CN103896729A - Method for preparing 4-dichlorodiphenylmethane - Google Patents
Method for preparing 4-dichlorodiphenylmethane Download PDFInfo
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- chlorobenzophenone
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- UGVRJVHOJNYEHR-UHFFFAOYSA-N 4-chlorobenzophenone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1=CC=CC=C1 UGVRJVHOJNYEHR-UHFFFAOYSA-N 0.000 claims abstract description 23
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011591 potassium Substances 0.000 claims abstract description 16
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 16
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 11
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- -1 4-chlorodiphenyl methyl alcohol Chemical compound 0.000 claims description 27
- 238000009835 boiling Methods 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- GSSJSUKUYXXPME-UHFFFAOYSA-N benzene;chloromethane Chemical compound ClC.C1=CC=CC=C1 GSSJSUKUYXXPME-UHFFFAOYSA-N 0.000 claims description 15
- 238000005660 chlorination reaction Methods 0.000 claims description 15
- 238000006722 reduction reaction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 2
- AJYOOHCNOXWTKJ-UHFFFAOYSA-N p-Chlorobenzhydrol Chemical compound C=1C=C(Cl)C=CC=1C(O)C1=CC=CC=C1 AJYOOHCNOXWTKJ-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 238000003756 stirring Methods 0.000 description 22
- 235000011167 hydrochloric acid Nutrition 0.000 description 14
- 230000009466 transformation Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 12
- 229940050176 methyl chloride Drugs 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- VCTHNOIYJIXQLV-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine;hydron;dichloride Chemical compound Cl.Cl.CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 VCTHNOIYJIXQLV-UHFFFAOYSA-N 0.000 description 2
- ALKWTKGPKKAZMN-UHFFFAOYSA-N 1-chloro-4-[chloro(phenyl)methyl]benzene Chemical compound C=1C=C(Cl)C=CC=1C(Cl)C1=CC=CC=C1 ALKWTKGPKKAZMN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000012965 benzophenone Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000011208 chromatographic data Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种制备4-氯双苯氯甲烷的方法，该方法包括1）使4-氯二苯甲酮与硼氢化钾或硼氢化钠进行还原反应，以获得4-氯二苯甲醇；2）使所述步骤1）获得的4-氯二苯甲醇与盐酸水溶液进行氯代反应，从而制备4-氯双苯氯甲烷。本发明的方法提高了产品的转化率和纯度，并且工艺简单，在反应过程中没有气体产生，安全稳定，成本低，在工业上有极高的实用价值。The invention provides a method for preparing 4-chlorobisphenylchloromethane, the method comprising 1) reducing 4-chlorobenzophenone with potassium borohydride or sodium borohydride to obtain 4-chlorobenzophenone ; 2) chlorinating the 4-chlorobenzhydryl alcohol obtained in the step 1) with aqueous hydrochloric acid to prepare 4-chlorobisphenylchloromethane. The method of the invention improves the conversion rate and purity of the product, has simple process, no gas is generated during the reaction process, is safe and stable, has low cost and has extremely high practical value in industry.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to the method for the two benzene methyl chloride of a kind of 4-of preparation chlorine.
Background technology
The molecular formula of the two benzene methyl chloride (English name: 4-Chlorobenzhydryl Chloride) of 4-chlorine is: C
13h
10cl
2, molecular weight is to be for 237.13, No. CAS 134-83-8, its structural formula is:
The two benzene methyl chloride of 4-chlorine are reactants of synthetic Meclozine or meclozine hydrochloride.Meclozine hydrochloride is applicable to various mucocutaneous anaphylactic diseases, also can be used for nauseating, vomiting that gestation, radiotherapy and motion sickness cause, is the antagonist of Histamine Receptors, and its effect is lasting far beyond diphenhydramine, can maintain 12-24 hour.
The method of preparing the two benzene methyl chloride of 4-chlorine of report is little at present, and known method is conventionally: 4-chlorobenzophenone, liquid caustic soda are added to reactor, stir and be warming up to 100 ℃, slowly add zinc powder, control temperature at 110-125 ℃.Add rear reaction 8h.Leave standstill, divide and get oil reservoir, with hot water and a small amount of salt acid elution, it is 6.5 that reusable heat is washed to pH, adds benzene stirring and dissolving.Leave standstill, divide and get benzene layer, steam benzene, remaining liquid is finished product.The method is used zinc powder as reductive agent, and zinc powder generally all needs activation, and has very strong reductibility, and with all releasing hydrogen gas of acid-base function, hydrogen very easily burns, explodes.Therefore the method temperature of reaction is high, meets air and very easily burns, explodes; Long reaction time, treating processes is relatively loaded down with trivial details; And owing to having used benzene to extract, therefore toxicity is large.
Summary of the invention
For solving existing problem in above-mentioned prior art, the invention provides the method for the two benzene methyl chloride of a kind of 4-of preparation chlorine.
Particularly, the invention provides:
(1) prepare the methods of the two benzene methyl chloride of 4-chlorine, the method comprises the following steps:
1) make 4-chlorobenzophenone and POTASSIUM BOROHYDRIDE or sodium borohydride carry out the reduction reaction as shown in reaction formula I, to obtain 4-chlorodiphenyl methyl alcohol:
Reaction formula I
Wherein said reduction reaction is carried out in low boiling point organic solvent, and temperature of reaction is 50 ℃ to 80 ℃;
2) the 4-chlorodiphenyl methyl alcohol and the aqueous hydrochloric acid that described step 1) are obtained carry out the chlorination as shown in reaction formula II, thus the two benzene methyl chloride of preparation 4-chlorine:
Reaction formula II
The temperature of reaction of wherein said chlorination is 74 ℃ to 82 ℃.
(2) according to the method (1) described, wherein, in described step 1), the time of described reduction reaction is at least 3 hours, is preferably 3-5 hour.
(3) according to the method (1) described, wherein in described step 2) in, the time of described chlorination is at least 3 hours, is preferably 3-5 hour.
(4) according to the method (1) described, wherein, in described step 1), the molar ratio of described 4-chlorobenzophenone and described POTASSIUM BOROHYDRIDE or sodium borohydride is 1:(0.32-0.6).
(5), according to the method (1) described, wherein, in described step 1), the envelope-bulk to weight ratio that feeds intake of described low boiling point organic solvent and described 4-chlorobenzophenone is for (2-3.5): 1.
(6) according to the method (1) described, wherein, in described step 1), described low boiling point organic solvent comprises methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), pyridine, acetone or its mixture.
(7) method according to (1), wherein said 4-chlorobenzophenone and described step 2) in the weightmeasurement ratio that feeds intake of described aqueous hydrochloric acid be 1:(4.5-5.5).
(8) according to the method (1) described, wherein in described step 2) in, the working concentration of described aqueous hydrochloric acid is 36 quality % to 37 quality %.
The present invention compared with prior art has the following advantages and positively effect:
1. method of the present invention is carried out in low boiling point organic solvent, not only can diluting reaction thing, and make reaction more abundant, and be convenient to reclaim solvent, improve solvent recovering rate; Reduce in addition the foreign matter content in the two benzene methyl chloride of end product 4-chlorine, be conducive to improve its quality and stability.
2. the present invention uses POTASSIUM BOROHYDRIDE or sodium borohydride as reductive agent, the many deficiencies while having avoided prior art to use zinc powder.
3. the present invention has found out the suitable temperature of reaction of each step, thereby has effectively improved transformation efficiency and the purity of product; In addition temperature of reaction lower (only needing 50 ℃ to 80 ℃), thus energy consumption can be saved.
4. the present invention's Reaction time shorten greatly, improves preparation efficiency.
5. the present invention, by further optimizing each step reaction conditions, has further effectively improved transformation efficiency and the purity of product.
6. method technique of the present invention is simple, there is no γ-ray emission in reaction process, safety and stability, and cost is low, has a high practical value industrial.
Embodiment
Below the invention will be further described for the description by embodiment, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
As described above, after considering shortcoming of the prior art, the present inventor gropes through a large amount of theoretical investigation and tests, and reactant, reaction solvent and corresponding reaction conditions are improved, and has finally completed the present invention.
Particularly, the invention provides the method for the two benzene methyl chloride of a kind of 4-of preparation chlorine, the method comprises the following steps:
1) make 4-chlorobenzophenone and POTASSIUM BOROHYDRIDE or sodium borohydride carry out the reduction reaction as shown in reaction formula I, to obtain 4-chlorodiphenyl methyl alcohol:
Reaction formula I
Wherein said reduction reaction is carried out in low boiling point organic solvent, and temperature of reaction is 50 ℃ to 80 ℃;
2) the 4-chlorodiphenyl methyl alcohol and the aqueous hydrochloric acid that described step 1) are obtained carry out the chlorination as shown in reaction formula II, thus the two benzene methyl chloride of preparation 4-chlorine:
Reaction formula II
The temperature of reaction of wherein said chlorination is 74 ℃ to 82 ℃.
In the method for the invention, under said temperature scope, can obtain the two benzene methyl chloride of 4-chlorine that transformation efficiency and purity improve.In step 1), in the time of excess Temperature, easily there is punching material, generating impurity can be more, can cause product content to only have 90%-95%, and expend the energy; In the time that temperature is too low, reaction not exclusively, affects yield and quality.In step 2) in, in the time of excess Temperature, hydrochloric acid easily gasifies, and cause reaction not exclusively, thereby low conversion rate affects quality; In the time that temperature is too low, also cause reaction not exclusively, thereby low conversion rate affect quality.
More preferably, in described step 1), described temperature of reaction is 70 ℃ to 80 ℃, more preferably 70 ℃ to 75 ℃, and more preferably 70 ℃.In described step 2) in, more preferably 80 ℃ of described temperature of reaction.
In described step 1) of the present invention and 2) in, reaction pressure is had no particular limits.
In step 1) of the present invention, the reaction times is preferably at least 3 hours, more preferably 3-5 hour.In step 2 of the present invention) in, the reaction times is preferably at least 3 hours, more preferably 3-5 hour.
In addition,, in described step 1), the molar ratio of described 4-chlorobenzophenone and described POTASSIUM BOROHYDRIDE or sodium borohydride is preferably 1:(0.32-0.6).The envelope-bulk to weight ratio that feeds intake of described low boiling point organic solvent and described 4-chlorobenzophenone is preferably (2-3.5): 1(unit is mL:g or L:kg).Described low boiling point organic solvent can comprise methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), pyridine, acetone or its mixture.
Described 4-chlorobenzophenone and described step 2) in the weightmeasurement ratio that feeds intake of described aqueous hydrochloric acid be preferably 1:(4.5-5.5) (unit is g:mL or kg:L).The working concentration of described aqueous hydrochloric acid can be 36 quality % to 37 quality %.
In the present invention, " low boiling point organic solvent " refers to that boiling point is lower than the solvent of 120 ℃.In reaction, preferred organic solvent is that boiling point is the solvent of approximately 50 ℃-120 ℃, preferred solvent is that boiling point is the solvent of approximately 50 ℃-90 ℃, and comprising methyl alcohol, its boiling point is 64.5 ℃, the organic solvent that another kind is more preferably is ethanol, and its boiling point is 78 ℃-80 ℃.The organic solvent of the boiling point that can also use in addition other below 120 ℃, such as Virahol, tetrahydrofuran (THF), pyridine, acetone etc., also can use the mixed solvent of multiple organic solvent, the combination of such as methyl alcohol and ethanol etc., but be not limited in this.The present invention utilizes lower boiling organic solvent, has not only improved solvent revolution rate, and has reduced the foreign matter content in the two benzene methyl chloride of 4-chlorine, is conducive to improve its quality and stability.
Preferably, in described step 1), after described reduction reaction completes, remove described low boiling point organic solvent, to obtain described 4-chlorodiphenyl methyl alcohol.
In one embodiment of the invention, the salt being generated by POTASSIUM BOROHYDRIDE or sodium borohydride in step 1) and excessive POTASSIUM BOROHYDRIDE or sodium borohydride can enter step 2 with 4-chlorodiphenyl methyl alcohol), and finally remove by organic phase-aqueous phase separation.
Further explain and describe content of the present invention by the mode of example below, but these examples should not be understood to the restriction to protection scope of the present invention.
Example
In following example, 4-chlorobenzophenone can derive from Xiangfan Chuan Long Chemical Co., Ltd..
The content of gained 4-chlorodiphenyl methyl chloride is measured by high performance liquid chromatography (HPLC) method:
Instrument: high performance liquid chromatograph (being equipped with high-pressure pump, UV-detector, chromatographic data processor) (can derive from Agilent company);
The condition of HPLC is: chromatographic column: C18,250 × 4.6mm, granularity 10 μ; Moving phase: methyl alcohol (chromatographically pure); Flow velocity: 0.7mL/ minute; Detect wavelength: 230nm; Sample size: 20 μ L;
Need testing solution: take about 5mg trial-product and be placed in 10mL volumetric flask, be diluted to scale with dissolve with methanol;
Press area normalization method and calculate 4-chlorodiphenyl methyl chloride content.
Embodiment 1: add 350ml dehydrated alcohol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 12g POTASSIUM BOROHYDRIDE, stir and heat up, react 4 hours at approximately 80 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 750ml 36 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 77 ℃, react 4.5 hours.Cooling reaction solution, separates organic layer, obtains 4-chlorodiphenyl methyl chloride 147.8g.Transformation efficiency 90%, content 99.5%.
Embodiment 2: add 350ml dehydrated alcohol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 22.5g POTASSIUM BOROHYDRIDE, stir and heat up, react 3.5 hours at approximately 70 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 700ml 36 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 80 ℃, react 4 hours.Cooling reaction solution, separates organic layer and obtains 4-chlorodiphenyl methyl chloride 149.5g.Transformation efficiency 91%, content 99.7%.
Embodiment 3: add 350ml dehydrated alcohol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 15g POTASSIUM BOROHYDRIDE, stir and heat up, react 4.5 hours at approximately 77 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 680ml 37 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 78 ℃, react 4.5 hours.Cooling reaction solution, separates organic layer and obtains 4-chlorodiphenyl methyl chloride 149.6g.Transformation efficiency 91%, content 99.5%.
Embodiment 4: add 400ml dehydrated alcohol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 12g POTASSIUM BOROHYDRIDE, stir and heat up, react 3 hours at approximately 80 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 675ml 37 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 77 ℃, react 4 hours.Cooling reaction solution, separates organic layer and obtains 4-chlorodiphenyl methyl chloride 147.8g.Transformation efficiency 90%, content 99.5%.
Embodiment 5: add 525ml dehydrated alcohol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 14g POTASSIUM BOROHYDRIDE, stir and heat up, react 5 hours at approximately 75 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 825ml 37 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 78 ℃, react 5 hours.Cooling reaction solution, layering, obtains 4-chlorodiphenyl methyl chloride 148.9g.Transformation efficiency 91%, content 99.6%.
Embodiment 6: add 300ml anhydrous methanol in three mouthfuls of reaction flasks, then add 150g 4-chlorobenzophenone and 18g POTASSIUM BOROHYDRIDE, stir and heat up, react 5 hours at approximately 50 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 680ml 37 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 74 ℃, react 4 hours.Cooling reaction solution, layering, obtains 4-chlorodiphenyl methyl chloride 148.5g.Transformation efficiency 90.5%, content 99.6%.
Embodiment 7: add 400ml anhydrous isopropyl alcohol in three mouthfuls of reaction flasks, then add 150g4-chlorobenzophenone and 15g sodium borohydride, stir and heat up, react 3 hours at approximately 80 ℃.React the most ethanol of rear distillation and obtained 4-chlorodiphenyl methyl alcohol.Add again 680ml 37 quality % aqueous hydrochloric acids to stir and carry out chlorination, at approximately 82 ℃, react 3 hours.Cooling reaction solution, layering, obtains 4-chlorodiphenyl methyl chloride 148.6g.Transformation efficiency 90.5%, content 99.6%.
Comparative example 1
150g 4-chlorobenzophenone, 100ml liquid caustic soda are added to reactor, stir and be warming up to 100 ℃, slowly add 25g zinc powder, control temperature and be about 112 ℃, add rear reaction 8h.Leave standstill, point get oil reservoir, with the 25% salt acid elution of the 100ml hot water of 78 ℃ and 20ml, then with the 100ml hot water wash of 78 ℃ to pH be 6.5, add 120ml benzene stirring and dissolving.Leave standstill, divide and get benzene layer, steam benzene, remaining liquid is 4-chlorodiphenyl methyl chloride 139.5g.Transformation efficiency 85%, content 98.7%.
Comparative example 2
Two 150g 4-chlorine benzophenones, 110ml liquid caustic soda are added to reactor, stir and be warming up to 100 ℃, slowly add 27g zinc powder, control temperature and be about 113 ℃.Add rear reaction 8h.Leave standstill, point get oil reservoir, with the 25% salt acid elution of the 150ml hot water of 80 ℃ and 25ml, then with the 150ml hot water wash of 80 ℃ to pH be 6.5, add 125ml benzene stirring and dissolving.Leave standstill, divide and get benzene layer, steam benzene, remaining liquid is 4-chlorodiphenyl methyl chloride 141.3g.Transformation efficiency 86%, content 99.1%.
Comparative example 3
Two 150g 4-chlorine benzophenones, 150ml liquid caustic soda are added to reactor, stir and be warming up to 100 ℃, slowly add 30g zinc powder, control temperature and be about 110 ℃.Add rear reaction 8h.Leave standstill, point get oil reservoir, with the 25% salt acid elution of the 140ml hot water of 80 ℃ and 30ml, then with the 140ml hot water wash of 80 ℃ to pH be 6.5, add 150ml benzene stirring and dissolving.Leave standstill, divide and get benzene layer, steam benzene, remaining liquid is 4-chlorodiphenyl methyl chloride 141.2g.Transformation efficiency 86%, content 98.8%.
Claims (8)
1. a method of preparing the two benzene methyl chloride of 4-chlorine, the method comprises the following steps:
1) make 4-chlorobenzophenone and POTASSIUM BOROHYDRIDE or sodium borohydride carry out the reduction reaction as shown in reaction formula I, to obtain 4-chlorodiphenyl methyl alcohol:
Reaction formula I
Wherein said reduction reaction is carried out in low boiling point organic solvent, and temperature of reaction is 50 ℃ to 80 ℃;
2) the 4-chlorodiphenyl methyl alcohol and the aqueous hydrochloric acid that described step 1) are obtained carry out the chlorination as shown in reaction formula II, thus the two benzene methyl chloride of preparation 4-chlorine:
Reaction formula II
The temperature of reaction of wherein said chlorination is 74 ℃ to 82 ℃.
2. method according to claim 1, wherein, in described step 1), the time of described reduction reaction is at least 3 hours, is preferably 3-5 hour.
3. method according to claim 1, wherein in described step 2) in, the time of described chlorination is at least 3 hours, is preferably 3-5 hour.
4. method according to claim 1, wherein, in described step 1), the molar ratio of described 4-chlorobenzophenone and described POTASSIUM BOROHYDRIDE or sodium borohydride is 1:(0.32-0.6).
5. method according to claim 1, wherein, in described step 1), the envelope-bulk to weight ratio that feeds intake of described low boiling point organic solvent and described 4-chlorobenzophenone is for (2-3.5): 1.
6. method according to claim 1, wherein, in described step 1), described low boiling point organic solvent comprises methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), pyridine, acetone or its mixture.
7. method according to claim 1, wherein said 4-chlorobenzophenone and described step 2) in the weightmeasurement ratio that feeds intake of described aqueous hydrochloric acid be 1:(4.5-5.5).
8. method according to claim 1, wherein in described step 2) in, the working concentration of described aqueous hydrochloric acid is 36 quality % to 37 quality %.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1998052898A1 (en) * | 1997-05-19 | 1998-11-26 | Nymox Corporation | Pharmaceutical agents for the treatment of cerebral amyloidosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998052898A1 (en) * | 1997-05-19 | 1998-11-26 | Nymox Corporation | Pharmaceutical agents for the treatment of cerebral amyloidosis |
Non-Patent Citations (1)
| Title |
|---|
| 姚凤鸣等: "脑益嗪合成方法的改进", 《中国医药工业杂志》, no. 4, 31 December 1984 (1984-12-31), pages 41 - 42 * |
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