CN115108995A - Preparation method of dihydralazine sulfate hydrate crystal form - Google Patents
Preparation method of dihydralazine sulfate hydrate crystal form Download PDFInfo
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- CN115108995A CN115108995A CN202210840151.2A CN202210840151A CN115108995A CN 115108995 A CN115108995 A CN 115108995A CN 202210840151 A CN202210840151 A CN 202210840151A CN 115108995 A CN115108995 A CN 115108995A
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- Prior art keywords
- dihydralazine
- preparation
- crystal form
- hydrate crystal
- sulfate hydrate
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- BWHAMWGGORIDBK-UHFFFAOYSA-N (4-hydrazinylphthalazin-1-yl)hydrazine;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=C2C(NN)=NN=C(NN)C2=C1 BWHAMWGGORIDBK-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960004865 dihydralazine sulfate Drugs 0.000 title claims abstract description 45
- 239000013078 crystal Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 229960002877 dihydralazine Drugs 0.000 claims abstract description 25
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012065 filter cake Substances 0.000 claims abstract description 20
- 239000008213 purified water Substances 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000001291 vacuum drying Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract 1
- 238000004042 decolorization Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicine preparation, and more particularly relates to a preparation method of a dihydralazine sulfate hydrate crystal form. The preparation method comprises the following specific steps: adding dihydralazine into a solvent, stirring, gradually dropwise adding concentrated sulfuric acid, heating after dropwise adding, and stirring until the solution is clear to obtain a solution A; adding activated carbon for decolorization, filtering to remove the activated carbon, keeping the temperature, and stirring to form salt to obtain a solution B; cooling and crystallizing, filtering to obtain a filter cake, washing the filter cake with purified water, and vacuum drying to obtain the dihydralazine crystal form containing the bishemihydrate sulfate. The molar yield ranges from 80% to 90%, and white dihydralazine sulfate is obtained. The temperature is strictly controlled to be 60-100 ℃ in the salifying process, so that the dihydralazine sulfate prepared by the preparation method is high in purity, stable in yield, high in yield, good in crystallization effect, stable in crystal form, white in finished product color, better in quality control, cheap and easily available in required raw materials, simple in required equipment and suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, and more particularly relates to a preparation method of a dihydralazine sulfate hydrate crystal form.
Background
Dihydralazine sulfate gives the chemical name: 1, 4-bis-hydrazino-2, 3-naphthyridine sulfate hemihydrate, formula: c 8 H 10 N 6 ·H 2 SO 4 ·2.5H 2 O ， Molecular weight: 333.32, structural formula:
dihydralazine sulfate is a vascular smooth muscle dilator which has been used in clinical tests in the last 70 th century, has similar action with hydralazine, and is characterized by lasting drug effect, adverse reaction after long-term administration and limited application. The reasonable Chinese guidelines on the administration of hypertension do not recommend a single drug. In recent years, medical researches show that the dihydralazine sulfate is combined with reserpine or chlorothiazide drugs, so that the dosage of reserpine and the like can be reduced, the drug resistance to the dihydralazine sulfate can be avoided, and the dihydralazine sulfate can also be combined with a blocking agent, has a synergistic effect on blood pressure reduction and can mutually offset side effects, so that the dihydralazine sulfate is also considered to be used in recent years. At present, a plurality of preparation enterprises in China have obtained a batch text. According to the IMS sales data of 2016-2020, dihydralazine is sold in India, Germany and the like, and the global sales volume tends to be stable.
In the prior art, dihydralazine sulfate is prepared by directly salifying dihydralazine in the process of preparing patent medicines, the yield of the prepared dihydralazine sulfate is unstable, the crystal form is unstable, the color is sometimes white or sometimes yellow, and the quality control is difficult to control.
Disclosure of Invention
The present invention is directed to at least one of the technical problems of the prior art, and therefore, an aspect of the present invention is to provide a method for preparing a dihydralazine sulfate hydrate crystal form.
The preparation method comprises the following specific steps:
s1, adding dihydralazine into a solvent, stirring, gradually dropwise adding concentrated sulfuric acid, heating after dropwise adding, and stirring until the solution is clear to obtain a solution A;
s2, adding activated carbon into the solution A obtained in the step S1 for decoloring, filtering to remove the activated carbon, and stirring at a maintained temperature to form a salt to obtain a solution B;
and S3, cooling and crystallizing the solution B obtained in the step S2, filtering to obtain a filter cake, washing the filter cake with purified water, and drying in vacuum to obtain the dihydralazine crystal form containing the bishemihydrate.
Preferably, the reaction equation of the preparation method is as follows:
preferably, the amount of the dihydralazine substance in the S1 is 47.32mmol, the solvent is purified water, and the concentrated sulfuric acid concentration is 98%.
Preferably, the mass ratio of the dihydralazine, the solvent and the concentrated sulfuric acid in the S1 is 1: 3-7: 0.2-1.
Preferably, the temperature in the S1 is increased to 60-100 ℃.
Preferably, the activated carbon in the S2 is decolorized for 0.5h-2 h.
Preferably, the S2 is kept at the temperature of 50-60 ℃ and stirred for 0.5-2 h to form salt.
Preferably, the temperature in the S3 is reduced to 0-25 ℃ for crystallization.
Preferably, the purified water in S3 washes the filter cake to a pH of 6-7.
Preferably, the vacuum drying temperature in the S3 is 30-40 ℃, and the time is 4-8 h.
Preferably, the preparation method has a molar yield ranging from 80% to 90% and obtains white dihydralazine sulfate.
The invention has the following beneficial effects:
the method comprises the steps of dropwise adding concentrated sulfuric acid into purified water by taking dihydralazine as a raw material, heating, stirring, dissolving, decoloring, cooling and crystallizing to obtain white dihydralazine sulfate. The temperature is strictly controlled to be 60-100 ℃ in the salifying process, so that the dihydralazine sulfate prepared by the preparation method is high in purity, stable in yield, high in yield, good in crystallization effect and stable in crystal form, the hydrate crystal form is a medicinal crystal form of the dihydralazine sulfate, the content of water is controlled by controlling the drying weight loss to be 13.0-15.0% in European pharmacopoeia, the color of a finished product is white, and the product control is better controlled; no catalyst is used, no high-pressure reaction is performed, the reaction condition is mild, the solvent is easy to recover, the method is safe and environment-friendly, the needed raw materials are cheap and easy to obtain, the three wastes are less, the needed equipment is simple, and the method is suitable for large-scale industrial production.
Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, the present invention will be described in further detail with reference to specific embodiments. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as specifically described and, therefore, the scope of the present invention is not limited by the specific embodiments disclosed below.
According to the embodiment one provided by the invention
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 80 ℃ after the dropwise adding is finished, stirring to be clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 80 ℃, stirring for 1h for salifying, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 7, vacuum drying at 40 ℃ for 6h to obtain the dihydralazine sulfate crystal form containing two times of half water. The molar yield was 85.00% yielding 13.40g of white dihydralazine sulfate.
Example two according to the present invention
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 90 ℃ after dropwise adding, stirring until the concentrated sulfuric acid is clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 90 ℃, stirring for 1h for salification, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 6, vacuum drying at the temperature of 40 ℃ for 6h to obtain the dihydralazine sulfate crystal form containing the diploid hemihydrate. The molar yield was 83.54%, yielding 13.17g of white dihydralazine sulfate.
Example III provided in accordance with the present invention
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 95 ℃ after the dropwise adding is finished, stirring to be clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 95 ℃, stirring for 1h for salifying, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 6, vacuum drying at 40 ℃ for 6h to obtain the dihydralazine sulfate crystal form containing two times of half water. The molar yield was 84.40%, yielding 13.31g of white dihydralazine sulfate.
According to the fourth embodiment of the invention
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 85 ℃ after the dropwise adding is finished, stirring to be clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 85 ℃, stirring for 1h for salifying, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 7, vacuum drying at 40 ℃ for 6h to obtain the dihydralazine sulfate crystal form containing two times of half water. The molar yield was 84.10%, yielding 13.26g of white dihydralazine sulfate.
Comparative example five
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 20 ℃ after the dropwise adding is finished, stirring until the solution is clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 20 ℃, stirring for 0.5h for salifying, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 7, and drying at 40 ℃ for 5h under vacuum. The molar yield was 58.66, yielding 9.25g of yellow dihydralazine sulfate.
Comparative example six
Adding 9.0g of dihydralazine (the amount of the dihydralazine substance is 47.32mmol) into 45g of purified water, stirring, gradually dropwise adding 4.7g of concentrated sulfuric acid (the concentration of the concentrated sulfuric acid is 98%), heating to 30 ℃ after the dropwise adding is finished, stirring until the solution is clear, adding 0.9g of activated carbon for decoloring for 1h, filtering to remove the activated carbon, keeping the temperature at 30 ℃, stirring for 0.5h for salifying, cooling to 10 ℃ for crystallization, filtering to obtain a filter cake, washing the filter cake with the purified water until the pH value is 6, and drying at 40 ℃ for 5h under vacuum. The molar yield was 57.26%, yielding 9.03g of yellow dihydralazine sulfate.
The loss on drying of dihydralazine sulfate of examples one to six was measured by the EP loss on drying test method and the results are shown in table 1.
The EP drying weight loss detection method comprises the following steps: 1.000g of dihydralazine sulfate is taken and dried for 5 hours in vacuum at 50 ℃ under the pressure of not more than 0.7 kPa.
| Name (R) | Molar yield | Colour(s) | Purity of | Loss on drying |
| Example one | 85.00％ | White colour | 99.3％ | 13.9％ |
| Example two | 83.54％ | White colour | 99.8％ | 13.8％ |
| EXAMPLE III | 84.40％ | White colour | 99.8％ | 13.9％ |
| Example four | 84.10％ | White colour | 99.4％ | 13.7％ |
| Comparative example five | 58.66％ | Yellow colour | 99.5％ | 3.9％ |
| Comparative example six | 57.26％ | Yellow colour | 99.7％ | 2.8％ |
TABLE 1 comparison of data in examples one to six
The quality of the dihydralazine sulfate prepared by the method conforms to European pharmacopoeia, the generation of a hydrate crystal form is easier to control, the hydrate crystal form is a medicinal crystal form of the dihydralazine sulfate, the moisture content is controlled by controlling the drying weight loss of 13.0-15.0% in the European pharmacopoeia, and meanwhile, the dihydralazine sulfate prepared by the preparation method has high yield and low cost and is suitable for industrial production.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and it is obvious to those skilled in the art that various modifications and variations can be made in the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a dihydralazine sulfate hydrate crystal form is characterized by comprising the following steps: the preparation method comprises the following specific steps:
s1, adding dihydralazine into a solvent, stirring, gradually dropwise adding concentrated sulfuric acid, heating after dropwise adding, and stirring until the solution is clear to obtain a solution A;
s2, adding activated carbon into the solution A obtained in the step S1 for decoloring, filtering to remove the activated carbon, and stirring at a maintained temperature to form a salt to obtain a solution B;
s3, cooling and crystallizing the solution B obtained in the step S2, filtering to obtain a filter cake, washing the filter cake with purified water, and drying in vacuum to obtain the dihydralazine crystal form containing the bishemihydrate.
2. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: the reaction equation of the preparation method is as follows:
3. the preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: the amount of the dihydralazine substance in the S1 is 47.32mmol, the solvent is purified water, and the concentration of concentrated sulfuric acid is 98%.
4. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: the mass ratio of the dihydralazine, the solvent and the concentrated sulfuric acid in the S1 is 1: 3-7: 0.2-1.
5. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: and in the S1, heating to 60-100 ℃.
6. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized by comprising the following steps: and the activated carbon in the S2 is decolorized for 0.5h-2 h.
7. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized by comprising the following steps: and (3) keeping the temperature in the S2, and stirring for 0.5-2 h at 50-60 ℃ to form salt.
8. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: and cooling the S3 to 0-25 ℃ for crystallization, and washing the filter cake with purified water to pH 6-7.
9. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized by comprising the following steps: the vacuum drying temperature in the S3 is 30-40 ℃, and the time is 4-8 h.
10. The preparation method of the dihydralazine sulfate hydrate crystal form according to claim 1, characterized in that: the preparation method has the molar yield ranging from 80% to 90% and obtains the white dihydralazine sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210840151.2A CN115108995A (en) | 2022-07-18 | 2022-07-18 | Preparation method of dihydralazine sulfate hydrate crystal form |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210840151.2A CN115108995A (en) | 2022-07-18 | 2022-07-18 | Preparation method of dihydralazine sulfate hydrate crystal form |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2484785A (en) * | 1947-12-19 | 1949-10-11 | Ciba Pharm Prod Inc | 1,4-hydrazino-phthalazine and its acid salts |
| CN85105944A (en) * | 1985-12-25 | 1987-03-18 | 武汉化工学院 | The tertiary amine catalytic synthesis method of dihydrallazine sulphate |
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2022
- 2022-07-18 CN CN202210840151.2A patent/CN115108995A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2484785A (en) * | 1947-12-19 | 1949-10-11 | Ciba Pharm Prod Inc | 1,4-hydrazino-phthalazine and its acid salts |
| CN85105944A (en) * | 1985-12-25 | 1987-03-18 | 武汉化工学院 | The tertiary amine catalytic synthesis method of dihydrallazine sulphate |
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Application publication date: 20220927 |