CN107089918B - Preparation method of benzhydrylamine hydrochloride - Google Patents
Preparation method of benzhydrylamine hydrochloride Download PDFInfo
- Publication number
- CN107089918B CN107089918B CN201710225957.XA CN201710225957A CN107089918B CN 107089918 B CN107089918 B CN 107089918B CN 201710225957 A CN201710225957 A CN 201710225957A CN 107089918 B CN107089918 B CN 107089918B
- Authority
- CN
- China
- Prior art keywords
- reaction
- benzophenone
- preparation
- formamide
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- CIHWJRSPVJBHGT-UHFFFAOYSA-N benzhydrylazanium;chloride Chemical compound Cl.C=1C=CC=CC=1C(N)C1=CC=CC=C1 CIHWJRSPVJBHGT-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 40
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 36
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012965 benzophenone Substances 0.000 claims abstract description 28
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 16
- 238000006547 Leuckart Thiophenol synthesis reaction Methods 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 12
- 230000035484 reaction time Effects 0.000 claims abstract description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 16
- 239000007858 starting material Substances 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 abstract description 4
- 229950004646 azelnidipine Drugs 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- 238000004904 shortening Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 9
- 238000010606 normalization Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011946 reduction process Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000005474 detonation Methods 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000010814 metallic waste Substances 0.000 description 1
- VGXHNTCQRKYIMY-UHFFFAOYSA-N n-benzhydryl-1,1-diphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)NC(C=1C=CC=CC=1)C1=CC=CC=C1 VGXHNTCQRKYIMY-UHFFFAOYSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of azelnidipine starting material benzhydrylamine hydrochloride, which takes benzophenone and formamide as raw materials to carry out Leuckart reaction, and adds catalyst silicon dioxide into a reaction system, thereby greatly shortening the reaction time from more than 8 hours to 3-4 hours and greatly reducing the energy consumption; and the yield of the crude product of the compound II is obviously improved to 96-98%, and the HPLC purity is not lower than 96.5%, so that the benzhydrylamine hydrochloride obtained by hydrochloric acid hydrolysis is purified once, the yield can reach 80%, the purity is not lower than 99.9%, and the method is very suitable for industrial production.
Description
Technical Field
The invention relates to a method for preparing azelnidipine key starting material benzhydrylamine hydrochloride by utilizing an improved Leuckart reaction, belonging to the technical field of medicines.
Background
The benzhydrylamine hydrochloride is a starting material for preparing azelnidipine, is stable to high temperature, high humidity and illumination, and free benzhydrylamine has poor stability and cannot be stored for a long time. The existing reported synthetic routes of benzhydrylamine hydrochloride (or free base) mainly comprise three routes:
(mono) oxime reduction process
In the route, benzophenone is used as a starting material and reacts with hydroxylamine to form oxime, and the oxime is reduced to obtain the benzhydrylamine. The oxime reduction method reported in the literature comprises reduction by a reducing agent and high-pressure hydrogenation reduction, wherein the reducing agent mainly comprises sodium borohydride, sodium cyanoborohydride, metallic sodium, magnesium powder or zinc powder. The disadvantage of the route is that the second step of reduction reaction is not easy to realize, and the reduction by sodium borohydride and sodium cyanoborohydride has high preparation cost; the reduction process is not easy to control, a large amount of hydrogen is generated in the reduction process, so that the detonation danger is caused, and more metal waste residues and waste liquid are generated; in addition to high-pressure equipment, the high-pressure hydrogenation mode can also generate obvious side reactions, and the formed product is very easy to deaminate to obtain diphenylmethane and bis-diphenylmethylamine byproducts, so that the yield is low and the separation is difficult.
(di) imine reduction process
The reaction of the route is simple, only one step is needed, and the used reducing agent is basically consistent with the route (I). The disadvantage is that the starting material benzophenone imine is not an industrial product, needs to be prepared, has high cost, and the use of the reducing agent still has the disadvantages of the route (I), and is not suitable for industrial mass production.
(III) Leuckart reaction method
The first step is a classical Leuckart reaction, the reaction temperature is higher, the general requirement is more than 180 ℃, and the yield is low; and hydrolyzing hydrochloric acid to obtain benzhydrylamine hydrochloride.
The Leuckart reaction is a process for converting aldehydes (or ketones) with formamide (or ammonium formate) to amines at elevated temperatures above 180 ℃ and was first discovered by the German chemist Carl Louis Rudolf Alexander Leuckart (1854) -1889) and named after it. The reaction was known for a long time, but it was not widely used, for the following reasons:
(1) the reaction temperature is high, and the reaction can be carried out at the temperature of more than 180 ℃;
(2) the reaction time is long, generally more than 8 hours, and the energy consumption is high;
(3) the reaction conversion rate is low, the generated impurities are more, and the yield of the compound II is lower than the moderate (60 percent);
(4) the purity of the benzhydrylamine hydrochloride obtained by hydrolysis is not high;
since raw materials used in the Leuckart reaction are easy to obtain, the process is easy to control and realize, and the Leuckart reaction is very suitable for industrial production, the reaction is continuously improved later, for example, Tetrahedron Letters, 37(45), 8177-. Patent US2009143622a1 reports that addition of formic acid to a classical Leuckart reaction system also increases the yield of the product with a significant reduction in reaction time, a yield of 95% and unknown purity. In the disclosed reaction system, the feeding molar ratio of benzophenone, formic acid and formamide is 1: 1.9: 18.3, the use amount of formamide is too large, so that a large amount of waste liquid is generated after reaction, and the environmental protection requirement and the cost control are not facilitated. Experiments prove that when the amount of formamide is reduced, the reaction effect is poor, the reaction efficiency is obviously reduced, the reaction time is greatly prolonged, and the experimental conditions refer to the control example 2 in the example.
Disclosure of Invention
The invention aims to provide a preparation method of azelnidipine starting material benzhydrylamine hydrochloride.
The technical scheme of the invention is a preparation method of benzhydrylamine hydrochloride, which is characterized in that benzophenone and formamide are subjected to Leuckart reaction under the action of silicon dioxide to obtain a compound II, and then hydrochloric acid is used for acidification to obtain the benzhydrylamine hydrochloride:
the Leuckart reaction time is 3-4 hours.
According to the invention, the silica functions as a catalyst in the Leuckart reaction, the reaction temperature preferably being 180-.
According to the present invention, the silica mesh number is preferably 100-300 mesh. According to the invention, the influence of the mesh number of the silicon dioxide on the reaction is researched, and the fact that the catalytic effect is not increased when the mesh number of the silicon dioxide is more than 300 is found, and the difficulty of filtration is increased when the filtration is carried out in large-scale production; the mesh number is less than 100 meshes, the catalytic effect is obviously reduced, and the reaction time is prolonged.
According to the invention, the amount of silica is preferably 5% to 20% by mass of benzophenone. According to the invention, researches show that the use amount of silicon dioxide is increased and the reaction time is shortened in a certain range. When the using amount of the silicon dioxide is more than 20 percent of the mass of the benzophenone, the increase amplitude of the catalytic activity is not obvious, and the viscosity of the system is also obviously increased along with the increase of the using amount of the silicon dioxide; when the catalytic amount of silica is less than 5%, the time of the reaction system is prolonged.
In addition, the research shows that the reaction time can be further shortened to about 2.5 hours by the combined catalysis of anhydrous magnesium chloride and silicon dioxide, wherein the anhydrous magnesium chloride is used in an amount of 1-5% of the mass of the benzophenone, and the silicon dioxide is used in the same amount as before. Further increase in the amount of anhydrous magnesium chloride causes deterioration of the reaction and deterioration of the yield and quality of the product.
According to the invention, the molar ratio of formamide to benzophenone is preferably 5 to 6: 1. when the molar ratio of formamide to benzophenone is more than 6, the reaction effect is not obviously improved; when the molar ratio of formamide to benzophenone is less than 5: 1, the system becomes viscous, the reaction effect becomes poor, and the post-treatment is not favorable.
The method has the beneficial effects that the catalyst silicon dioxide is added into the reaction system, so that the classical Leuckart reaction time is greatly shortened from more than 8 hours to 3-4 hours, and the energy consumption is greatly reduced; and the yield of the crude product of the compound II is obviously improved to 96-98%, and the HPLC purity is not lower than 96.5%, so that the benzhydrylamine hydrochloride obtained by hydrochloric acid hydrolysis is purified once, the yield can reach 80%, the purity is not lower than 99.9%, and the method is very suitable for industrial production.
The specific implementation mode is as follows:
for a better understanding of the present invention, reference will now be made to the following examples, which are set forth to illustrate, but are not to be construed as the limit of the present invention.
COMPARATIVE EXAMPLE 1 preparation of intermediate (II) (No catalyst)
Adding 148g formamide into 100g benzophenone, heating to 185-190 ℃, and reacting for 4 hours. Sampling HPLC monitoring (area normalization method): product 37.21%, benzophenone starting material: 50.44%, others are impurities. The reaction effect was poor and the subsequent steps were not carried out.
COMPARATIVE EXAMPLE 2 preparation of intermediate (II) (US 2009143622A 1)
100g (0.549 mol) of benzophenone, 25.2g of anhydrous formic acid (0.549 mol) and 148g of formamide (3.29mol) are added, the temperature is raised to 168 ℃, reflux is achieved, the reaction is carried out for 15min, and a sample is taken for HPLC monitoring (area normalization): 30.79% of product, benzophenone raw material: 65.07%, others are impurities. Reflux was continued for 3 hours and samples were monitored by HPLC (area normalization): 86.14% of product, benzophenone raw material: 2.71% (5.01% after correction by adding correction factor) and more raw materials remained.
EXAMPLE 1 preparation of intermediate (II)
Adding 148g formamide and 5.0g of 200-300 mesh chromatographic silica gel into 100g of benzophenone, heating to 185-190 ℃, and reacting for 4 hours. Sampling HPLC monitoring (area normalization method): product 96.10%, benzophenone starting material: 0.06 percent. Cooling the reaction liquid, adding water, stirring and dispersing uniformly, filtering, washing and drying to obtain 112.7g of a product, wherein the yield is 97.2%, and the HPLC purity is as follows: 97.17 percent.
EXAMPLE 2 preparation of intermediate (II)
Adding 148g formamide and 10g of 200-300 mesh chromatographic silica gel into 100g of benzophenone, heating to 185-190 ℃, and reacting for 3 hours. Sampling HPLC monitoring (area normalization method): product 95.15%, benzophenone starting material: 0.03 percent. Cooling the reaction liquid, adding water, stirring and dispersing uniformly, filtering, washing and drying to obtain 114.0g of a product, wherein the yield is 98.4%, and the HPLC purity is as follows: 96.94 percent.
EXAMPLE 3 preparation of intermediate (II)
Adding 148g formamide and 20g of 200-300 mesh chromatographic silica gel into 100g of benzophenone, heating to 180 ℃ and 185 ℃, and reacting for 3 hours. Sampling HPLC monitoring (area normalization method): 96.43% of product, benzophenone raw material: 0.02 percent. Cooling the reaction liquid, adding water, stirring and dispersing uniformly, filtering, washing and drying to obtain 113.4g of a product, wherein the yield is 97.8%, and the HPLC purity is as follows: 97.34 percent.
EXAMPLE 4 preparation of intermediate (II)
Adding 148g formamide and 10g 100-200 mesh chromatographic silica gel into 100g of benzophenone, heating to 180 ℃ and 185 ℃, and reacting for 3 hours. Sampling HPLC monitoring (area normalization method): product 96.03%, benzophenone starting material: 0.04 percent. Cooling the reaction liquid, adding water, stirring and dispersing uniformly, filtering, washing and drying to obtain 113.7g of a product, wherein the yield is 98.1%, and the HPLC purity is as follows: 97.41 percent.
EXAMPLE 5 preparation of intermediate (II)
Adding 148g of formamide, 10g of 200-300 mesh chromatographic silica gel and 5.0g of anhydrous magnesium chloride into 100g of benzophenone, heating to 180-195 ℃, and reacting for 2.5 hours. Sampling HPLC monitoring (area normalization method): 95.93% of product, and benzophenone raw material: 0.07 percent. Cooling the reaction liquid, adding water, stirring and dispersing uniformly, filtering, washing and drying to obtain 112.2g of a product, wherein the yield is 96.8%, and the HPLC purity is as follows: 97.41 percent.
EXAMPLE 6 preparation of benzhydrylamine hydrochloride (III)
Adding 120g of the prepared intermediate (II) into 12g of activated carbon and 360ml of absolute ethanol, refluxing and decoloring, filtering to remove the activated carbon and silicon dioxide, adding 110g of concentrated hydrochloric acid into the filtrate, refluxing for 1.5 hours, and completely reacting. Cooling, crystallizing, filtering, washing and drying to obtain 95.3g of product, the yield is 80.3%, and the HPLC purity is as follows: 99.93 percent.
Claims (3)
1. A preparation method of benzhydrylamine hydrochloride is characterized in that benzophenone and formamide are subjected to Leuckart reaction under the action of silicon dioxide to obtain a compound II, and then hydrochloric acid acidification is carried out to obtain the benzhydrylamine hydrochloride:
the Leuckart reaction time is 3-4 hours, and the silica is selected from 100-300 mesh chromatography silica gel.
2. The preparation method according to claim 1, wherein the amount of the chromatographic silica gel is 5-20% of the mass of the benzophenone.
3. The preparation method according to claim 1, wherein the molar ratio of formamide to benzophenone is 5-6: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710225957.XA CN107089918B (en) | 2017-04-08 | 2017-04-08 | Preparation method of benzhydrylamine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710225957.XA CN107089918B (en) | 2017-04-08 | 2017-04-08 | Preparation method of benzhydrylamine hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107089918A CN107089918A (en) | 2017-08-25 |
| CN107089918B true CN107089918B (en) | 2020-06-16 |
Family
ID=59636822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710225957.XA Active CN107089918B (en) | 2017-04-08 | 2017-04-08 | Preparation method of benzhydrylamine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107089918B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2603661A (en) * | 1952-07-15 | Letjckart synthesis x | ||
| CN104450813A (en) * | 2014-11-22 | 2015-03-25 | 太原理工大学 | Synthesis method for benzhydrylamine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2876689B1 (en) * | 2004-10-14 | 2008-02-22 | Aventis Pharma Sa | NOVEL PROCESS AND INTERMEDIATES FOR PREPARING N- (1-BENZHYDRYL-AZETIDIN-3-YL) -N-PHENYL-METHYLSULFONAMIDE DERIVATIVES |
| CA2695203A1 (en) * | 2007-07-31 | 2009-02-05 | University Of North Dakota Research Foundation | Improved method for the synthesis of substituted formylamines and substituted amines |
-
2017
- 2017-04-08 CN CN201710225957.XA patent/CN107089918B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2603661A (en) * | 1952-07-15 | Letjckart synthesis x | ||
| CN104450813A (en) * | 2014-11-22 | 2015-03-25 | 太原理工大学 | Synthesis method for benzhydrylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107089918A (en) | 2017-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112028755B (en) | Method for preparing 1,3 cyclohexanedione | |
| CN110615744A (en) | Buvalracetam intermediate and preparation method thereof | |
| CN104072565A (en) | High-yield simple preparation method of 17alpha-hydroxy progesterone | |
| CN108558679B (en) | Synthetic method of Parylene A precursor | |
| EP2524909B1 (en) | Preparation method of 4-aminomethylbenzoic acid | |
| CN107089918B (en) | Preparation method of benzhydrylamine hydrochloride | |
| CN101270058B (en) | Process for preparing 3-(1-dimethylamino- ethyl)phynol | |
| CN111138351A (en) | Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate | |
| CN107365251B (en) | Preparation method of cyclohexyl formic acid | |
| CN104961692A (en) | Improved preparation method of 7-chlorin-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide | |
| CN105669469B (en) | A kind of synthetic method of methoxyphenamine hydrochloride | |
| CN104292113A (en) | Preparation method of 3-chloro-4-fluoroaniline | |
| CN111170932A (en) | Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt | |
| CN103804294B (en) | Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one | |
| CN102173993B (en) | Method for synthesizing 4,6-diamino resorcinol dihydrochloride (DAR) | |
| CN103214384A (en) | Preparation method of p-aminophenylacetic acid | |
| CN101538212A (en) | Method for preparing 4-hydroxy-3-methoxybenzylamine hydrochloride | |
| CN110713442A (en) | Preparation method of o-nitrobenzaldehyde | |
| CN109912430B (en) | Method for synthesizing chloro-p-phenylenediamine | |
| CN104876858A (en) | One-pot method for synthesizing sodium 3,5,6-trichloropyridin-2-olate | |
| CN104910033A (en) | Method for preparing 5-aminolevulinic acid hydrochloride | |
| CN112266360B (en) | Synthesis method of high-purity histamine dihydrochloride | |
| CN104649994B (en) | A kind of preparation method of 4-methyl-5-alkoxy-oxazole | |
| CN114436944B (en) | Synthesis method of ibrutinib intermediate | |
| CN116178210B (en) | Preparation method of citronellyl nitrile derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200520 Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264400 No.268, Tianrun Road, Wendeng Economic Development Zone, Weihai City, Shandong Province Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210610 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |