CN115724758A - Camptothecin derivative intermediate, synthetic method thereof and method for synthesizing camptothecin derivative by using intermediate - Google Patents

Camptothecin derivative intermediate, synthetic method thereof and method for synthesizing camptothecin derivative by using intermediate Download PDF

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CN115724758A
CN115724758A CN202110972653.6A CN202110972653A CN115724758A CN 115724758 A CN115724758 A CN 115724758A CN 202110972653 A CN202110972653 A CN 202110972653A CN 115724758 A CN115724758 A CN 115724758A
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reaction
catalyst
palladium
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郑骏浩
俞哲健
周靖
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
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    • 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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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • 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 camptothecin derivative intermediate, a synthesis method thereof and a method for synthesizing a camptothecin derivative by using the intermediate. The preparation method has the advantages of cheap and easily-obtained raw materials, simple synthetic route of the intermediate, avoidance of oximation, catalytic hydrogenolysis and one-pot reaction of amino protection, great reduction of reaction steps, mild operation conditions, reduction of operation difficulty, low energy consumption and suitability for industrial scale-up production; the atom utilization rate is improved, and the method is more suitable for the industrial application of green chemistry; the yield of the synthesis of the derivatives of the ixitacon is improved, and the cost is further reduced.

Description

Camptothecin derivative intermediate, synthetic method thereof and method for synthesizing camptothecin derivative by using intermediate
Technical Field
The invention belongs to the technical field of medical intermediates and organic synthesis, and particularly relates to an intermediate for synthesizing a camptothecin derivative, a preparation method of the intermediate and a synthesis method for synthesizing the camptothecin derivative by using the intermediate.
Background
The antibody-conjugated drug (ADC) combines the high specificity of a monoclonal antibody drug with the high activity of a small molecular cytotoxic drug, so as to improve the targeting property of a tumor drug and reduce toxic and side effects. The ADC medicine has accurate identification of target spots and no influence on non-cancer cells, greatly improves the medicine effect, reduces toxic and side effects, and is concerned by people in the field of medicine research and development. (patent documents 1 and 2 and non-patent documents 1 to 3)
As one such antibody-drug conjugate, an antibody-drug conjugate comprising an antibody and irinotecan, which is a topoisomerase I inhibitor, as its components is known (patent documents 3 to 5 and non-patent documents 4 and 5). Since these antibody-drug conjugates exert particularly excellent antitumor effects and safety, they are currently under clinical research. The structure of Exatecan (eicitan) is shown below:
Figure BDA0003226448570000011
patent EP0495432B1 discloses an Exatecan (irinotecan) compound and a process for its preparation, the reaction process being as follows:
Figure BDA0003226448570000021
another synthesis of derivatives of irinotecan is also disclosed in patent WO1996026181 A1:
Figure BDA0003226448570000031
the two process routes are continuously subjected to repeated reactions: in the first route, the upper carbonyl group is oxidized after decarbonylation, the upper amino group is protected after acetyl group is protected by deamination, and the yield is only 5.6 percent; and the second route repeatedly carries out processes such as ring closing, ring opening, oxidation, reduction and the like, and potassium permanganate is adopted in the reaction process, so that certain danger is caused to the production process. The two routes have long reaction steps, low atom utilization rate and more complex reaction operation, and are not suitable for industrial scale-up production.
Patent document WO2019044946A1 carries out a series of optimizations for the synthesis of an ixitacon derivative intermediate and discloses the following synthetic route three:
Figure BDA0003226448570000041
the process route for synthesizing and preparing the ixitakang from the 2-fluoro-1-methyl-4-nitrobenzene comprises 10 steps, and the total yield is about 5 percent.
Another synthetic route for intermediates of derivatives of ixitekang is also disclosed in patent CN111470998B by the company goshao shanghai:
Figure BDA0003226448570000051
the bromination reagent used in the bromination reaction in the synthetic route is liquid bromine, belongs to highly toxic products and corrosive products, has certain danger in the amplification production, and the reaction process involves the use of a Grignard reagent, which is easy to degrade when meeting air, needs to be carried out in an ultralow temperature environment, and has higher requirements on reaction equipment. The rearrangement reaction has low selectivity and complex post-treatment, and is not suitable for industrial scale-up production. The third synthetic route and the fourth synthetic route can not avoid oximation, catalytic hydrogenolysis and one-pot reaction of amino protection, relate to dangerous processes such as nitration, hydrogenation and the like, and have larger industrial production difficulty.
Therefore, in order to meet the production requirement of the ixitakang, a synthesis route of an ixitakang intermediate which is high in yield and suitable for industrial production needs to be developed urgently.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of the ixitaconate mesylate, an intermediate and a preparation method thereof.
The invention relates to a preparation method of Icetikang mesylate, which comprises the following steps:
(f) Carrying out intramolecular Friedel-crafts acylation reaction on the compound A under the action of an intramolecular cyclization reagent to obtain a compound 6;
(g) Carrying out selective deamination protection on the compound 6 to obtain a compound B;
(h) Carrying out condensation reaction on the compound B and a compound 7 to obtain a compound 8;
(i) Hydrolyzing the compound 8 under the action of methanesulfonic acid to obtain the ixitankan, namely a compound 9;
Figure BDA0003226448570000061
wherein, in the step (f), the cyclizing reagent is selected from Friedel-crafts acylation reagents, such as a mixed reagent of protonic acid and anhydride or a mixed reagent of chlorinated reagent and Lewis acid or PPA polyphosphate;
preferably, the protonic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;
and/or the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;
preferably, the chlorinating reagent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;
and/or the Lewis acid is selected from aluminum trichloride, stannic chloride and ferric salt.
In one embodiment, in step (f), the cyclizing reagent is added in an amount at least sufficient to allow the reaction to proceed, and preferably the ratio of the amount of the cyclizing reagent to the amount of the compound a is 0.5 to 20:1, more preferably 1 to 5:1.
further, the reaction temperature in the step (f) is preferably-40 to 150 ℃, more preferably 0 to 100 ℃, and still more preferably 0 to 80 ℃. Further, the reaction time in step (f) is preferably 0.5 to 24 hours, more preferably 2 to 12 hours.
Further, in step (g), it is preferably carried out using hydrochloric acid or a mixed solution of hydrochloric acid and alcohol, and may be more preferably carried out using 2N hydrochloric acid/ethanol.
Further, in the step (g), the reaction temperature is preferably 40 to 100 ℃, and more preferably 50 to 80 ℃; the reaction time is preferably from 2 to 8 hours, more preferably from 3 to 6 hours.
In one embodiment, in step (h), compound B and compound 7 undergo a condensation reaction under the action of pyridinium p-toluenesulfonate, o-cresol and toluene to obtain compound 8.
Further, in the step (h), it is preferable that the amount of the compound B to the compound 7 is 1:0.9 to 1.5, more preferably 1:1.0 to 1.1.
Further, in the step (h), it is preferable that the amount ratio of the compound B to the pyridinium p-toluenesulfonate is 1:0.01 to 0.30, more preferably 1:0.05 to 0.20.
Further, in the step (h), it is preferable that the mass ratio of the compound B to the o-cresol is 1:0.5 to 4.0, more preferably 1:1.0 to 3.5.
Further, in the step (h), the reaction temperature is preferably 80 to 130 ℃, more preferably 100 to 120 ℃.
Further, in the step (h), the reaction time is preferably 18 to 72 hours, and more preferably 24 to 36 hours. As an embodiment, in step (i), the reaction is performed in a solvent, preferably, the solvent is selected from one or more of water, 2-methoxyethanol, ethylcyclohexane or toluene, preferably a mixed solution of water and toluene; the adding amount of the solvent is 10-60 ml/g based on the mass of the compound 8.
Further, in the step (i), the reaction temperature is preferably 70 to 100 ℃, more preferably 80 to 90 ℃.
Further, in step (i), the reaction time is preferably 4 to 12 hours, more preferably 6 to 8 hours.
The invention also relates to a new intermediate compound A which can be used as a synthetic compound 6 or the imatinib or the mesylate thereof,
Figure BDA0003226448570000081
the invention also relates to a preparation method of the intermediate compound A, which comprises the following steps:
(e) Carrying out catalytic hydrogenation reaction on the compound 5 in the presence of a catalyst to obtain a compound A,
Figure BDA0003226448570000082
further, in the step (e), the catalyst is selected from a palladium catalyst, a platinum catalyst, a nickel catalyst, a ruthenium catalyst or a rhodium catalyst, more preferably a palladium on carbon catalyst, and still more preferably a 5% palladium on carbon catalyst.
Further, in the step (e), the amount of the catalyst added is at least based on the reaction, and it is preferable that the mass ratio of the catalyst to the compound 5 is 0.02 to 0.4:1, more preferably 0.05 to 0.15.
Further, in the step (e), the reaction is carried out in an organic solvent selected from acetonitrile, dichloromethane, chloroform, methanol, ethanol, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, water, and a mixed solvent thereof.
Further, in the step (e), the adding amount of the organic solvent is 10 to 60ml/g based on the mass of the compound 5.
Further, in the step (e), the reaction temperature is 40-70 ℃, preferably 50-70 ℃; the reaction time is 0.5 to 24 hours, preferably 6 to 12 hours.
The invention also relates to a method for preparing the intermediate compound 5, which is used as an intermediate for preparing the compound 6 or the incarnate or the mesylate thereof,
Figure BDA0003226448570000091
the invention also relates to a preparation method of the compound 5, which comprises the following steps:
(d) The compound 4 and 2-acetamido-butyl-3-olefine acid are subjected to coupling reaction under the action of a coupling catalyst and an alkaline substance to obtain a compound 5,
Figure BDA0003226448570000092
wherein R is selected from halogen, sulfonate group or diazo group, e.g. iodine, trifluoromethanesulfonyloxy.
Further, in the step (d), the coupling catalyst is a complex formed by palladium salt and phosphine ligand;
and/or said palladium salt is selected from palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium, palladium nitrate or triphenylphosphine palladium dichloride, preferably palladium acetate;
and/or said phosphine ligand is selected from the group consisting of triphenylphosphine, tricyclohexylphosphine, tri (o-tolyl) phosphine, tris [3, 5-bis (trifluoromethyl) phenyl ] phosphine, triisopropylphosphine and dicyclohexyl- (2, 6-diisopropylphenyl) phosphine, preferably tri (o-tolyl) phosphine.
Further, in the step (d), the basic substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium tert-butoxide, and is preferably triethylamine.
Further, in step (d), the ratio of the amounts of said compound 4 and 2-acetamido but-3-enoic acid in step (d) is 1:1.0 to 3.0, such as 1.2 to 1.5;
and/or the coupling catalyst is added in an amount based on the amount of the phosphine ligand substance, and the ratio of the amount of the compound 4 to the amount of the phosphine ligand substance is 1:0.05 to 0.75, for example 1:0.15 to 0.30;
and/or the ratio of the amount of said compound 4 to the amount of basic material is 1:1.0 to 15.0, for example 1:3.0 to 10.0.
Further, in the step (d), the reaction is carried out in an organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethylacetamide, toluene, water and a mixed solvent thereof; the adding amount of the organic solvent is 10-60 ml/g based on the mass of the compound 4.
Further, in the step (d), the reaction temperature is 20-110 ℃, for example, 50-80 ℃; the reaction time is 2 to 24 hours, preferably 8 to 16 hours.
The invention also relates to a preparation method of the compound 4, which comprises the following steps:
(a) Converting the compound 1 to obtain a compound 2;
(b) The compound 2 is subjected to catalytic hydrogenation reaction under the action of a catalyst to obtain a compound 3;
(c) Carrying out acylation reaction on the compound 3 and an acylating agent under the action of a catalyst to obtain a compound 4;
Figure BDA0003226448570000111
r is selected from halogen, sulfonate group or diazo group, e.g. iodine, trifluoromethanesulfonyloxy.
Further, in step (a), preferably, the iodinating agent is selected from iodine and N-iodosuccinimide, more preferably N-iodosuccinimide; the amount of N-iodosuccinimide is not limited as long as the reaction proceeds, and is preferably 1 to 1.5 equivalents. This step may be preferably carried out in a mixed solvent of sulfuric acid and other solvents.
Further, in the step (a), it is preferable that the reaction solvent is selected from the group consisting of dichloromethane, chloroform, 1, 2-dimethoxyethane, hexane, pentane, heptane, cyclohexane, ethylcyclohexane, benzene, toluene, chlorobenzene, and a mixed solvent thereof.
Further, in the step (a), the reaction temperature is preferably-10 to 30 ℃ and more preferably 0 to 10 ℃.
Further, in the step (a), the reaction time is preferably 0.5 to 4 hours, more preferably 1.5 to 2 hours.
Further, in the step (b), preferably, the catalyst is one or more selected from rhodium carbon catalyst, platinum dioxide, titanium trichloride, nickel chloride, zinc powder and iron powder, and more preferably, is platinum carbon catalyst; the amount of the catalyst is not limited as long as the reaction proceeds, and preferably, the mass ratio of the catalyst to the compound 2 is 0.05 to 0.4.
Further, in the step (b), it is preferable that the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, ethyl acetate and water and a mixed solvent thereof; the adding amount of the reaction solvent is 10-60 ml/g based on the mass of the compound 1.
Further, in the step (b), the reaction temperature is preferably 40 to 70 ℃, more preferably 50 to 70 ℃.
Further, in the step (b), the reaction time is preferably 0.5 to 8 hours, more preferably 2 to 4 hours.
Further, in the step (c), preferably, the acylating agent is selected from one or more of acetic anhydride, acetyl chloride, ketene, chloroacetate and nitriloacetate, and is more preferably acetic anhydride; the mass ratio of the acylating agent to the compound 2 is 0.5-1.5: 1, more preferably 0.75 to 1.
Further, in step (c), preferably, the reaction is carried out under the action of a base selected from triethylamine, isopropylamine, pyridine, sodium carbonate, potassium carbonate and potassium tert-butoxide, more preferably triethylamine; the ratio of the amount of the base to the amount of the compound 2 is 0.5 to 1.5:1, more preferably 0.75 to 1.5.
Further, in the step (c), preferably, the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene, ethyl acetate and water and a mixed solvent thereof, more preferably ethyl acetate; the adding amount of the reaction solvent is 10-60 ml/g based on the mass of the compound 2.
Further, in the step (c), the reaction temperature is preferably from-10 to 40 ℃, more preferably from 0 to 30 ℃.
Further, in the step (c), the reaction time is preferably 2 to 24 hours, more preferably 3 to 12 hours.
The E and Z forms represented by compounds 5, 6 described herein exist as geometric isomers, and both are included in the compounds represented and are therefore included within the scope of the present invention. The compound represented by compound 5 of the present invention may be a mixture of forms E and Z, and the mixture may be directly used in the next step.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a new intermediate 5 and A of the ixitaconate mesylate, and develops the research field of important intermediates of the ixitaconate derivatives;
(2) The raw materials are cheap and easy to obtain, the synthetic route of the intermediate is simple, the one-pot reaction of oximation, catalytic hydrogenolysis and amino protection is avoided, the reaction steps are greatly reduced, the operation condition is mild, the operation difficulty is reduced, the energy consumption is low, and the method is suitable for industrial large-scale production;
(3) The atom utilization rate is improved, and the method is more suitable for the industrial application of green chemistry; the yield of the synthesis of the derivatives of the Icetirizine is improved, and the cost is further reduced.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments, but those skilled in the art will understand that the following described examples are a part of the examples of the present invention, rather than all examples, and are only used for illustrating the present invention, and should not be construed as limiting the scope 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. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Preparation of Compound 4a
Figure BDA0003226448570000131
Concentrated sulfuric acid (90%, 50 mL) was added to a three-necked flask, and after cooling to about 1 deg.C, compound 1 (10g, 64.5 mmol) was added, and then N-iodosuccinimide (20.4g, 90.2 mmol) was added to the reaction flask in six portions. The mixture was stirred at about 2 ℃ for 2 hours. The resulting reaction solution was added to cold water (100 mL). Toluene (50 mL) was added for extraction separation, and the aqueous layer was removed. Then, the organic layer was washed with water (50 mL), 5.0wt% aqueous sodium carbonate (50 mL), 5wt% aqueous sodium sulfite (25mL, 3 times). The organic layer was then concentrated under reduced pressure to give crude compound 2 (200 g).
To the reaction vessel were added compound 2 and ethyl acetate (15 mL), followed by a suspension of 1% platinum-on-carbon catalyst (2.1 g) and ethyl acetate (90 mL), the atmosphere was replaced with nitrogen, and then replaced with hydrogen. The reaction solution was stirred at 65 ℃ for 3 hours in a stream of hydrogen (0.2 MPa) and cooled to room temperature. Insoluble material was separated from the resulting suspension by filtration and washed with ethyl acetate (30 mL). Then, the filtrate was washed with 6.5wt% aqueous sodium bicarbonate (25 mL) and 5wt% brine (25 mL), and the resulting organic layer was concentrated under reduced pressure to give a solution of Compound 3 in ethyl acetate (50 mL).
An ethyl acetate solution of compound 3 and triethylamine were added to a three-necked flask, cooled to about 0 ℃, acetic anhydride (3.4 ml,35.4 mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, saturated saline (50 ml) was added thereto, and the aqueous layer was removed after separation. The organic layer was concentrated under reduced pressure. Acetonitrile (50 mL) and water (50 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (20 mL). The obtained crystals were dried at 40 ℃ under reduced pressure to obtain compound 4a as white crystals (6.4 g, yield 38%).
1 H NMR(500MHz,CDCl 3 )δ7.43(s,1H),7.38(d,J＝7.8Hz,1H), 7.19(m,1H),2.27(d,J＝7.8Hz,,3H),2.15(s,3H).
Example 2
Preparation of Compound A
Figure BDA0003226448570000151
A solution of compound 4a (10.0g, 34.1 mmol), 2-acetamido-but-3-enoic acid (6.1 g, 42.6 mmol) and triethylamine (23.7mL, 170.6 mmol) in acetonitrile (200 mL) was degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tris (o-tolyl) phosphine (1.5 g, 5.12 mmol) and palladium (II) acetate (0.4g, 1.71mmol) were added, and the mixture was degassed under reduced pressure, the atmosphere was replaced with nitrogen, then heated under reflux for 8 hours, and cooled to room temperature. 2-Methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution which had been cooled to room temperature, and a 25w/v% aqueous solution of sodium hydroxide (6.5mL, 40.2mmol) was added to remove the organic layer. The aqueous layer was washed with 2-methyltetrahydrofuran (30mL, 2X) to remove the organic layer. Concentrated hydrochloric acid (36%, 6.0g,60.1 mmol) and 2-methyltetrahydrofuran (30mL, 2X) were added to the aqueous layer. After separation, the aqueous layer was removed and the organic layer was washed with 10wt% brine (60 mL). Concentration under reduced pressure gave an organic layer which gave crude compound 5 (10.8 g) containing the geometric isomer.
A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on charcoal (2.1 g) to a crude compound 5 (10.8 g) containing geometric isomers, replacing the atmosphere with nitrogen and then hydrogen. The mixture was stirred at 60 ℃ for 8 hours in a stream of hydrogen (0.5 MPa) and cooled to room temperature. Insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (30 mL). The filtrate was adjusted to a pH of about 2 with 1N hydrochloric acid solution. The solvent was concentrated to dryness under reduced pressure, acetonitrile (40 mL) and water (80 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried at 40 ℃ under reduced pressure to obtain compound a as white crystals (9.2 g, yield 87%).
1 H NMR(500MHz,DMSO-d6)δ12.64(s,1H),9.99(s,1H),8.29(d, J＝7.8Hz,1H),7.41(dd,J＝12.2,2.1Hz,1H),7.07(d,J＝2.1Hz,1H), 4.21(m,1H),1.75-1.88(m,2H),2.59(m,2H),2.08(s,3H),2.02(s,3H), 1.89(s,3H).
13 C NMR(126MHz,DMSO-d6)δ174.02,169.93,168.88,161.73, 159.83,142.40,138.36,117.15,115.18,104.20,52.05,32.07,29.34,24.45, 22.84,10.07.
ESI-MS:m/z C 15 H 19 FN 2 O 4 [M+H]+ calculated value of 311.13; fruit of Chinese wolfberryMeasured value 311.18;
example 3
Preparation of Compound A
Figure BDA0003226448570000161
Compound 4a (10.0g, 34.1mmol), 2-acetamido-but-3-enoic acid (6.1 g, 42.6 mmol) and sodium hydrogencarbonate (8.6 g, 102mmol) were added to a mixed solvent of toluene and water (150 mL/50 mL), the reaction solution was degassed under reduced pressure and the atmosphere was replaced with nitrogen, and then triphenylphosphine palladium dichloride (1.2g, 1.7mmol) was added, and the mixture was degassed under reduced pressure, and the atmosphere was replaced with nitrogen, and heated at 100 ℃ for reflux reaction for 24 hours. 2-Methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution which had been cooled to room temperature, and a 25w/v% aqueous solution of sodium hydroxide (6.5mL, 40.2mmol) was added to remove the organic layer. The aqueous layer was washed with 2-methyltetrahydrofuran (30mL, 2X) to remove the organic layer. Concentrated hydrochloric acid (36%, 6.0g,60.1 mmol) and 2-methyltetrahydrofuran (30mL, 2X) were added to the aqueous layer. After separation, the aqueous layer was removed and the organic layer was washed with 10wt% brine (60 mL). Concentration under reduced pressure gave an organic layer which gave crude compound 5 (9.2 g).
A suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on charcoal (2.1 g) to a crude compound 5 (9.0 g) containing the geometric isomer, replacing the atmosphere with nitrogen and then with hydrogen. The mixture was stirred in a stream of hydrogen (0.4 MPa) at 40 ℃ for 16 hours and cooled to room temperature. Insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (20 mL). The filtrate was adjusted to a pH of about 2 with 1N hydrochloric acid solution. The solvent was concentrated to dryness under reduced pressure, acetonitrile (40 mL) and water (80 mL) were added to the concentrated residue, and the concentrated residue was stirred at 25 ℃. The precipitated crystals were collected by filtration and washed with 50% aqueous acetonitrile (10 mL). The obtained crystals were dried at 40 ℃ under reduced pressure to obtain compound a as white crystals (8.5 g, yield 80%).
Comparative example 1
Figure BDA0003226448570000171
A solution of compound 4a (0.84g, 3.4 mmol), 2-butenoic acid-3- (acetylamino) -phenylmethyl ester (1.2g, 4.2mmol) and triethylamine (2.3mL, 17.1mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tris (o-tolyl) phosphine (0.3g, 0.48mmol) and palladium (II) acetate (0.08g, 0.16mmol) were added, and the mixture was degassed under reduced pressure, replaced with nitrogen, then heated under reflux for 8 hours, and cooled to room temperature.
And (4) sampling the reaction liquid, detecting LCMS, and not obtaining the target compound in the reaction.
Comparative example 2
Figure BDA0003226448570000181
A solution of compound 4b (0.84g, 3.4 mmol), 2-amino-3-butyric acid (0.7 g, 4.2mmol) and triethylamine (2.3 mL,17.1 mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tris (o-tolyl) phosphine (0.3 g,0.48 mmol) and palladium (II) acetate (0.08g, 0.16mmol) were added, and the mixture was degassed under reduced pressure, the atmosphere was replaced with nitrogen, then heated under reflux for 8 hours, and cooled to room temperature.
And (4) sampling a reaction liquid, detecting LCMS, and obtaining no target compound in the reaction.
Comparative example 3
Figure BDA0003226448570000182
A solution of compound 4a (1.0 g,3.4 mmol), 2-amino-3-butyric acid (0.7 g,4.2 mmol) and triethylamine (2.3 mL,17.1 mmol) in N, N-dimethylformamide (10 mL) was degassed under reduced pressure and the atmosphere was replaced with nitrogen, then tris (o-tolyl) phosphine (0.3 g,0.48 mmol) and palladium (II) acetate (0.08g, 0.16 mmol) were added, and the mixture was degassed under reduced pressure, the atmosphere was replaced with nitrogen, then heated under reflux for 8 hours, and cooled to room temperature.
And (4) sampling the reaction liquid, detecting LCMS, and not obtaining the target compound in the reaction.
Example 4
Preparation of Compound 6
Figure BDA0003226448570000191
Trifluoroacetic anhydride (25mL, 176.8mmol) was placed in a reaction flask, cooled to 0 ℃ and added with compound A (5.0g, 16.1mmol), followed by addition of concentrated sulfuric acid (2 mL), stirring at 0 ℃ for 1 hour, slowly increased to 35 ℃ and further stirring for reaction for 12 hours. The resulting reaction solution was added dropwise to a 50% acetonitrile aqueous solution (120 mL) which had been cooled to 5 ℃. After adjusting the pH to about 7 with a 25wt% aqueous solution of sodium hydroxide, water (20 mL) was added. Then, the reaction solution was allowed to warm to room temperature, and the precipitated crystals were collected by filtration and washed with water (60 mL) and 75% acetonitrile in water (60 mL). The obtained crystals were dried under reduced pressure to obtain compound 6 as white crystals (4.2 g, yield 90%).
1 H NMR(500MHz,CDCl 3 )δ11.77(s,1H),8.41(d,1H),6.58(d, 1H),4.63(dt,1H),2.95-3.06(m,2H),2.71-2.76(m,1H),2.23(s,3H),2.14 (d,3H),2.11(s,3H),1.79-1.88(m,1H).
ESI-MS:m/z C 15 H 18 FN 2 O 3 [M+H]+ calculated value 293.1301; found 293.1310;
example 5
Preparation of Compound 6
Figure BDA0003226448570000192
1, 2-dichloroethane (50 mL) was charged into a reaction flask, cooled to-40 ℃ and added with Compound A (3.1g, 10mmol) and phosphorus pentachloride (2.1g, 10mmol) and stirred at-40 ℃ for 2 hours, then slowly warmed to room temperature. Adding AlCl into the reaction solution 3 (2.8g, 21 mmol), and the reaction was heated under reflux for 10 hours. TLC to monitor the reaction completion, the reaction solution was slowly added to iceIn water (200 mL), extracted with ethyl acetate, dried, filtered, and dried, and the resulting solid was dried under reduced pressure to give compound 6 as white crystals (1.4 g, yield 48%). The structural characterization data are the same as in example 3.
Comparative example 4
Preparation of Compound 6a
Figure BDA0003226448570000201
Polyphosphoric acid (2 mL) and Compound A (100 mg) were placed in a reaction flask and reacted at 100 ℃ for 12 hours. Then, the reaction solution was allowed to warm to room temperature, neutralized to PH =7 under ice bath conditions, extracted with dichloromethane, and the organic phase was collected. The organic phase is treated with Na 2 SO 4 Drying, filtration and spin-drying gave white compound 6a (80 mg, yield 91%).
1 H NMR(500MHz,DMSO-d6/CDCl 3 )δ10.01(s,1H),9.86(s,1H), 8.27(s,1H),7.87(d,J＝9.1Hz,1H),7.75(d,J＝9.1Hz,1H),7.54(d,J＝ 11.1Hz,1H),2.49(s,3H),2.26(s,3H),2.17(s,1H).
ESI-MS calculated as M/z [ M + H ] + 275.12; found 275.18;
example 6
Preparation of Compound B
Figure BDA0003226448570000211
A suspension of Compound 6 (5.0 g,17.1 mmol) in 2N hydrochloric acid/ethanol (50 mL) was stirred at 50 ℃ for 6 hours. Water (45 mL) was added to the resulting reaction solution, and the mixture was cooled to 1 ℃. Triethylamine (14.5mL, 103.9mmol) was added dropwise at 1 deg.C, and sodium sulfite (45mg, 0.3mmol) was added. After the mixture was stirred at 1 ℃ for 2 hours, the precipitated crystals were collected by filtration and washed with a cold 60% aqueous ethanol solution (50 mL) and water (15 mL). The resulting suspension of crystals in acetone (30 mL) was stirred at 50 ℃ for 2 hours and then cooled to room temperature. The precipitated crystals were collected by filtration and washed with acetone (10 mL). The obtained crystals were dried at 40 ℃ under reduced pressure to obtain compound B (3.6 g, yield 85%).
1 H NMR(500MHz,DMSO_d6)δ8.08(d,1H),7.41(s,2H),6.39(d, 1H),4.48(dt,1H),2.93(d,1H),2.78-2.85(m,1H),2.16(m,1H),2.14(s, 3H),2.13(s,3H),1.81-1.98(m,1H).
ESI-MS:m/z C 13 H 16 FN 2 O 2 [M+H]+ calculated value is 251.1196; found 251.1194;
example 7
Preparation of Compound 8
Figure BDA0003226448570000212
Compound B (10g, 40.0mmol), compound 7 (10g, 38.0mmol), pyridinium p-toluenesulfonate (1.5g, 6.0mmol) and o-cresol (30ml, 264mmol) were charged into a three-necked flask, toluene (400 mL) was added, reacted at 108 ℃ for 32 hours, and cooled. The precipitated crystals were collected by filtration and washed with acetone (30 mL). The obtained crystals were dried at 40 ℃ under reduced pressure to obtain compound 8 (15.4 g, yield 85%).
ESI-MS:m/z C 26 H 25 FN 3 O 5 [M+H]+ calculated 478.1778; found 478.1782;
example 8
Preparation of Compound 9
Figure BDA0003226448570000221
Compound 8 (10g, 20.9mmol) was suspended in water (300 mL) and toluene (300 mL), methanesulfonic acid (150 mL) was slowly added, and the solid was dissolved and an exothermic phenomenon occurred. Heated to 90 ℃ for 8h reaction, cooled to room temperature, separated and the organic phase removed. The aqueous phase was filtered, the filtrate diluted with ethanol (4L), the solid precipitated, stirred at room temperature for 20min, filtered, drained and the crude product suspended in ethanol/water =4:1, heating and refluxing for 2h, cooling to room temperature, filtering, washing the solid with a small amount of ethanol, draining, and drying to obtain compound 9, namely the imatinib mesylate (4.6 g, 45%).
1 H NMR(500MHz,DMSO_d6)δ8.47(s,3H),7.88(d,1H),7.34(s, 1H),6.59(s,1H),5.72-5.40(m,4H),5.11(s,1H),3.30(m,1H),3.10(t, 1H),2.53(m,1H),2.42(s,3H),2.32(s,3H),2.19(m,1H),1.88(m,2H), 0.88(t,3H).
ESI-MS:m/z C 24 H 23 FN 3 O 4 [M+H]+ calculation of 436.1673; found 436.1678.

Claims (24)

1. A method for preparing compound 6, comprising the steps of:
(d) Carrying out coupling reaction on the compound 4 to obtain a compound 5;
(e) The compound 5 is subjected to double bond reduction or hydrogenation reaction to obtain a compound A;
(f) Carrying out intramolecular Friedel-crafts acylation reaction on the compound A under the action of an intramolecular cyclization reagent to obtain a compound 6;
the reaction formula is as follows:
Figure FDA0003226448560000011
wherein R is selected from halogen, sulfonate group or diazo group, e.g. iodine, trifluoromethanesulfonyloxy.
2. A method for preparing compound 6, comprising the steps of:
(f) Performing intramolecular Friedel-crafts acylation reaction on the compound A under the action of an intramolecular cyclization agent to obtain a compound 6,
Figure FDA0003226448560000012
3. the process according to claim 1 or 2, wherein in step (f), the cyclisation reagent is selected from friedel-crafts acylation reagents, such as a mixture of protic acids and anhydrides or chlorinated reagents with lewis acids or PPA polyphosphate;
preferably, the protonic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;
and/or the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;
preferably, the chlorinating reagent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;
and/or the Lewis acid is selected from aluminum trichloride, stannic chloride and ferric salt.
4. The process according to claim 1 or 2, wherein in step (f), the cyclizing reagent is added in an amount at least sufficient to allow the reaction, and preferably, the ratio of the amount of the cyclizing reagent to the amount of the substance of compound A is from 0.5 to 20:1, more preferably 1 to 10:1, and more preferably 1 to 5.
5. The method of claim 1 or 2, wherein: in the step (f), the reaction temperature is-40 to 150 ℃, for example, 0 to 100 ℃;
and/or the reaction time is from 0.5 to 24 hours, for example from 2 to 12 hours.
6. An intermediate compound A, which is a compound A,
Figure FDA0003226448560000021
7. a process for the preparation of an intermediate compound a, comprising the steps of:
(e) Carrying out catalytic hydrogenation reaction on the compound 5 in the presence of a catalyst to obtain a compound A,
Figure FDA0003226448560000022
8. the method of claim 1 or 7, wherein in step (e), the catalyst is selected from a palladium catalyst, a platinum catalyst, a nickel catalyst, a ruthenium catalyst, or a rhodium catalyst, preferably a palladium on carbon catalyst, more preferably a 5% palladium on carbon catalyst.
9. The production method according to claim 1 or 7, characterized in that: in the step (e), the amount of the catalyst added is at least based on the reaction, and preferably, the mass ratio of the catalyst to the compound 5 is 0.02 to 0.4:1, more preferably 0.05 to 0.15.
10. The production method according to claim 1 or 7, characterized in that: in the step (e), the reaction is carried out in an organic solvent, wherein the organic solvent is selected from acetonitrile, dichloromethane, chloroform, methanol, ethanol, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, water or a mixed solvent of any of the solvents.
11. The production method according to claim 1 or 7, characterized in that: in the step (e), the reaction temperature is 25-100 ℃, for example, 40-60 ℃; the reaction time is from 0.5 to 24 hours, for example from 6 to 12 hours.
12. The use of compound A as claimed in claim 6 as an intermediate in the preparation of compound 6 or piroxicam mesylate,
Figure FDA0003226448560000031
13. an intermediate compound 5 which is a mixture of two compounds,
Figure FDA0003226448560000032
14. a method for preparing compound 5, comprising the steps of:
(d) The compound 4 and 2-acetamido-butyl-3-olefine acid are subjected to coupling reaction under the action of a coupling catalyst and an alkaline substance to obtain a compound 5,
Figure FDA0003226448560000041
wherein R is selected from halogen, sulfonate group or diazo group, e.g. iodine, trifluoromethanesulfonyloxy.
15. The method of claim 1 or 14, wherein: in the step (d), the coupling catalyst is a complex formed by palladium salt and phosphine ligand;
preferably, the palladium salt is selected from palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium, palladium nitrate or triphenylphosphine palladium dichloride, for example palladium acetate;
and/or the phosphine ligand is selected from the group consisting of triphenylphosphine, tricyclohexylphosphine, tri (o-tolyl) phosphine, tris [3, 5-bis (trifluoromethyl) phenyl ] phosphine, triisopropylphosphine, and dicyclohexyl- (2, 6-diisopropylphenyl) phosphine, for example tri (o-tolyl) phosphine.
16. The production method according to claim 1 or 14, characterized in that: in step (d), the basic substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium tert-butoxide, for example triethylamine.
17. The production method according to claim 1 or 14, characterized in that: in step (d), the ratio of the amounts of said compound 4 to 2-acetamido-but-3-enoic acid is 1:1.0 to 3.0, such as 1.2 to 1.5;
and/or the amount of the coupling catalyst added is calculated by the amount of the substance of the phosphine ligand, the ratio of the amount of the compound 4 to the amount of the substance of the phosphine ligand is 1:0.05 to 0.75, for example 1:0.15 to 0.30;
and/or the ratio of the amount of said compound 4 to the amount of basic material is 1:1.0 to 15.0, for example 1:3.0 to 10.0.
18. The method of claim 1 or 14, wherein: in the step (d), the reaction is carried out in an organic solvent selected from acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethylacetamide, toluene, water and a mixed solvent thereof.
19. The production method according to claim 1 or 14, characterized in that: in the step (d), the reaction temperature is 20-110 ℃, for example, 50-80 ℃; the reaction time is 2 to 24 hours, preferably 8 to 16 hours.
20. Use of compound 5 according to claim 13 as an intermediate in the preparation of compound a or icariin mesylate,
Figure FDA0003226448560000051
21. a preparation method of the Icetin mesylate is characterized by comprising the following steps: the method comprises the following steps:
(g) Carrying out selective deamination protection on the compound 6 to obtain a compound B;
(h) Carrying out condensation reaction on the compound B and the compound 7 to obtain a compound 8;
(i) The compound 8 is hydrolyzed under the acidic condition to obtain the itaconate mesylate, namely a compound 9;
the reaction formula is as follows:
Figure FDA0003226448560000061
the compound 6 is prepared from the compound A according to the preparation method of one of claims 2 to 5.
22. The method of claim 21, wherein: the compound A is prepared by the method of one of claims 7 to 11 and is prepared from a compound 5.
23. The method of claim 22, wherein: compound 5 is prepared from compound 4 according to the method of any one of claims 14 to 19.
24. The method of claim 1 or 23, wherein: the preparation method of the compound 4 comprises the following steps:
(a) Converting the compound 1 to obtain a compound 2;
(b) Carrying out catalytic hydrogenation reaction on the compound 2 to obtain a compound 3;
(c) Carrying out acylation reaction on the compound 3 to obtain a compound 4;
Figure FDA0003226448560000071
r is selected from halogen, sulfonate group or diazo group, e.g. iodine, trifluoromethanesulfonyloxy.
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