3 ~ 2 times of volume.
According to embodiments of the invention, in above-mentioned step (2), described polar aprotic solvent is be selected from least one in DMF, DMSO, acetone, and preferred described polar aprotic solvent is DMF.
According to embodiments of the invention, in above-mentioned step (2), polar aprotic solvent can be 1 ~ 4 times of volume of BUZ-C, according to embodiments of the invention, in above-mentioned step (2), BUZ-C and mineral alkali mol ratio can be the time for adding of 1:0.5 ~ 1:2.0,4-bromobutyrate be 2 ~ 20h, be preferably 6 ~ 18h.The mol ratio of BUZ-C and 4-bromobutyrate can be 1:0.8 ~ 1:4.0, is preferably 1:1.0 ~ 1:2.0, most preferably is 1:1.1 ~ 1.3.Reaction times can be 0.5 ~ 8h, and temperature of reaction can be 100 ~ 150 DEG C.According to a particular embodiment of the invention, in above-mentioned step (2),
According to embodiments of the invention, described mineral alkali is at least one being selected from the oxyhydroxide of basic metal or alkaline-earth metal, carbonate or supercarbonate, and described mineral alkali is preferably selected from least one in sodium hydroxide, salt of wormwood, sodium bicarbonate.
According to embodiments of the invention, in above-mentioned step (3), the mol ratio of BUZ-D and mineral alkali can be 1:0.5 ~ 1:6, and mineral alkali/water concentration range is 10% ~ 50%(m/v).Churning time can be 0.5 ~ 3h, and temperature of reaction can be 20 ~ 40 DEG C, and the reaction times can be 3 ~ 8h.
According to embodiments of the invention, in above-mentioned step (4), chemically acceptable acid can be 2 ~ 10 times of volumes of BUZ-E, after dripping, churning time can be 0.5 ~ 3.0h, according to embodiments of the invention, in above-mentioned step (4), temperature of reaction can be 15 ~ 50 DEG C, and the reaction times can be 1 ~ 8h.According to a particular embodiment of the invention, in above-mentioned step (4), described chemically acceptable acid is for being selected from hydrochloric acid, sulfuric acid, acetic acid, citric acid, 2, at least one in 5-resorcylic acid, Hydrogen bromide, described chemically acceptable acid is preferably selected from least one in hydrochloric acid, sulfuric acid.
In another aspect of this invention, the present invention proposes the more optimal method that one prepares Buzolic acid (BUZ).With reference to synthetic route of the present invention proposed above, according to embodiments of the invention, the method comprises: (I) ring-closure reaction, identical with the step of non-polar solvent stirring and crystallizing with the ring-closure reaction of (1), obtains BUZ-C.With the dissolve with methanol of 1 ~ 8 times of volume, then drip the water of 2 ~ 10 times of volumes, stirring and crystallizing 0.5 ~ 4h, suction filtration, filter cake water wash, drying obtains purer BUZ-C; (II) dehydration reaction is identical with (2), obtains BUZ-D; (III) reduction reaction is identical with (3), obtains BUZ-E; After (IV) adopts (4) deprotection reaction to obtain BUZ, drip the water of 3 ~ 10 times of volumes, at 10 ~ 60 DEG C of stirring and crystallizing 0.5 ~ 5h, suction filtration, after filter cake water wash, is directly warming up to 40 ~ 100 DEG C of making beating, then is cooled to 20 ~ 80 DEG C of filtrations, obtain BUZ sterling.Or dry after filter cake water wash, add the water of 4 ~ 10 times of volumes, to 10 ~ 90 DEG C of making beating, then be cooled to 20 ~ 80 DEG C of filtrations, obtain purer BUZ.
In still another aspect of the invention, the present invention proposes the more optimal method that one prepares Buzolic acid (BUZ).With reference to synthetic route of the present invention proposed above, according to embodiments of the invention, the method comprises: (a) adopts the ring-closure reaction of (1) or (I), obtains BUZ-C; B () condensation reaction is identical with (2), obtain BUZ-D; C () saponification reaction is identical with (3), obtain BUZ-E; D () adopts (4) deprotection reaction to obtain BUZ after; the water of 3 ~ 10 times of volumes can be dripped; at 10 ~ 60 DEG C of stirring and crystallizing 0.5 ~ 5h, suction filtration, after filter cake water wash; dry; clarified by dissolving crude product with mineral alkali/aqueous solution, then add the immiscible non-polar organic solvent with water, impurity is fallen in extraction; regulate aqueous pH values, obtain purer BUZ.
According to embodiments of the invention, in above-mentioned step (d), described mineral alkali/aqueous solution usage quantity is fixed according to aqueous solution pH, and institute regulates aqueous pH values to be 1 ~ 7, and preferably 3 ~ 4.
According to embodiments of the invention, described nonpolar class organic solvent is be selected from hexane, pentane, heptane, octane or its isomer alkane or contain the mixed alkanes of its composition, at least one of methyl tertiary butyl ether, and preferred described nonpolar class organic solvent is be selected from the one in sherwood oil, hexane, heptane.
According to embodiments of the invention, described mineral alkali is at least one being selected from the oxyhydroxide of basic metal or alkaline-earth metal, carbonate or supercarbonate, and preferred described mineral alkali is be selected from least one in sodium hydroxide, salt of wormwood, sodium bicarbonate.
Thus, according to embodiments of the invention, the present invention proposes a kind of preparation method being suitable for the intermediate B uzolic acid of suitability for industrialized production, the method at least has one of following advantages:
1, bibliographical information is had no according to the synthetic route preparing the method for intermediate B uzolic acid of the embodiment of the present invention.
2, be easy to get according to the raw material preparing the method for intermediate B uzolic acid of the embodiment of the present invention, technological operation is simple, and reaction conditions is gentle, does not need the equipment of special reaction.
3, according to the method preparing intermediate B uzolic acid of the embodiment of the present invention; the compound be separated is not needed in preparation process; condensation, saponification and deprotection reaction do not need concentrated solvent or are replaced by other reaction solvents and directly carry out next step reaction or operation; realize direct continuous dosing, reduce energy consumption.
4, according to the method preparing intermediate B uzolic acid of the embodiment of the present invention, after de-pseudoallyl obtains BUZ crude product, by crystallization, add water the simple process such as making beating, can further improve yield and the purity of each step reactor product, high yield is realized by this low cost solvent of water, environmental protection, economical and practical, be very suitable for suitability for industrialized production.
5, according to the method preparing intermediate B uzolic acid of the embodiment of the present invention, starting raw material used and most of reagent all can be bought from market, low price, and input cost is low, are applicable to suitability for industrialized production.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Accompanying drawing explanation
Product purity HPLC spectrogram after Fig. 1: BUZ-C purifying;
Fig. 2: BUZ product purity HPLC spectrogram;
Fig. 3: BUZ-C reference substance HPLC spectrogram;
Fig. 4: BUZ reference substance HPLC spectrogram;
The route of Fig. 5: BUZ synthetic method.
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to text or the synthesis of known method, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
Embodiment 1
Step (1) ring-closure reaction:
In the 500mL there-necked flask of drying, add 420mL dimethylbenzene, under stirring, add O-Phenylene Diamine (108g, 1.0mol), heat to 120 DEG C, drip methyl aceto acetate (143g, 1.1mol), divide with water trap phase of anhydrating simultaneously.About 3h dropwises, then is warmed up to 130 DEG C of reactions, 3h start sampling, to raw material primitive reaction complete (HPLC≤0.5%) and double sampling product purity change≤2%, total reaction time is 4h.System is concentrated into about 1.5 volumes, in reaction system, adds 600mL sherwood oil, after, by system at 20 DEG C of stirring and crystallizing 2h, suction filtration, the drip washing of 50mL sherwood oil used again by filter cake, dry 148gBUZ-C solid, yield 85%.
Embodiment 2
Step (1) ring-closure reaction:
In the 500mL there-necked flask of drying, add 420mL dimethylbenzene, under stirring, add O-Phenylene Diamine (108g, 1.0mol), heat to 100 DEG C, drip methyl aceto acetate (651g, 5.0mol), divide with water trap phase of anhydrating simultaneously.About 5h dropwises, then is warmed up to 150 DEG C of reactions, 3h start sampling, to raw material primitive reaction complete (HPLC≤0.5%) and double sampling product purity change≤2%, total reaction time is 5h.System is concentrated into about 5 volumes, in reaction system, adds 2000mL hexane, after, by system at 30 DEG C of stirring and crystallizing 4h, suction filtration, 200mL hexane used again by filter cake, dry 152gBUZ-C solid, yield 87%.
320mL(4 times of volume is added in 1L there-necked flask) methyl alcohol, 80g reacts the crude product taken, after, system is stirred to CL at 20 ~ 30 DEG C, drip 320ml(4 times of volume again) tap water, stirring and crystallizing 2h, suction filtration, filter cake uses 40mL(0.5vol again) tap water drip washing, dry BUZ-C solid 59g (KF≤0.5%).Detect purity with HPLC and reach 99%, total recovery is 64%.
Embodiment 3
Step (1) ring-closure reaction:
In 500L enamel reaction still, add 30.5L dimethylbenzene, under stirring, add O-Phenylene Diamine (10.8kg, 100mol), heat to 100 DEG C, drip methyl aceto acetate (15.6kg, 120mol), about 5h dropwises, be warmed up to 150 DEG C of reactions again, 3h start sampling, to raw material primitive reaction complete (HPLC≤0.5%) and double sampling product purity change≤2%, total reaction time is 4h.System is concentrated into about 3 volumes, in reaction system, adds 20L sherwood oil and hexane mixed solvent (v:v=1:1), after, by system at 30 DEG C of stirring and crystallizing 3h, suction filtration, the drip washing of 15L sherwood oil used again by filter cake, dry 15.3kg BUZ-C solid, yield 88%.
Embodiment 4
Step (2) condensation reaction:
In the 500mL there-necked flask of drying, add the 148g(0.8mol of embodiment 1 gained) BUZ-C and 300mLDMF, then add salt of wormwood (176g, 1.3mol).Be warmed up to 125 DEG C, drip 4-bromobutyrate (182g, 0.9mol), time for adding is 8h.Dropwise rear reaction 4h, obtain BUZ-D.System purity detects starting material left through HPLC and is less than 1%, and system, without the need to being separated, directly drops into next step saponification reaction.
Embodiment 5
Step (2) condensation reaction:
In the 500mL there-necked flask of drying, add the 152g(0.87mol of embodiment 2 gained) BUZ-C and 304mLDMF, then add salt of wormwood (181g, 1.3mol).Be warmed up to 100 DEG C, drip 4-bromobutyrate (220g, 1.13mol), time for adding is 2h.Dropwise rear 130 DEG C of reaction 2h, obtain BUZ-D.System purity detects starting material left through HPLC and is less than 1%, and system, without the need to being separated, directly drops into next step saponification reaction.
Embodiment 6
Step (2) condensation reaction:
In the 500mL there-necked flask of drying, add 70g(0.4mol) BUZ-C and 140mLDMF, then add salt of wormwood (83.2g, 0.6mol).Be warmed up to 100 DEG C, drip 4-bromobutyrate (124.8g, 0.64mol), time for adding is 2h.Dropwise rear 130 DEG C of reaction 2h, obtain BUZ-D.System purity detects starting material left through HPLC and is less than 1%, and system, without the need to being separated, directly drops into next step saponification reaction.
Embodiment 7
Step (2) condensation reaction:
In 500L enamel still, add the 15.3Kg(87.4mol of embodiment 3 gained) BUZ-C and 30.6Kg DMF, then add salt of wormwood (17.7Kg, 131mol).Be warmed up to 100 DEG C, drip 4-bromobutyrate (22.2Kg, 113.7mol), time for adding is 10h.Dropwise rear 130 DEG C of reaction 2h, obtain BUZ-D.System purity detects starting material left is less than 1% through HPLC, and system, without the need to being separated, directly drops into next step saponification reaction.
Embodiment 8
Step (3) saponification reaction:
Example 5 gained reaction solution is cooled to 10 DEG C, sodium hydroxide (48.3g sodium hydroxide the is dissolved in 98mL water) aqueous solution is dripped under stirring, dropwise at stirring 30min, to rise again again 40 DEG C of reactions, 1h starts sampling, to raw material primitive reaction complete (HPLC≤0.5%), total reaction time is 5h, obtains BUZ-E.System purity detects through HPLC and reaches 93%.
Embodiment 9
Step (3) saponification reaction:
Example 7 gained reaction solution is cooled to 10 DEG C, (48.3kg sodium hydroxide is dissolved in 98kg water to drip sodium hydroxide under stirring, be chilled to room temperature for subsequent use) aqueous solution, dropwise at stirring 30min, rise again 40 DEG C of reactions, 1h starts sampling, to raw material primitive reaction complete (HPLC≤0.5%) again, total reaction time is 5h, obtains BUZ-E.System purity detects through HPLC and reaches 93%.
Embodiment 10
Step (4) deprotection reaction:
The reaction solution of example 8 gained is cooled to-10 DEG C, under stirring, drips aqueous sulfuric acid (the 131mL vitriol oil is dissolved in 131mL water).During dropwise reaction, heat release venting obviously, needs to carry out emptying.Dropwise and stir 30min at 0 DEG C, then 30 DEG C of reactions of rising again, 4h starts sampling, to raw material primitive reaction complete (HPLC≤0.5%).Total reaction time is 5h.Obtain BUZ crude product, purity is 93%, second, and three, four step total recoverys are 85%.
Embodiment 11
Step (4) deprotection reaction:
The reaction solution of example 9 gained is transferred to the enamel still of a 1000L, system is cooled to-10 DEG C, under stirring, drip aqueous sulfuric acid (the 131kg vitriol oil is dissolved in 131kg water, is chilled to room temperature for subsequent use).During dropwise reaction, heat release venting obviously, needs to carry out emptying.Dropwise and stir 30min at 0 DEG C, then 30 DEG C of reactions of rising again, 4h starts sampling, to raw material primitive reaction complete (HPLC≤0.5%).Total reaction time is 5h.BUZ crude product 77kg, purity is 95%, (2), (3), (4) step total recovery are 87%.
Embodiment 12
The purifying of BUZ crude product:
Add in 1000L reactor in 77kgBUZ crude product and drip 385kg water, drip the 2M sodium hydroxide aqueous solution again to dissolution of solid, add 205kg dichloromethane extraction, after leaving standstill separatory, aqueous phase regulates PH to 3 ~ 4 with 2M dilute hydrochloric acid again, stirring and crystallizing 1 ~ 2h, suction filtration, 308 kg water drip washing used again by filter cake.Filter cake is transferred to air dry oven at 40 ~ 50 DEG C of dry solid 67kg (KF≤0.5%), is the BUZ that purity is higher.Purity is greater than 98.5%, and purification yield is 85%.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (10)
1. be suitable for a preparation method of the intermediate B uzolic acid of suitability for industrialized production, it is characterized in that: with O-Phenylene Diamine and methyl aceto acetate for starting raw material, the synthetic route of described method is:
Wherein, described method comprises:
(1) ring-closure reaction
Stir in dimethylbenzene and add starting raw material O-Phenylene Diamine (BUZ-A), heat temperature raising, methyl aceto acetate (BUZ-B) is dripped with molar ratio 1:1.0 ~ 1:5.0, time for adding is 2 ~ 5h, and dropwise and follow-up continuing be warmed up to 120 ~ 150 DEG C of reactions, the reaction times is 1 ~ 5h, reaction solution is concentrated, add non-polar solvent stirring and crystallizing, suction filtration, obtain BUZ-C;
(2) condensation reaction
In described BUZ-C, add the polar aprotic solvent of 1 ~ 4 times of volume, then add the mineral alkali of 0.5 ~ 2 mol ratio, be warming up to 100 ~ 150 DEG C, drip 4-bromobutyrate, BUZ-C and its mol ratio are 1:0.8 ~ 1:4.0, and time for adding is 2 ~ 20h, and reaction 0.5 ~ 8h obtains BUZ-D;
(3) saponification reaction
Without the need to aftertreatment after upper step reaction, the system containing described BUZ-D is lowered the temperature, drips mineral alkali/aqueous solution, carry out saponification reaction, obtain BUZ-E; Without the need to process after upper step reaction, system containing described BUZ-D is cooled to-5 ~ 15 DEG C, mineral alkali/the aqueous solution of agitation and dropping 0.5 ~ 6 mol ratio, mineral alkali/water concentration range is 10% ~ 50%(m/v), dropwise rear stirring 0.5 ~ 3h, rise again 20 ~ 40 DEG C of reactions, reaction 3 ~ 8h, obtains BUZ-E again;
(4) deprotection reaction
System containing described BUZ-E is cooled to-10 ~ 25 DEG C, and the chemically acceptable acid of agitation and dropping 2 ~ 10 times of volumes, dropwises rear stirring 0.5 ~ 3h, then 15 ~ 50 DEG C of reaction 1 ~ 8h that rise again, and obtains BUZ.
2. method according to claim 1, it is characterized in that: non-polar solvent described in step (1) is be selected from hexane, pentane, heptane, octane or its isomer alkane or contain the mixed alkanes of its composition, at least one of methyl tertiary butyl ether, and preferred described non-polar solvent is be selected from least one in sherwood oil, hexane, heptane; Described in step (2), polar aprotic solvent is be selected from least one in DMF, DMSO, acetone, and preferred described polar aprotic solvent is DMF.
3. method according to claim 1, it is characterized in that: in step (1), reaction solution is concentrated into 1.0 ~ 5.0 volumes of starting material O-Phenylene Diamine, non-polar solvent is its 2 ~ 10 times of volumes, whipping temp is 10 ~ 30 DEG C, the crystallization time is 0.5 ~ 4h, suction filtration, the filter cake non-polar solvent drip washing of 0.3 ~ 2 times of volume.
4. method according to claim 1, is characterized in that: in step (2), and the mol ratio of described BUZ-C and 4-bromobutyrate is preferably 1:1.0 ~ 1:2.0, most preferably is 1:1.1 ~ 1.3, and the time dripping 4-bromobutyrate is preferably 6 ~ 18h.
5. method according to claim 1, it is characterized in that: described mineral alkali is at least one being selected from the oxyhydroxide of basic metal or alkaline-earth metal, carbonate or supercarbonate, and described mineral alkali is preferably selected from least one in sodium hydroxide, salt of wormwood, sodium bicarbonate; Described chemically acceptable acid is for being selected from least one in hydrochloric acid, sulfuric acid, acetic acid, citric acid, DHB, Hydrogen bromide, and preferably, chemically acceptable acid is for being selected from least one in hydrochloric acid, sulfuric acid.
6. method according to claim 1, is characterized in that: the BUZ-C that the ring-closure reaction of step (1) obtains with the dissolve with methanol of 1 ~ 8 times of volume, then can drip the water of 2 ~ 10 times of volumes, stirring and crystallizing 0.5 ~ 4h, suction filtration, filter cake water wash, dry purer BUZ-C.
7. method according to claim 1; it is characterized in that: after step (4) deprotection reaction obtains BUZ; the water of 3 ~ 10 times of volumes can be dripped; at 10 ~ 60 DEG C of stirring and crystallizing 0.5 ~ 5h; suction filtration, after filter cake water wash, is directly warming up to 40 ~ 100 DEG C of making beating; be cooled to 20 ~ 80 DEG C of filtrations again, obtain purer BUZ.
8. method according to claim 1; it is characterized in that: after step (4) deprotection reaction obtains BUZ; the water of 3 ~ 10 times of volumes can be dripped, at 10 ~ 60 DEG C of stirring and crystallizing 0.5 ~ 5h, suction filtration; filter cake water wash; drying, adds the water of 4 ~ 10 times of volumes, to 10 ~ 90 DEG C of making beating; be cooled to 20 ~ 80 DEG C of filtrations again, obtain purer BUZ.
9. method according to claim 1; it is characterized in that: after step (4) deprotection reaction obtains BUZ, the water of 3 ~ 10 times of volumes can be dripped, at 10 ~ 60 DEG C of stirring and crystallizing 0.5 ~ 5h; suction filtration; after filter cake water wash, dry, with mineral alkali/aqueous solution, dissolving crude product is clarified; add the immiscible non-polar organic solvent with water again; impurity is fallen in extraction, regulates aqueous pH values, obtains purer BUZ.
10. method according to claim 9, is characterized in that: described mineral alkali/aqueous solution usage quantity is determined according to aqueous solution pH, regulate aqueous pH values to be 1 ~ 7, be preferably 3 ~ 4.
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| CN113200922A (en) * | 2021-05-17 | 2021-08-03 | 上海红象生物医药科技有限公司 | Process for preparing 2, 3-dihydro-2-oxo-1H-benzimidazole-1-butyric acid |
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