CN113173885A - Method for synthesizing benzydamine hydrochloride impurity B - Google Patents
Method for synthesizing benzydamine hydrochloride impurity B Download PDFInfo
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- CN113173885A CN113173885A CN202110257024.5A CN202110257024A CN113173885A CN 113173885 A CN113173885 A CN 113173885A CN 202110257024 A CN202110257024 A CN 202110257024A CN 113173885 A CN113173885 A CN 113173885A
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- hydrochloric acid
- benzydamine hydrochloride
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- HNNIWKQLJSNAEQ-UHFFFAOYSA-N Benzydamine hydrochloride Chemical compound Cl.C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 HNNIWKQLJSNAEQ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 24
- 229960001689 benzydamine hydrochloride Drugs 0.000 title claims abstract description 23
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 5
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 5
- 239000013067 intermediate product Substances 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 16
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 claims description 7
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 5
- 229940095102 methyl benzoate Drugs 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- OHNUZSZAYZGRKA-UHFFFAOYSA-N methyl 2-amino-5-benzylbenzoate Chemical compound C1=C(N)C(C(=O)OC)=CC(CC=2C=CC=CC=2)=C1 OHNUZSZAYZGRKA-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000006193 diazotization reaction Methods 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- 229960002903 benzyl benzoate Drugs 0.000 abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing benzydamine hydrochloride impurity B, which comprises the steps of hydrolyzing methyl ester in a molecule by using 2-amino-5-benzyl benzoate methyl ester as an initial raw material, diazotizing amino to convert the amino into hydrazine, and using hydrochloric acid to close the carboxyl and the hydrazine in the molecule to obtain a benzopyrazolyl derivative; then respectively carrying out alkylation reaction on the nitrogen atom and the oxygen atom to finally obtain the benzydamine hydrochloride impurity B. The method provided by the invention takes 2-amino-5-benzyl benzoate as an initial raw material, obtains a final target product through five-step reaction, and has the advantages of simple and efficient whole reaction route and very strong practical value. Because the content of the impurities in the production process is very low, compared with a scheme of directly extracting the impurities from the reaction liquid, the scheme of synthesizing is more convenient and economic, and simultaneously, the blank that the compound has no literature report so far is made up.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing benzydamine hydrochloride impurity B.
Background
Benzydamine hydrochloride (benzydamine hydrochloride), also known as indomethacin or indomethacin, has the chemical name of 1-benzyl-3- [3- (dimethylamino) propoxy ] -1H-indazole hydrochloride, is a non-steroidal anti-inflammatory drug with local action, has local anesthetic and analgesic properties, is used for relieving pain and diminishing inflammation to treat inflammatory conditions of mouth and throat, and can be combined with antibiotics or sulfonamides for better curative effect, so that the quality of the benzydamine hydrochloride needs to be strictly controlled.
The benzydamine hydrochloride impurity B (as shown in the following formula I) is an impurity which is inevitably generated in the production process of benzydamine hydrochloride, and has a low content, so that the synthetic scheme is more convenient and economical than the scheme of directly extracting the impurity from the reaction solution. However, no report on the synthesis method is available. Therefore, a method for synthesizing benzydamine hydrochloride impurity B is needed, and the method has important significance for preparing impurity standard products and controlling the quality of simvastatin.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing benzydamine hydrochloride impurity B, which comprises the steps of taking 2-amino-5-benzyl methyl benzoate as an initial raw material, hydrolyzing methyl ester in a molecule, diazotizing amino to convert the amino into hydrazine, and using hydrochloric acid to close a carboxyl group and a hydrazine group in the molecule to obtain a benzopyrazolyl derivative; and then respectively carrying out alkylation reaction on the nitrogen atom and the oxygen atom to finally obtain a target product.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for synthesizing benzydamine hydrochloride impurity B, which comprises the steps of hydrolyzing methyl ester in a molecule by using 2-amino-5-benzyl benzoate methyl ester as an initial raw material, diazotizing amino to convert the amino into hydrazine, and using hydrochloric acid to close the carboxyl and the hydrazine in the molecule to obtain a benzopyrazolyl derivative; then respectively carrying out alkylation reaction on the nitrogen atom and the oxygen atom to finally obtain the benzydamine hydrochloride impurity B.
Further, the method comprises the following steps:
step one, adding 2-amino-5-benzyl methyl benzoate, lithium hydroxide hydrate, 1, 4-dioxane and water into a reaction vessel in sequence, and heating and refluxing; after the reaction is finished, EA is adopted for extraction and spin-drying to obtain an intermediate product 2;
step two, dissolving the intermediate product 2 in a hydrochloric acid solution, cooling, and then dropwise adding NaNO2Stirring the aqueous solution for 20 to 4 minutes; then SnCl is added dropwise2Hydrochloric acid solution, and finally reacting at room temperature overnight, and filtering to obtain an intermediate product 3 after the reaction is finished;
step three, sequentially adding the intermediate product 3 and a hydrochloric acid solution into a three-necked bottle, and heating and refluxing; after the reaction is finished, extracting and spin-drying to obtain an intermediate product 4;
step four, sequentially dissolving the intermediate product 4, NaOH and BnCl in DMSO to react for 50-70 minutes; after the reaction is finished, EA is adopted for extraction, water washing and column chromatography are carried out to obtain an intermediate product 5;
and step five, dissolving the intermediate product 5 in DMF, then sequentially adding NaH and 3-dimethylaminopropyl chloride hydrochloride, heating to 90-120 ℃ and reacting for 40-80 minutes to obtain the benzydamine hydrochloride impurity B.
Further, in the first step, the molar ratio of methyl 2-amino-5-benzylbenzoate to lithium hydroxide hydrate is 1: (2-4).
Further, in the first step and the third step, the reaction time is 40 to 80 minutes.
Further, in step two, intermediate 2 and NaNO2Is 1: 1.
Further, in the second step, the temperature is reduced to 0-5 ℃.
Further, in step two, intermediate 2, NaNO2And SnCl2In a molar ratio of 1:1: 3.
Further, in the third step, the concentration of the hydrochloric acid solution is 30-35%; the ratio of intermediate 3 to hydrochloric acid was 1:10 mmol/ml.
Further, in step four, the molar ratio of intermediate 4, NaOH, and BnCl was 1:4: 1.
Further, in the fifth step, the molar ratio of the intermediate product 5 to the 3-dimethylaminopropyl chloride hydrochloride is 1: 1-1.2.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the method provided by the invention takes 2-amino-5-benzyl benzoate as an initial raw material, obtains a final target product through five-step reaction, and has the advantages of simple and efficient whole reaction route and very strong practical value. Because the content of the impurities in the production process is very low, compared with a scheme of directly extracting the impurities from the reaction liquid, the scheme of synthesizing is more convenient and economic, and simultaneously, the blank that the compound has no literature report so far is made up.
Detailed Description
The invention provides a method for synthesizing benzydamine hydrochloride impurity B, which comprises the steps of hydrolyzing methyl ester in a molecule by using 2-amino-5-benzyl benzoate methyl ester as an initial raw material, diazotizing amino to convert the amino into hydrazine, and using hydrochloric acid to close the carboxyl and the hydrazine in the molecule to obtain a benzopyrazolyl derivative; then respectively carrying out alkylation reaction on the nitrogen atom and the oxygen atom to finally obtain the benzydamine hydrochloride impurity B.
In a preferred embodiment of the present invention, the method comprises the steps of:
step one, adding 2-amino-5-benzyl methyl benzoate, lithium hydroxide hydrate, 1,4 dioxane and water into a reaction vessel in sequence, and heating and refluxing; after the reaction is finished, EA is adopted for extraction and spin-drying to obtain an intermediate product 2;
step two, dissolving the intermediate product 2 in a hydrochloric acid solution, cooling, and then dropwise adding NaNO2Stirring the aqueous solution for 20 to 4 minutes; then SnCl is added dropwise2Hydrochloric acid solution, and finally reacting at room temperature overnight, and filtering to obtain an intermediate product 3 after the reaction is finished;
step three, sequentially adding the intermediate product 3 and a hydrochloric acid solution into a three-necked bottle, and heating and refluxing; after the reaction is finished, extracting and spin-drying to obtain an intermediate product 4;
step four, sequentially dissolving the intermediate product 4, NaOH and BnCl in DMSO to react for 50-70 minutes; after the reaction is finished, EA is adopted for extraction, water washing and column chromatography are carried out to obtain an intermediate product 5;
and step five, dissolving the intermediate product 5 in DMF, then sequentially adding NaH and 3-dimethylaminopropyl chloride hydrochloride, heating to 90-120 ℃ and reacting for 40-80 minutes to obtain the benzydamine hydrochloride impurity B.
In a preferred embodiment of the present invention, in step one, the molar ratio of methyl 2-amino-5-benzylbenzoate to lithium hydroxide hydrate is 1: (2-4); more preferably 1: 3.
In a preferred embodiment of the present invention, in step one and step three, the reaction time is 40 to 80 minutes; more preferably 60 minutes.
In a preferred embodiment of the present invention, in step two, intermediate 2 and NaNO are added2Is 1: 1.
In a preferred embodiment of the present invention, in the second step, the temperature is reduced to 0 to 5 ℃; more preferably 0 deg.c.
In a preferred embodiment of the present invention, in step two, intermediate 2, NaNO2And SnCl2In a molar ratio of 1:1: 3.
In a preferred embodiment of the present invention, in step three, the concentration of the hydrochloric acid solution is 30-35%; the ratio of intermediate 3 to hydrochloric acid was 1/10 mmol/ml.
In a preferred embodiment of the present invention, in step four, the molar ratio of intermediate 4, NaOH and BnCl is 1:4: 1.
In a preferred embodiment of the present invention, in the fifth step, the molar ratio of the intermediate product 5 to the 3-dimethylaminopropyl chloride hydrochloride is 1: 1-1.2.
In a preferred embodiment of the invention, in the fifth step, after the reaction is finished, EA is added, the mixture is washed with water for three times, the solvent is dried by spinning, and column chromatography is carried out to obtain the benzydamine hydrochloride impurity B.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.
Example 1
This example provides a method for synthesizing benzydamine hydrochloride impurity B, comprising the following steps:
step one, raw materials of methyl 1-2-amino-5-benzylbenzoate (50mg, 0.2mmol), lithium hydroxide hydrate (26mg, 0.6mmol), 1, 4-dioxane (3ml) and water (5ml) are sequentially added into a three-necked flask, heated and refluxed for 1 hour, and EA extraction of the spin-dried solvent gives intermediate 2(40mg, yield: 85%).
1H NMR(300MHz,DMSO)δ8.58(s,1H),7.51(d,J＝2.0Hz,1H),7.33–7.12(m,5H),7.08(d,J＝8.4Hz,1H),6.65(d,J＝8.4Hz,1H),3.76(s,2H).
Step two, adding the intermediate product 2(250mg, 1.036mmol) into 2ml of hydrochloric acid solution, cooling the temperature to 0 ℃, and dropwise adding NaNO2(71.5mg, 1.036mmol) in water, followed by stirring at 0 ℃ for 0.5 h, SnCl2(701mg, 3.1mmol) of hydrochloric acid was added dropwise to the above solution, followed by reaction at room temperature overnight and the reaction solution was filtered to obtain intermediate 3(188mg, yield: 70%).
Step three, sequentially adding the intermediate product 3(60mg, 0.15mmol) and concentrated hydrochloric acid (1.5ml) into a three-necked bottle, and heating and refluxing for reaction for 1 hour; EA extraction, spin-drying, column chromatography to obtain intermediate 4(40mg, yield: 70%).
1H NMR(300MHz,DMSO)δ11.28(s,1H),10.54(s,1H),7.12-7.39(m,8H),3.97(s,2H).
Step four, intermediate 4(50mg, 0.22mmol), NaOH (35mg, 0.88mmol), BnCl (28mg, 0.22mmol) and DMSO (2ml) were sequentially added to a three-necked flask, followed by reaction at room temperature for 1 hour, EA extraction, water washing, and column chromatography to give intermediate 5(35mg, yield: 50%).
1H NMR(300MHz,DMSO)δ10.85(m,1H),7.21-7.45(m,13H),5.29(s,2H),3.97(s,2H).
Step five, intermediate 5(100mg, 0.318mmol), DMF (2ml), 60% NaH (32mg), 3-dimethylaminopropyl chloride hydrochloride (60mg, 0.379mmol) were added to a three-necked flask, which was then heated to 110 ℃ to react for 1 hour, EA was added, washed three times with water, the solvent was spin-dried, and column chromatography gave product 6(76mg, yield: 60%).
1H NMR(300MHz,DMSO)δ7.47–7.34(m,2H),7.30–7.07(m,11H),5.37(s,2H),4.27(t,J＝6.6Hz,2H),3.96(s,2H),2.34(t,J＝7.0Hz,2H),2.08(d,J＝16.6Hz,6H),1.95–1.78(t,J＝7.0Hz,2H).
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. A method for synthesizing benzydamine hydrochloride impurity B is characterized in that 2-amino-5-benzyl methyl benzoate is used as an initial raw material, methyl ester in molecules is hydrolyzed, amino is converted into hydrazine through diazotization, and carboxyl and hydrazino in the molecules are subjected to ring closure by hydrochloric acid to obtain benzopyrazolyl derivatives; and then respectively carrying out alkylation reaction on nitrogen atoms and oxygen atoms to finally obtain the benzydamine hydrochloride impurity B.
2. The method of claim 1, comprising the steps of:
step one, adding the 2-amino-5-benzyl methyl benzoate, lithium hydroxide hydrate, 1, 4-dioxane and water into a reaction vessel in sequence, and heating and refluxing; after the reaction is finished, EA is adopted for extraction and spin-drying to obtain an intermediate product 2;
step two, dissolving the intermediate product 2 in a hydrochloric acid solution, cooling, and then dropwise adding NaNO2Stirring the aqueous solution for 20 to 4 minutes; then SnCl is added dropwise2Hydrochloric acid solution, and finally reacting at room temperature overnight, and filtering to obtain an intermediate product 3 after the reaction is finished;
step three, sequentially adding the intermediate product 3 and a hydrochloric acid solution into a three-necked bottle, and heating and refluxing; after the reaction is finished, extracting and spin-drying to obtain an intermediate product 4;
step four, sequentially dissolving the intermediate product 4, NaOH and BnCl in DMSO to react for 50-70 minutes; after the reaction is finished, EA is adopted for extraction, water washing and column chromatography are carried out to obtain an intermediate product 5;
and step five, dissolving the intermediate product 5 in DMF, then sequentially adding NaH and 3-dimethylaminopropyl chloride hydrochloride, heating to 90-120 ℃ and reacting for 40-80 minutes to obtain the benzydamine hydrochloride impurity B.
3. The method according to claim 2, wherein in step one, the molar ratio of methyl 2-amino-5-benzylbenzoate to lithium hydroxide hydrate is 1: (2-4).
4. The method according to claim 2, wherein the reaction time in step one and step three is 40 to 80 minutes.
5. The method of claim 2, wherein in step two, the intermediate product 2 and NaNO2Is 1: 1.
6. The method according to claim 2, wherein in the second step, the temperature is reduced to 0-5 ℃.
7. The method of claim 2, wherein in step two, the intermediate product 2, NaNO2And SnCl2In a molar ratio of 1:1: 3.
8. The method according to claim 2, wherein in step three, the concentration of the hydrochloric acid solution is 30-35%; the ratio of intermediate 3 to hydrochloric acid was 1/10 mmol/ml.
9. The process of claim 2, wherein in step four, the molar ratio of intermediate 4, NaOH, and BnCl is 1:4: 1.
10. The method of claim 2, wherein in step five, the molar ratio of the intermediate product 5 to the 3-dimethylaminopropyl chloride hydrochloride is 1:1 to 1.2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2102416A (en) * | 1981-07-01 | 1983-02-02 | Acraf | Process for the manufacture and recovery of benzydamine |
| CN105884687A (en) * | 2016-04-14 | 2016-08-24 | 梯尔希（南京）药物研发有限公司 | Preparation method of 5-benzyl benzydamine |
| CN109897006A (en) * | 2019-03-19 | 2019-06-18 | 扬州大学 | A kind of preparation method of mesosulfuron |
-
2021
- 2021-03-09 CN CN202110257024.5A patent/CN113173885A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2102416A (en) * | 1981-07-01 | 1983-02-02 | Acraf | Process for the manufacture and recovery of benzydamine |
| CN105884687A (en) * | 2016-04-14 | 2016-08-24 | 梯尔希（南京）药物研发有限公司 | Preparation method of 5-benzyl benzydamine |
| CN109897006A (en) * | 2019-03-19 | 2019-06-18 | 扬州大学 | A kind of preparation method of mesosulfuron |
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