CN115521222A - Preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride - Google Patents
Preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride Download PDFInfo
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- CN115521222A CN115521222A CN202211144128.6A CN202211144128A CN115521222A CN 115521222 A CN115521222 A CN 115521222A CN 202211144128 A CN202211144128 A CN 202211144128A CN 115521222 A CN115521222 A CN 115521222A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride, which takes 3-fluoro-4-methylaniline as a substrate, shortens the synthesis method from 8 steps in the prior art into 4 steps by a four-step synthesis method, and also improves the total yield from 0.8 percent to 41.5 percent.
Description
Technical Field
The invention relates to the field of medicine synthesis, and in particular relates to a preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride.
Background
Chemical name of irinotecan (DX-8951): 7-ethyl-10- (4' -piperidinopiperidine) carbonyloxycamptothecin, CAS number 171335-80-1, is a DNA topoisomerase I (Toposisomerase I) inhibitor with an IC50 value of 2.2. Mu.M (0.975. Mu.g/mL), and can be used for cancer research. N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride is an important intermediate in the synthesis of irinotecan. The synthesis method of the prior art needs 8 steps and has the total yield of 0.8 percent. The existing preparation route is long, and four steps involve high-risk reactions such as nitration, hydrogenation, oxidation and the like, so that the large-batch production of the product is not facilitated.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride, which reduces the number of synthesis steps and improves the yield.
In order to solve the technical problems, the invention provides a preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride, which comprises the following steps:
the first step is as follows: in a first reaction solvent, compound 1 (3-fluoro-4-methylaniline) and an amino protective agent generate compound 2 under the action of acid 1;
the second step: in a second reaction solvent, carrying out bromination substitution on the compound 2 and a bromination reagent to generate a compound 3;
the third step: in a third reaction solvent, generating a compound 4 by the compound 3 and cyclobutanone under the action of a base 3;
the fourth step: in a fourth reaction solvent, reacting the compound 4 with an oxidant under the action of a catalyst to generate a compound 5 (N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride);
the reaction formula is as follows:
wherein the content of the first and second substances,
the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide and acetonitrile;
the amino protective agent is selected from any one or more of pivalic anhydride, boc anhydride and benzyl chloroformate;
the acid 1 is selected from any one or more of concentrated sulfuric acid, concentrated hydrochloric acid and glacial acetic acid;
the second reaction solvent is selected from any one or more of acetonitrile and tetrahydrofuran;
the brominating agent is selected from any one or more of N-bromosuccinimide, bromine, phosphorus tribromide and aluminum tribromide;
the third reaction solvent is selected from one or more of tetrahydrofuran, dioxane and normal hexane;
the base 3 is selected from any one or more of n-butyl lithium, methyl lithium, phenyl lithium, tert-butyl lithium and sec-butyl lithium;
the fourth reaction solvent is selected from any one or more of dichloromethane, water and acetonitrile;
the catalyst is selected from any one or more of silver nitrate, copper powder, copper sulfate, cuprous bromide, silver acetate and silver fluoride;
the oxidant is selected from any one or more of potassium peroxodisulfate, ammonium ceric nitrate, 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (selectflour).
Specifically, in the first step, the feeding molar ratio of the compound 1, the pivalic anhydride amino protecting agent and the acid 1 is 1: (2-8): (0.01-0.1).
Specifically, in the first step, the reaction temperature is 10-20 ℃ and the reaction time is 0.2-1 hour.
Specifically, in the second step, the feeding molar ratio of the compound 2 to the brominating agent is 1: (1-2).
Specifically, in the second step, the reaction temperature is 35-45 ℃, and the reaction time is 1-3 hours.
Specifically, in the third step, the feeding molar ratio of the compound 3, the alkali 3 and the cyclobutanone is 1 (1.8-2.8): (1.5-2.5).
Specifically, in the third step, the reaction temperature is-60 ℃ to-80 ℃, and the reaction time is 0.2 to 1 hour.
Specifically, in the fourth step, the feeding molar ratio of the compound 4, the oxidant and the catalyst is 1: (1-3): (0.05-0.2).
Specifically, in the fourth step, the reaction temperature is 10 ℃ to 30 ℃ and the reaction time is 6 to 10 hours.
The invention provides a method for synthesizing key intermediate N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride for preparing irinotecan by a stable process, which shortens the synthesis method from 8 steps in the prior art to 4 steps, improves the total yield from 0.8 percent to 41.5 percent, and has the advantages of simple and convenient operation, low cost and high environmental friendliness.
Detailed Description
The technical solutions in the present invention will be described clearly and completely below, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE one preparation of N- (3-fluoro-4-methyl) palmitic anhydride (Compound 2)
The reaction formula of this example is as follows:
to a solution of pivalic anhydride (4 eq), concentrated sulfuric acid (0.05 eq), and tetrahydrofuran (1.4 l) was added 3-fluoro-4-methylaniline (compound 1, 200g, 1eq) at 15 ℃. After this solution had reacted at 15 ℃ for half an hour and after the reaction was complete, the reaction was poured into 2 liters of ice water and stirred at 15 ℃ for half an hour. The solution was then filtered and the filter cake was washed with water (1 liter x 3) to give 316g of the product N- (3-fluoro-4 methyl) palmitic anhydride (compound 2, grey solid) in 95% yield.
EXAMPLE two, preparation of N- (2-bromo-5-fluoro-4-methyl) palmitic anhydride (Compound 3)
The reaction formula for this example is as follows:
NBS (1.1 eq) was added to a solution of N- (3-fluoro-4 methyl) palmitic anhydride (compound 2,2g, 1eq) in acetonitrile (12 ml) at 0 deg.C. This solution was reacted at 40 ℃ for 2 hours, and after completion of the reaction, the reaction solution was poured into 30 ml of ice water and stirred at 15 ℃ for half an hour. The solution was then filtered and the filter cake was washed with water (20 ml x 3) to give the product N- (2-bromo-5-fluoro-4-methyl) palmitic anhydride (compound 3, yellow solid) 2.64g, 96% yield.
EXAMPLE III preparation of N- (5 fluoro-2- (1-hydroxycyclobutyl) -4-methyl-palmitic anhydride (Compound 4)
The reaction formula of this example is as follows:
one tetrahydrofuran (1L) solution of N- (2-bromo-5-fluoro-4-methyl) palmitic anhydride (compound 3, 100g, 1eq) is cooled to-70 ℃, then N-butyllithium solution (2.5M, 2.5eq) is slowly added dropwise to the solution, the temperature is kept at-70 ℃, stirring is carried out for 15 minutes, then cyclobutanone (2 eq) tetrahydrofuran (100 mL) solution is added dropwise to the system, the solution is stirred at-70 ℃ for half an hour, and then the system is heated to 15-25 ℃ and is continuously stirred for half an hour. After the reaction was completed, a saturated aqueous ammonium chloride solution (500 ml) was added to the system, extracted three times with ethyl acetate (300 ml), and the organic phases were combined and washed with a saturated saline solution, dried over sodium sulfate for half an hour, filtered to obtain a mother liquor, and the mother liquor was vacuum-dried to obtain a crude product. Dissolving the crude product with ethanol (200 ml), heating and stirring the system to 80 ℃, keeping for 3 hours, naturally cooling the solution to 20 ℃, and continuously stirring for 12 hours to precipitate solids. The solution was filtered and the filter cake was washed with ethanol (10 ml x 2) to give 63.2g of N- (5 fluoro-2- (1-hydroxycyclobutyl) -4 methyl palmitic anhydride (compound 4, white solid) in 65% yield.
EXAMPLE preparation of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride (Compound 5)
The reaction formula of this example is as follows:
to a stirred solution of N- (5-fluoro-2- (1-hydroxycyclobutyl) -4-methyl palmitic anhydride (compound 4, 10.26g, 1eq) in water (30 ml) and dichloromethane (30 ml) was added silver nitrate (0.2 eq) and potassium peroxodisulfate (1.5 eq) at 20 ℃ after the solution had reacted for 8 hours, the reaction was filtered after completion, the mother liquor was extracted three times with dichloromethane (50 ml), the organic phases were combined and concentrated under vacuum and spin dried to give 7.13g of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride (compound 5, yellow solid) in 70% yield.
The total yield of the four steps in the route is 41.5 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A method for preparing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride, comprising the steps of:
the first step is as follows: in a first reaction solvent, compound 1 (3-fluoro-4-methylaniline) and an amino protective agent generate compound 2 under the action of acid 1;
the second step: in a second reaction solvent, carrying out bromination substitution on the compound 2 and a bromination reagent to generate a compound 3;
the third step: in a third reaction solvent, generating a compound 4 by the compound 3 and cyclobutanone under the action of a base 3;
the fourth step: in a fourth reaction solvent, reacting the compound 4 with an oxidant under the action of a catalyst to generate a compound 5 (N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride);
the reaction formula is as follows:
wherein, the first and the second end of the pipe are connected with each other,
the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide and acetonitrile;
the amino protective agent is selected from any one or more of pivalic anhydride, boc anhydride and benzyl chloroformate;
the acid 1 is selected from any one or more of concentrated sulfuric acid, concentrated hydrochloric acid and glacial acetic acid;
the second reaction solvent is selected from any one or more of acetonitrile and tetrahydrofuran;
the brominating agent is selected from any one or more of N-bromosuccinimide, bromine, phosphorus tribromide and aluminum tribromide;
the third reaction solvent is selected from one or more of tetrahydrofuran, dioxane and normal hexane;
the base 3 is selected from any one or more of n-butyl lithium, methyl lithium, phenyl lithium, tert-butyl lithium and sec-butyl lithium;
the fourth reaction solvent is selected from any one or more of dichloromethane, water and acetonitrile;
the catalyst is selected from any one or more of silver nitrate, copper powder, copper sulfate, cuprous bromide, silver acetate and silver fluoride;
the oxidant is selected from any one or more of potassium peroxodisulfate, ammonium ceric nitrate, 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (selectflour).
2. The process for preparing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein in the first step, the molar ratio of compound 1, amino protecting agent and acid 1 is 1: (2-8): (0.01-0.1).
3. The method for producing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the reaction temperature is 10 to 20 ℃ and the reaction time is 0.2 to 1 hour in the first step.
4. The method for preparing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the feeding molar ratio of the compound 2 to the brominating agent in the second step is 1: (1-2).
5. The process for producing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the reaction temperature in the second step is 35 to 45 ℃ and the reaction time is 1 to 3 hours.
6. The process for producing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the molar ratio of compound 3, base 3 and cyclobutanone in the third step is 1 (1.8-2.8): (1.5-2.5).
7. The process for producing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the reaction temperature in the third step is-60 ℃ to-80 ℃ and the reaction time is 0.2 to 1 hour.
8. The process according to claim 1, wherein in the fourth step, the molar ratio of the compound 4 to the oxidizing agent to the catalyst is 1: (1-3): (0.05-0.2).
9. The process for producing N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride according to claim 1, wherein the reaction temperature in the fourth step is 10 to 30 ℃ and the reaction time is 6 to 10 hours.
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| CN202211144128.6A CN115521222A (en) | 2022-09-20 | 2022-09-20 | Preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride |
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| CN202211144128.6A CN115521222A (en) | 2022-09-20 | 2022-09-20 | Preparation method of N- (3-fluoro-4-methyl-8-oxo-5, 6,7, 8-tetrahydronaphthalene) palmitic anhydride |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101005840A (en) * | 2004-06-04 | 2007-07-25 | 查塔姆生物技术有限公司 | Process to prepare camptothecin derivatives and novel intermediate and compounds thereof |
| CN111065621A (en) * | 2017-08-31 | 2020-04-24 | 第一三共株式会社 | Novel method for preparing antibody-drug conjugates |
| CN111470998A (en) * | 2020-06-28 | 2020-07-31 | 上海皓元生物医药科技有限公司 | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof |
| CN112584899A (en) * | 2018-07-03 | 2021-03-30 | 诺华股份有限公司 | NLRP modulators |
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- 2022-09-20 CN CN202211144128.6A patent/CN115521222A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101005840A (en) * | 2004-06-04 | 2007-07-25 | 查塔姆生物技术有限公司 | Process to prepare camptothecin derivatives and novel intermediate and compounds thereof |
| CN101659668A (en) * | 2004-06-04 | 2010-03-03 | 查塔姆生物技术有限公司 | Process to prepare camptothecin derivatives and novel intermediate and compounds thereof |
| CN111065621A (en) * | 2017-08-31 | 2020-04-24 | 第一三共株式会社 | Novel method for preparing antibody-drug conjugates |
| CN112584899A (en) * | 2018-07-03 | 2021-03-30 | 诺华股份有限公司 | NLRP modulators |
| CN111470998A (en) * | 2020-06-28 | 2020-07-31 | 上海皓元生物医药科技有限公司 | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof |
| CN111875517A (en) * | 2020-06-28 | 2020-11-03 | 上海皓元生物医药科技有限公司 | Intermediate for synthesizing camptothecin derivative and preparation method and application thereof |
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