CN116925093A - Synthesis method of irinotecan hydrochloride - Google Patents
Synthesis method of irinotecan hydrochloride Download PDFInfo
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- CN116925093A CN116925093A CN202310914912.9A CN202310914912A CN116925093A CN 116925093 A CN116925093 A CN 116925093A CN 202310914912 A CN202310914912 A CN 202310914912A CN 116925093 A CN116925093 A CN 116925093A
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- irinotecan hydrochloride
- organic phase
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- irinotecan
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- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 title claims abstract description 43
- 229960000779 irinotecan hydrochloride Drugs 0.000 title claims abstract description 32
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims abstract description 12
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- CVEUBJIEWLINAY-UHFFFAOYSA-N formyl chloride 1-piperidin-4-ylpiperidine hydrochloride Chemical compound Cl.ClC=O.C1CCN(CC1)C1CCNCC1 CVEUBJIEWLINAY-UHFFFAOYSA-N 0.000 claims abstract description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 4
- 239000012296 anti-solvent Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229960004768 irinotecan Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- XHHRVBFXAOFPGV-UHFFFAOYSA-N C(=O)Cl.N1CCC(CC1)N1CCCCC1 Chemical compound C(=O)Cl.N1CCC(CC1)N1CCCCC1 XHHRVBFXAOFPGV-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- XDOJRMUCNNHPFI-UHFFFAOYSA-N N1(CCCCC1)C1CCNCC1.N1(CCCCC1)C1CCNCC1 Chemical compound N1(CCCCC1)C1CCNCC1.N1(CCCCC1)C1CCNCC1 XDOJRMUCNNHPFI-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthesis method of irinotecan hydrochloride, which comprises the following steps of S1: fully reacting 7-ethyl-10-hydroxycamptothecin with 4-piperidyl piperidine formyl chloride hydrochloride in the presence of N, N-dimethylformamide and 1-methylpyrrolidine at room temperature, and then quenching the reaction with saturated sodium bicarbonate solution to separate an organic phase; s2: and (3) adding the organic phase obtained in the step (S1) into an organic solvent for crystallization, filtering, adding water and concentrated hydrochloric acid into a filter cake for reaction to obtain a crude irinotecan hydrochloride product, and purifying the crude irinotecan hydrochloride product to obtain the irinotecan hydrochloride. The preparation method of the invention takes 1-methylpyrrolidine as a reaction reagent, has convenient feeding and is friendly to a system; isopropyl ether is adopted as an anti-solvent for crystallization, so that the yield is high, the post-treatment is convenient, and the industrialized mass production is facilitated; the method overcomes the defects of the prior art, is particularly important for saving production, can reduce treatment cost, and has extremely important significance and great social and economic benefits.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of irinotecan hydrochloride.
Background
Irinotecan hydrochloride (Irinotecan Hydrochloride, CPT-11) is developed by Daiichi Seiyaku company and Yakulthonsha company in Japan, is one of camptothecins antitumor drugs, has a mechanism of action of DNA topoisomerase I inhibitor, is used as a first-line drug for advanced colorectal cancer, and can also be used for postoperative adjuvant chemotherapy; has certain curative effect on lung cancer, breast cancer, pancreatic cancer, etc. The earliest 1994 market in japan under the trade name Campto (Campto) and the chemical name 7-ethyl-10- [4- (1-piperidinyl) -1-piperidinyl ] carboxyoxycamptothecin hydrochloride, the specific structure is as follows:
at present, irinotecan is prepared mainly by semisynthesis, the main synthetic route is that 4-piperidyl piperidine (4-Piperidino Piperidine) reacts with triphosgene to generate 4-piperidyl piperidine formyl chloride, and then reacts with 7-Ethyl-10-hydroxycamptothecin (7-Ethyl-10-Hydroxy-campotoxin, SN-38) under the action of pyridine to obtain Irinotecan (Irinotecan). Pyridine has malodor, a test operator has dizziness and other uncomfortable feelings, and the pyridine is easy to oxidize and change color, so that the purity, the color and the like of a final product are influenced; in addition, the pyridine has higher boiling point, the low-temperature reduced pressure distillation is not easy to remove at 115 ℃ under normal pressure, and the irinotecan Kang Yi is deteriorated by the high-temperature reduced pressure distillation, so that the method for synthesizing the irinotecan hydrochloride is provided.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and provides a synthesis method of irinotecan hydrochloride, which aims to solve the problems in the background art.
In order to achieve the above purpose, the present invention provides the following technical solutions: the synthesis method of irinotecan hydrochloride comprises the following specific steps:
s1: fully reacting 7-ethyl-10-hydroxycamptothecin with 4-piperidyl piperidine formyl chloride hydrochloride in the presence of N, N-dimethylformamide and 1-methylpyrrolidine at room temperature, and then quenching the reaction with saturated sodium bicarbonate solution to separate an organic phase;
s2: and (3) adding the organic phase obtained in the step (S1) into an organic solvent for crystallization, filtering, adding water and concentrated hydrochloric acid into a filter cake for reaction to obtain a crude irinotecan hydrochloride product, and purifying the crude irinotecan hydrochloride product to obtain the irinotecan hydrochloride.
As a preferable technical scheme of the invention, the molar ratio of the 7-ethyl-10-hydroxycamptothecin to the 4-piperidyl piperidine formyl chloride hydrochloride in the S1 is 1:1.5-2.
As a preferable technical scheme of the invention, the molar ratio of the 7-ethyl-10-hydroxycamptothecin to the 1-methylpyrrolidine in the S1 is 1:10-20.
As a preferable technical scheme of the invention, the reaction time in the S1 is 1-2 hours; the organic phase is washed 1-2 times with water.
As a preferable embodiment of the present invention, the organic solvent in S2 is isopropyl ether.
As a preferable technical scheme of the invention, the concentration of the concentrated hydrochloric acid in the S2 is 6mol/L.
As a preferable technical scheme of the invention, the purification in S2 refers to crystallization of irinotecan hydrochloride crude product in acetone.
As a preferable embodiment of the present invention, the step S2: the volume ratio of acetone to water in the purification was 3.7:1.
The beneficial effects of the invention are as follows: the preparation method of the invention takes 1-methylpyrrolidine as a reaction reagent, has convenient feeding and is friendly to a system; in addition, isopropyl ether is adopted as an anti-solvent for crystallization, so that the yield is high, the post-treatment is convenient, and the industrialized mass production is facilitated; the existing irinotecan hydrochloride preparation process generally needs a silica gel column, so that the industrial cost is increased, the time is long, and the irinotecan hydrochloride preparation method is not suitable for industrial production, overcomes the defects of the prior process, is particularly important for saving production, can reduce treatment cost, and has extremely important significance and huge social and economic benefits.
Detailed Description
The following detailed description of the preferred embodiments of the invention is provided in order to make the advantages and features of the invention more readily understood by those skilled in the art, and to provide a more clear and concise definition of the scope of the invention.
Example 1: preparation of irinotecan;
to the reaction flask were added 45g of N, N-dimethylformamide 1L, 7-ethyl-10-hydroxycamptothecin (SN 38) and 50g of 4-piperidyl piperidine formyl chloride hydrochloride, and the mixture was stirred well at room temperature. 120g of 1-methylpyrrolidine was added dropwise. Continuing to react for 1-2 hours after the addition is finished; 2500mL of saturated sodium bicarbonate solution is added to neutralize the reaction mixture, and the mixture is extracted and layered; the organic phase was separated, 2500mL of water was added to the organic phase, washed with shaking for 20 minutes, and the organic phase was separated. Adding 800mL of isopropyl ether into the organic phase, stirring and crystallizing for 2 hours, filtering, adding a filter cake into a reaction bottle, adding 300mL of purified water, and dropwise adding 40mL of concentrated hydrochloric acid (6 mol/L) solution under stirring; when the pH is measured to be about 1, stirring is continued for 15 minutes, 1100mL of acetone is evenly added dropwise under stirring, and crystallization is carried out under stirring overnight. The next day filtration, washing the filter cake with appropriate amount of acetone, and vacuum drying at 35 ℃ for 2 hours to obtain pale yellow solid with 94% yield and 99.9% HPLC purity.
Example 2: preparation of irinotecan;
to the reaction flask were added 45g of N, N-dimethylformamide 1L, 7-ethyl-10-hydroxycamptothecin (SN 38) and 50g of 4-piperidyl piperidine formyl chloride hydrochloride, and the mixture was stirred well at room temperature. 147g of 1-methylpyrrolidine are added dropwise. Continuing to react for 1-2 hours after the addition is finished; 2500mL of saturated sodium bicarbonate solution is added to neutralize the reaction mixture, and the mixture is extracted and layered; the organic phase was separated, 2500mL of water was added to the organic phase, washed with shaking for 20 minutes, and the organic phase was separated. Adding 800mL of isopropyl ether into the organic phase, stirring and crystallizing for 2 hours, filtering, adding a filter cake into a reaction bottle, adding 300mL of purified water, and dropwise adding 40mL of concentrated hydrochloric acid (6 mol/L) solution under stirring; when the pH is measured to be about 1, stirring is continued for 15 minutes, 1100mL of acetone is evenly added dropwise under stirring, and crystallization is carried out under stirring overnight. The next day filtration, washing the filter cake with appropriate amount of acetone, and vacuum drying at 35 ℃ for 2 hours to obtain pale yellow solid with 93% yield and 99.9% HPLC purity.
Example 3: preparation of irinotecan;
to the reaction flask were added 45g of N, N-dimethylformamide 1L, 7-ethyl-10-hydroxycamptothecin (SN 38) and 61g of 4-piperidyl piperidine formyl chloride hydrochloride, and the mixture was stirred well at room temperature. 120g of 1-methylpyrrolidine was added dropwise. Continuing to react for 1-2 hours after the addition is finished; 2500mL of saturated sodium bicarbonate solution is added to neutralize the reaction mixture, and the mixture is extracted and layered; the organic phase was separated, 2500mL of water was added to the organic phase, washed with shaking for 20 minutes, and the organic phase was separated. Adding 800mL of isopropyl ether into the organic phase, stirring and crystallizing for 2 hours, filtering, adding a filter cake into a reaction bottle, adding 300mL of purified water, and dropwise adding 40mL of concentrated hydrochloric acid (6 mol/L) solution under stirring; when the pH is measured to be about 1, stirring is continued for 15 minutes, 1100mL of acetone is evenly added dropwise under stirring, and crystallization is carried out under stirring overnight. The next day filtration, washing the filter cake with appropriate amount of acetone, and vacuum drying at 35 ℃ for 2 hours to obtain pale yellow solid with 93% yield and 99.9% HPLC purity.
Example 4: preparation of irinotecan;
to the reaction flask were added 45g of N, N-dimethylformamide 1.2L, 7-ethyl-10-hydroxycamptothecin (SN 38) and 50g of 4-piperidyl piperidine formyl chloride hydrochloride, and the mixture was stirred well at room temperature. 196g of 1-methylpyrrolidine are added dropwise. Continuing to react for 1-2 hours after the addition is finished; 2500mL of saturated sodium bicarbonate solution is added to neutralize the reaction mixture, and the mixture is extracted and layered; the organic phase was separated, 2500mL of water was added to the organic phase, washed with shaking for 20 minutes, and the organic phase was separated. Adding 800mL of isopropyl ether into the organic phase, stirring and crystallizing for 2 hours, filtering, adding a filter cake into a reaction bottle, adding 300mL of purified water, and dropwise adding 40mL of concentrated hydrochloric acid (6 mol/L) solution under stirring; when the pH is measured to be about 1, stirring is continued for 15 minutes, 1100mL of acetone is evenly added dropwise under stirring, and crystallization is carried out under stirring overnight. The next day filtration, washing the filter cake with appropriate amount of acetone, and vacuum drying at 35 ℃ for 2 hours to obtain pale yellow solid with 92% yield and 99.9% HPLC purity.
It can be seen from the above that: the preparation method of the invention takes 1-methylpyrrolidine as a reaction reagent, has convenient feeding and is friendly to a system; in addition, isopropyl ether is adopted as an anti-solvent for crystallization, so that the yield is high, the post-treatment is convenient, and the industrialized mass production is facilitated; the existing irinotecan hydrochloride preparation process generally needs a silica gel column, so that the industrial cost is increased, the time is long, and the irinotecan hydrochloride preparation method is not suitable for industrial production, overcomes the defects of the prior process, is particularly important for saving production, can reduce treatment cost, and has extremely important significance and huge social and economic benefits.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.
Claims (8)
1. A synthesis method of irinotecan hydrochloride, which is characterized in that: the method comprises the following specific steps:
s1: fully reacting 7-ethyl-10-hydroxycamptothecin with 4-piperidyl piperidine formyl chloride hydrochloride in the presence of N, N-dimethylformamide and 1-methylpyrrolidine at room temperature, and then quenching the reaction with saturated sodium bicarbonate solution to separate an organic phase;
s2: and (3) adding the organic phase obtained in the step (S1) into an organic solvent for crystallization, filtering, adding water and concentrated hydrochloric acid into a filter cake for reaction to obtain a crude irinotecan hydrochloride product, and purifying the crude irinotecan hydrochloride product to obtain the irinotecan hydrochloride.
2. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the molar ratio of the 7-ethyl-10-hydroxycamptothecin to the 4-piperidyl piperidine formyl chloride hydrochloride in the S1 is 1:1.5-2.
3. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the molar ratio of the 7-ethyl-10-hydroxycamptothecin to the 1-methylpyrrolidine in the S1 is 1:10-20.
4. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the reaction time in the step S1 is 1-2 hours; the organic phase is washed 1-2 times with water.
5. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the organic solvent in S2 is isopropyl ether.
6. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the concentration of the concentrated hydrochloric acid in the S2 is 6mol/L.
7. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the purification in S2 refers to crystallization of the crude irinotecan hydrochloride product in acetone.
8. The method for synthesizing irinotecan hydrochloride according to claim 1, characterized in that: the volume ratio of acetone to water in the purification of S2 is 3.7:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202310914912.9A CN116925093A (en) | 2023-07-25 | 2023-07-25 | Synthesis method of irinotecan hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310914912.9A CN116925093A (en) | 2023-07-25 | 2023-07-25 | Synthesis method of irinotecan hydrochloride |
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| CN202310914912.9A Pending CN116925093A (en) | 2023-07-25 | 2023-07-25 | Synthesis method of irinotecan hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117986204A (en) * | 2024-04-02 | 2024-05-07 | 华泰民康(沈阳)科技有限公司 | Synthesis method of dyclonine hydrochloride |
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2023
- 2023-07-25 CN CN202310914912.9A patent/CN116925093A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117986204A (en) * | 2024-04-02 | 2024-05-07 | 华泰民康(沈阳)科技有限公司 | Synthesis method of dyclonine hydrochloride |
| CN117986204B (en) * | 2024-04-02 | 2024-06-04 | 华泰民康(沈阳)科技有限公司 | Synthesis method of dyclonine hydrochloride |
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