CN116143723A - Preparation method of diltiazem hydrochloride - Google Patents
Preparation method of diltiazem hydrochloride Download PDFInfo
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- CN116143723A CN116143723A CN202211564976.2A CN202211564976A CN116143723A CN 116143723 A CN116143723 A CN 116143723A CN 202211564976 A CN202211564976 A CN 202211564976A CN 116143723 A CN116143723 A CN 116143723A
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- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960005316 diltiazem hydrochloride Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 118
- 239000007787 solid Substances 0.000 claims abstract description 115
- 229940125898 compound 5 Drugs 0.000 claims abstract description 88
- 238000010992 reflux Methods 0.000 claims abstract description 88
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 65
- 229940125782 compound 2 Drugs 0.000 claims abstract description 63
- 239000000706 filtrate Substances 0.000 claims abstract description 58
- 238000001914 filtration Methods 0.000 claims abstract description 58
- 238000000967 suction filtration Methods 0.000 claims abstract description 58
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000001291 vacuum drying Methods 0.000 claims abstract description 55
- 238000003756 stirring Methods 0.000 claims abstract description 35
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 239000012153 distilled water Substances 0.000 claims abstract description 33
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 33
- 238000001816 cooling Methods 0.000 claims abstract description 32
- 238000010438 heat treatment Methods 0.000 claims abstract description 31
- 238000001035 drying Methods 0.000 claims abstract description 30
- 239000005457 ice water Substances 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 87
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 60
- 239000002253 acid Substances 0.000 claims description 32
- 239000007864 aqueous solution Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims 1
- 238000010907 mechanical stirring Methods 0.000 abstract description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000011010 flushing procedure Methods 0.000 description 26
- 238000001556 precipitation Methods 0.000 description 26
- NTHKNMPHBNQTJM-UHFFFAOYSA-N 1-chloro-n,n-dimethylethanamine;hydrochloride Chemical compound Cl.CC(Cl)N(C)C NTHKNMPHBNQTJM-UHFFFAOYSA-N 0.000 description 25
- 239000012295 chemical reaction liquid Substances 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 19
- 238000005886 esterification reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 230000032050 esterification Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229960004166 diltiazem Drugs 0.000 description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007038 hydrochlorination reaction Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- LBMSLCXNKFZXJB-UHFFFAOYSA-N nitrooxyboronic acid Chemical compound OB(O)O[N+]([O-])=O LBMSLCXNKFZXJB-UHFFFAOYSA-N 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 210000001992 atrioventricular node Anatomy 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of diltiazem hydrochloride, which comprises the following steps: s1: adding a compound 1, a catalyst and an organic solvent into a reaction device, connecting a water diversion device, heating to a first temperature, carrying out heat preservation reaction, cooling the liquid obtained by the reaction in an ice water bath, filtering to obtain an off-white solid, pouring the off-white solid into alkali liquor, stirring, filtering and drying to obtain a compound 2; s2, sequentially adding acetone, a compound 2, N-dimethylamino chloroethane hydrochloride 3, potassium carbonate, distilled water and FeCl into a reactor 2 Refluxing, cooling to room temperature after the reaction is finished, and carrying out suction filtration to obtain filtrate; s3: continuously introducing dry HCl gas into the filtrate in the step S2, maintaining the temperature at a second temperature, performing suction filtration to obtain an off-white solid, recrystallizing with an ethanol-diethyl ether system, and performing vacuum drying to obtain a compound 5; s4: to CH 2 Cl 2 Adding compound 5 and compound 6 to N 2 The reaction solution was concentrated to an off-white solid under reflux with mechanical stirring under protection to give compound 6.
Description
Technical Field
The invention relates to a preparation method of a medicine for treating angina, in particular to a preparation method of diltiazem hydrochloride.
Background
Diltiazem, the chemical name of which is cis- (+) -5- (2-dimethylamino) ethyl ] -2- (4-methoxyphenyl) -3-acetoxyl-2, 3-dihydro-1, 5-phenylpropanolethion-4 (5H) -ketone, is a high-selectivity calcium ion channel blocker of the phenylpropanolethion type, and is widely applied to the treatment of coronary heart disease, hypertension, cardiomyopathy and other diseases by inhibiting the inflow of calcium ions into cells through vascular smooth muscles and atrioventricular node acting on coronary blood vessels and peripheral blood vessels to display the vascular dilation effect and the effect of prolonging the conduction time of the atrioventricular node.
At present, the chemical preparation of diltiazem hydrochloride mainly comprises a resolution method and an asymmetric preparation method. The resolution method adopts the diltiazem which is a cinchoni Ding Cafen product at the earliest, but has the defects of large raw material waste and high cost, and adopts ephedrine or lysine for resolution, but has poor resolution effect, and can also adopt tartaric acid for resolution to obtain diltiazem, but has expensive reagent and little industrial significance; the asymmetric preparation method has the defects of long reaction time, low yield and the like.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the diltiazem hydrochloride preparation method which is short in time consumption, high in yield and raw material-saving.
In order to achieve the above purpose, the invention provides a preparation method of diltiazem hydrochloride, which comprises the following steps:
step S1: adding a compound 1, a catalyst and an organic solvent into a reaction device, connecting a water diversion device, heating to a first temperature, carrying out heat preservation reaction, cooling the liquid obtained by the reaction in an ice water bath, filtering to obtain an off-white solid, pouring the off-white solid into alkali liquor, stirring, filtering and drying to obtain a compound 2;
step S2, sequentially adding acetone, a compound 2, N-dimethylamino chloroethane hydrochloride 3, potassium carbonate, distilled water and FeCl into a reactor 2 Heating to reflux, cooling to room temperature after the reaction is finished, and carrying out suction filtration to obtain filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, maintaining the temperature at a second temperature, performing suction filtration to obtain white-like fixation, recrystallizing with an ethanol-diethyl ether system, and performing vacuum drying to obtain a compound 5;
step S4: to CH 2 Cl 2 Adding compound 5 and compound 6 to N 2 Mechanically stirring and refluxing under protection, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain compound 6;
the reaction formula is:
in a preferred embodiment, the catalyst in the step S1 is m-nitroboric acid, the organic solvent is xylene, the first temperature is 120-140 ℃, the reaction time is 30-50 min, and the alkali liquor is 5% sodium hydroxide aqueous solution.
In a preferred embodiment, the ratio of compound 1, m-nitroboric acid, xylene is 5g: (0.2-0.4) g:60ml.
In a preferred embodiment, the ratio of compound 1, m-nitroboric acid, xylene is 5g:0.3g:60ml.
In a preferred embodiment, the reflux temperature in step S2 is 60 ℃, and the ratio of compound 2, N-dimethylaminoethyl chloride hydrochloride (3), acetone, potassium carbonate, distilled water, feCl2 is 5g:2.8g:60ml:5.5g 1ml: (0.1-0.2) g.
In a preferred embodiment, compound 2, N-dimethylaminoethyl chloride hydrochloride (3), acetone, potassium carbonate, distilled water, feCl 2 The ratio of (2) is 5g:2.8g:60ml:5.5g:1ml:0.15g.
In a preferred embodiment, the second temperature in step S3 is 30 to 40 ℃.
In a preferred embodiment, the reflux temperature in S4 is 110℃and the ratio of CH2Cl2, compound 5, compound 6 is (35-45) ml: (4-6) g: (4-6) g.
In a preferred embodiment, CH 2 Cl 2 The ratio of compound 5 to compound 6 was 8ml:1g:1g.
As can be seen from the scheme, the invention has the following beneficial effects:
(1) In step S2, feCl is used 2 The catalyst is further improved in yield on the basis of the prior art, further increases the reaction speed and FeCl 2 Is less toxic and safer;
(2) Compared with the prior art, the method can prevent the esterification product from hydrolyzing during the esterification and then the acidification, thereby improving the yield.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below in conjunction with the embodiments of the present invention. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Example 1
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.2g of m-nitroboric acid, keeping the temperature of 130 ℃ for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example two
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example III
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.4g of m-nitroboric acid, keeping the temperature of 130 ℃ for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example one
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, reacting 0.2g of p-toluenesulfonic acid at 130 ℃ for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example two
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, reacting 0.28g of p-toluenesulfonic acid at 130 ℃ for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example three
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, reacting 0.35g of p-toluenesulfonic acid at 130 ℃ for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Table 1 comparison of process parameters for examples one to three and comparative examples one to three
As can be seen from the comparison examples I and II, II and III, and the comparison example and III, the catalytic efficiency of m-nitroboric acid is higher than that of p-benzenesulfonic acid in S1, the yield 1 position 92.5% in the examples is higher than that of the comparison example 1, the nitroboric acid can improve the yield of the compound 2, the nitroboric acid is used for catalytic reaction, and the byproducts are only water and can be removed through a water division device, so that the reaction balance is promoted to move towards the product direction, the problem of metal residue can be effectively avoided, and the nitroboric acid is low in price and convenient to recycle; by comparing the first, second and third examples, the best proportion of the compound (1), m-nitroboric acid and dimethylbenzene is 5g:0.3g:60ml.
Example IV
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 120 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example five
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 140 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
The following conclusions can be drawn by comparing example two, example four and example five: when other reaction conditions are controlled to be unchanged and only the first temperature is changed, the yield is 93.1% at 1 position when the first temperature is controlled to be 120 ℃; changing the first temperature, wherein when the first temperature is 130 ℃, the yield 1 is 94.1%; when the first temperature is 140 ℃, the yield 1 is 92.8%, and the yield can be improved by controlling the first temperature to 130 ℃.
Example six
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for 30min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example seven
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for 40min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml of the mixture was sequentially introduced into a three-necked flaskCH 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
By comparing the second, sixth and seventh examples, the yield 1 was 92.5% when the incubation time was 30min, the yield 1 was improved when the incubation time was 40min, the yield 1 was highest when the incubation time was 50min, the reaction was most sufficient when the reaction time was 50min, and the yield was highest.
Comparative example four
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium bicarbonate aqueous solution, stirring for 30min, filtering and drying to obtain compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Mechanically stirring reflux reaction under protection, concentrating reactionThe off-white solid of the solution was recrystallized from an ethanol-diethyl ether system and dried under vacuum to give compound 6.
From comparative example two and comparative example four, it can be concluded that the yield 1 can be improved by washing the white solid with 5% aqueous sodium hydroxide solution; by combining the above examples and comparative examples, it can be concluded that the optimal choice of conditions in step S1 is that the catalyst is m-nitroboric acid 0.3g, the reaction is incubated at 130℃for 50min, and rinsed with 5% aqueous sodium hydroxide.
Example eight
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.1g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example nine
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.2g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example five
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: sequentially adding 5g of compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.1g of gKI and reflux reaction for 3 hours, wherein the reflux temperature is 60 ℃, and after the reaction is finished, carrying out suction filtration to keep filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example six
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: sequentially adding 5g of compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.14 and gKI into a flask, carrying out reflux reaction for 3 hours, carrying out suction filtration after the reaction is finished at the reflux temperature of 60 ℃, and reserving filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example seven
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: sequentially adding 5g of compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.2g of gKI and reflux reaction for 3 hours, wherein the reflux temperature is 60 ℃, and after the reaction is finished, carrying out suction filtration to keep filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
FeCl was controlled by comparing example two, example eight and example nine 2 The dosage affects the yield 2, when FeCl 2 When the amount of (C) was 0.1g, the yield 2 was 85.0%, and 0.15g of FeCl was used 2 The catalytic reaction is carried out, the yield is 91.0% at the 2-position, the yield is greatly improved, and FeCl is continuously increased 2 The amount of (C) used shows that the yield is not greatly improved, and 0.15g of FeCl 2 Is the optimal catalyst amount; KI can also be used as a catalyst by the comparative examples II, five, six and seven, but the catalytic efficiency is low and the yield is far lower than FeCl 2 。
Examples ten
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 4 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example eight
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: sequentially adding 5g of compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.14 and gKI into a flask, carrying out reflux reaction for 4 hours, wherein the reflux temperature is 60 ℃, and after the reaction is finished, carrying out suction filtration to keep filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example nine
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: sequentially adding 5g of compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.2g of gKI and reflux reaction for 4 hours, wherein the reflux temperature is 60 ℃, and after the reaction is finished, carrying out suction filtration to keep filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
FeCl was prepared by comparing example two with example ten 2 The reaction time of 3h and 4h as the catalyst has no influence on the yield 2, and the reaction is complete at 3 h; with reference to comparative examples six, seven, eight and nine, the reaction was not completed at 3 hours with KI as the catalyst, and FeCl was used as the catalyst 2 The catalyst can improve the yield by 2 and can also accelerate the reaction speed.
Example eleven
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively added 5g of Compound 2, 60ml of acetone, 2.8g of N, NDimethylaminochloroethane hydrochloride 3, 5.5g potassium carbonate, 1ml distilled water, 0.15g FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 30 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Example twelve
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 40 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Comparative example ten
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3 (i.e. example step S4): 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Mechanically stirring and refluxing under protection, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain compound 6;
step S4 (i.e. example step S3): continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5.
Comparative example eleven
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3 (i.e. example step S4): 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Mechanically stirring reflux reaction under protection, concentrating the white-like color of the reaction liquidRecrystallizing the solid with ethanol-diethyl ether system, and vacuum drying to obtain compound 6;
step S4 (i.e. example step S3): continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 30 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5.
Comparative example twelve
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3 (i.e. example step S4): 40ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Mechanically stirring and refluxing under protection, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain compound 6;
step S4 (i.e. example step S3): continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 40 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5.
By comparing the second, the eleventh and the twelfth examples, the second temperature is controlled at 30 ℃,35 ℃ and 40 ℃, the purity of the product obtained in the step S3 is highest when the second temperature is 35 ℃, so that the total yield 3 of S3 and S4 is affected, and the optimal second temperature is 35 ℃; in comparative examples ten, eleven and twelve, the steps S3 and S4 of the examples were exchanged, i.e., the original first-stage hydrochlorination re-esterification was changed to first-stage esterification re-hydrochlorination, and the total yield 3 of the comparative examples was lowered, whereby it was seen that the first-stage hydrochlorination (original S3) and then the esterification (original S4) were carried out to avoid hydrolysis of the esterified product (compound 7) due to water.
Example thirteen
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 35ml CH was added sequentially to a three-necked flask 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Examples fourteen
Step S1: adding 5g of compound 1 and 60ml of dimethylbenzene into a three-neck flask, connecting a water separator device, heating to 130 ℃, adding 0.3g of m-nitroboric acid, keeping the temperature of 130 ℃ for reaction for 50min, cooling by an ice water bath, filtering to obtain a white solid, flushing with 5% sodium hydroxide aqueous solution, stirring for 30min, filtering and drying to obtain a compound 2;
step S2: into a flask were successively charged 5g of Compound 2, 60ml of acetone, 2.8g of N, N-dimethylaminochloroethane hydrochloride 3, 5.5g of potassium carbonate, 1ml of distilled water, 0.15g of FeCl 2 Reflux reaction is carried out for 3 hours at the reflux temperature of 60 ℃, and after the reaction is finished, suction filtration is carried out, and filtrate is reserved;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, keeping the temperature at 35 ℃, carrying out suction filtration to obtain white solid after white solid precipitation is not generated, recrystallizing with an ethanol-diethyl ether system to obtain a compound 5, and carrying out vacuum drying on the compound 5;
step S4: 45ml CH was added to a three-necked flask in sequence 2 Cl 2 5g of Compound 5, 5g of Compound 6 in N 2 Under the protection of mechanical stirring and reflux reaction, concentrating off white solid of the reaction liquid, recrystallizing with ethanol-diethyl ether system, and vacuum drying to obtain the compound 6.
Selection of CH in the esterification step of Synthesis of Compound 7 2 Cl 2 Can be used as a solvent to reduce the consumption of acetic anhydride which is easy to be made into toxin, and is safer and CH 2 Cl 2 The optimal ratio of the compound (5) to the compound (6) is 8ml:1g:1g.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Claims (9)
1. The preparation method of diltiazem hydrochloride is characterized by comprising the following steps of:
step S1: adding a compound 1, a catalyst and an organic solvent into a reaction device, connecting a water diversion device, heating to a first temperature, carrying out heat preservation reaction, cooling the liquid obtained by the reaction in an ice water bath, filtering to obtain an off-white solid, pouring the off-white solid into alkali liquor, stirring, filtering and drying to obtain a compound 2;
step S2, sequentially adding acetone, a compound 2, N-dimethylamino ethyl chloride hydrochloride 3, potassium carbonate, distilled water and FeCl2 into a reactor, heating to reflux, cooling to room temperature after the reaction is finished, and carrying out suction filtration to obtain filtrate;
step S3: continuously introducing dry HCl gas into the filtrate in the step S2, maintaining the temperature at a second temperature, performing suction filtration to obtain white-like fixation, recrystallizing with an ethanol-diethyl ether system, and performing vacuum drying to obtain a compound 5;
step S4: adding a compound 5 and a compound 6 into CH2Cl2, mechanically stirring and refluxing under the protection of N2, concentrating an off-white solid of a reaction solution, recrystallizing with an ethanol-diethyl ether system, and drying in vacuum to obtain the compound 6;
the reaction formula is:
2. the method for preparing diltiazem hydrochloride according to claim 1, wherein in the step S1, the catalyst is m-nitroboric acid, the organic solvent is xylene, the first temperature is 120-140 ℃, the reaction time is 30-50 min, and the alkali solution is 5% sodium hydroxide aqueous solution.
3. The method for preparing diltiazem hydrochloride according to claim 2, wherein the ratio of compound 1, m-nitroboric acid and xylene is 5g: (0.2-0.4) g:60ml.
4. A process for the preparation of diltiazem hydrochloride according to claim 3, characterized in that the ratio of compound 1, m-nitroboric acid, xylene is 5g:0.3g:60ml.
5. The method for preparing diltiazem hydrochloride according to claim 1, wherein the reflux temperature in S2 is 60 ℃, and the ratio of compound 2, N-dimethylaminoethyl chloride hydrochloride 3, acetone, potassium carbonate, distilled water, feCl2 is 5g:2.8g:60ml:5.5g 1ml: (0.1-0.2) g.
6. The method for preparing diltiazem hydrochloride according to claim 5, wherein the ratio of compound 2, N-dimethylaminoethyl chloride hydrochloride, acetone, potassium carbonate, distilled water, feCl2 is 5g:2.8g:60ml:5.5g:1ml:0.15g.
7. The method for preparing diltiazem hydrochloride according to claim 1, wherein the second temperature in S3 is 30-40 ℃.
8. The preparation method of diltiazem hydrochloride according to claim 1, wherein the reflux temperature in S4 is 110 ℃, and the ratio of CH2Cl2, compound 5 and compound 6 is (35-45) ml:5g:5g.
9. The method for preparing diltiazem hydrochloride according to claim 1, wherein the proportion of CH2Cl2, compound 5 and compound 6 is 8ml:1g:1g.
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