CN117142976A - Preparation method of key intermediate of ADC drug toxin irinotecan - Google Patents
Preparation method of key intermediate of ADC drug toxin irinotecan Download PDFInfo
- Publication number
- CN117142976A CN117142976A CN202111661348.1A CN202111661348A CN117142976A CN 117142976 A CN117142976 A CN 117142976A CN 202111661348 A CN202111661348 A CN 202111661348A CN 117142976 A CN117142976 A CN 117142976A
- Authority
- CN
- China
- Prior art keywords
- compound
- irinotecan
- key intermediate
- zinc powder
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960004768 irinotecan Drugs 0.000 title claims abstract description 19
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound 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 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- 239000003053 toxin Substances 0.000 title claims abstract description 11
- 231100000765 toxin Toxicity 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940125782 compound 2 Drugs 0.000 claims abstract description 11
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The invention provides a preparation method of an ADC drug toxin irinotecan key intermediate, which comprises the following steps: (1) Reacting the compound 1 with isoamyl nitrite under the action of potassium tert-butoxide to generate a compound 2; (2) And reacting the compound 2 with zinc powder under the action of acetic acid and acetic anhydride to obtain a compound 3. The method adopts low-cost reducing agent zinc powder to replace expensive metal platinum carbon catalyst, avoids using pressure hydrogenation equipment, greatly reduces cost, and has important significance for industrialized production of irinotecan.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of an ADC drug toxin irinotecan intermediate.
Background
The irinotecan is a camptothecine derivative, developed by the first Sanzhu company, and is used as an independent chemotherapy medicament in the early stage until the clinical stage, and the main indications are bone cancer, prostatic cancer, breast cancer, pancreatic cancer and the like. However, as with most camptothecins, high fat solubility and low water solubility seriously affect the efficacy of the use. In addition, as a topoisomerase inhibitor, the specificity to tumor cells is lacking, and the use side effect is large, so that the clinical application of the topoisomerase inhibitor is limited. Increasing water solubility and targeting is a great advantage of ADC drugs. The specific antibody is combined with the antigen, the toxin is carried around the target cells, and the toxin is released near the target cells, so that the tumor cells are effectively killed, the toxic and side effects are reduced, and the irinotecan has a good application prospect as an ADC drug toxin molecule. Irinotecan is a brand new topoisomerase I inhibitor camptothecin analogue, the activity of which is 10 times that of irinotecan, and the structure of the irinotecan is shown as a formula I.
The structure of the irinotecan contains 2 chiral centers, and the synthetic and preparation routes of the irinotecan are complex. In the process of synthesizing the irinotecan, a key intermediate, namely a compound 3, is needed, and the structure is as follows:
in the prior art, after oximation reaction is carried out on the alpha-position of carbonyl of a compound 1, a platinum carbon catalyst is used for reduction under the condition of pressure hydrogenation to obtain a compound 3. Because platinum carbon catalyst is expensive, the cost is increased, and the pressure hydrogenation has high requirements on equipment, which is unfavorable for industrial production.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of an ADC drug toxin irinotecan key intermediate, which adopts low-cost reducing agent zinc powder to replace a metal platinum carbon catalyst, and avoids using pressurized hydrogenation equipment. The method has mild reaction conditions, easy purification and simple operation, can be used for carrying out amplified production with stable and acceptable yield, and can meet the requirements of the following steps in purity. Greatly reduces the cost and has important significance for industrialized production of the irinotecan.
In order to achieve the purpose of the invention, the inventor finally obtains the following technical scheme through a large amount of experimental researches:
the invention provides a preparation method of an irinotecan key intermediate, which is characterized by comprising the following steps of:
in the step (1), the reaction temperature is-10-0 ℃, the reaction time is about 2 hours, the molar ratio of the compound 1 to the isoamyl nitrite is 1:1.3, the molar ratio of the compound 1 to the potassium tert-butoxide is 1:1.15, and the reaction solvent is tetrahydrofuran.
In the step (2), zinc powder is selected as a reducing agent and no pressurized hydrogenation condition is needed, the reaction temperature is 20-30 ℃, the reaction time is about 18 hours, the mass ratio of the compound 2 to the zinc powder is 1:1, the mass volume ratio of the compound 2 to the acetic acid is 1:3, and the volume ratio of the acetic acid to the acetic anhydride is 1:1.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the present invention and are not intended to limit the invention to the embodiments described.
Example 1
Preparation of Compound 2
50.0g of compound 1, 27.5g of potassium tert-butoxide, 750mL of tetrahydrofuran and nitrogen are sequentially added into a reaction bottle, the temperature is reduced to-10 to-5 ℃, 32.5g of isoamyl nitrite is dropwise added into the system, and the reaction is carried out after the addition, and the temperature is kept. After the reaction, 1N HCl is added dropwise into the system to adjust the pH, the solvent is removed by reduced pressure distillation, 350mL of methyl tertiary butyl ether and 500mL of water are added into the residue to be pulped, suction filtration is carried out, a filter cake is leached by a proper amount of water, 250mL of methyl tertiary butyl ether is used for flushing the filter cake, and the filter cake is dried, thus 44.8g of compound 2 is obtained, and the yield is 83%.
Example 2
Preparation of Compound 3
10.0g of compound 2, 30mL of acetic acid and 30mL of acetic anhydride are sequentially added into a single-port reaction bottle, stirred under nitrogen atmosphere, then 10.0g of zinc powder is added into the reaction system, after the addition, the mixture is replaced by nitrogen, and the mixture is reacted for 18 hours at 30 ℃ under nitrogen atmosphere. After the reaction is finished, 200mL of acetonitrile and 50mL of water are added into the reaction system, suction filtration is carried out, the filtrate is crystallized in an ice bath, suction filtration is carried out, and a filter cake is dried, thus 8.5g of compound 3 is obtained as yellow solid, and the yield is 65%.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. The preparation method of the key intermediate of the ADC drug toxin irinotecan is characterized by comprising the following steps of:
(1) The compound 1 reacts with isoamyl nitrite under the action of potassium tert-butoxide to obtain a compound 2:
(2) The compound 2 reacts with zinc powder under the action of acetic acid and acetic anhydride to obtain a compound 3:
2. the method for preparing the key intermediate of the ADC drug toxin irinotecan, which is disclosed in claim 1, is characterized in that: in the step (1), the reaction temperature is-10-0 ℃, the reaction time is about 2 hours, the molar ratio of the compound 1 to the isoamyl nitrite is 1:1.3, the molar ratio of the compound 1 to the potassium tert-butoxide is 1:1.15, and the reaction solvent is tetrahydrofuran.
3. The method for preparing the key intermediate of the ADC drug toxin irinotecan, which is disclosed in claim 1, is characterized in that: in the step (2), zinc powder is selected as a reducing agent and no pressurized hydrogenation condition is needed, the reaction temperature is 20-30 ℃, the reaction time is about 18 hours, the mass ratio of the compound 2 to the zinc powder is 1:1, the mass volume ratio of the compound 2 to the acetic acid is 1:3, and the volume ratio of the acetic acid to the acetic anhydride is 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111661348.1A CN117142976A (en) | 2021-12-30 | 2021-12-30 | Preparation method of key intermediate of ADC drug toxin irinotecan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111661348.1A CN117142976A (en) | 2021-12-30 | 2021-12-30 | Preparation method of key intermediate of ADC drug toxin irinotecan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117142976A true CN117142976A (en) | 2023-12-01 |
Family
ID=88906681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111661348.1A Pending CN117142976A (en) | 2021-12-30 | 2021-12-30 | Preparation method of key intermediate of ADC drug toxin irinotecan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117142976A (en) |
-
2021
- 2021-12-30 CN CN202111661348.1A patent/CN117142976A/en active Pending
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