CN117088786A - Eptification intermediate and preparation method thereof - Google Patents

Eptification intermediate and preparation method thereof Download PDF

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CN117088786A
CN117088786A CN202210521012.3A CN202210521012A CN117088786A CN 117088786 A CN117088786 A CN 117088786A CN 202210521012 A CN202210521012 A CN 202210521012A CN 117088786 A CN117088786 A CN 117088786A
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formula
solvent
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compound
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张中占
肖晓飞
陆镇嘉
杨玉雷
朱雪焱
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China Pharmaceutical Industry Research Institute Co ltd
Shanghai Pharmaceutical Industry Research Institute Co ltd
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China Pharmaceutical Industry Research Institute Co ltd
Shanghai Pharmaceutical Industry Research Institute 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
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • 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
    • 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
    • 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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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses an isatecan intermediate and a preparation method thereof. The invention provides a preparation method of a compound shown in a formula 7, wherein R 1 For the purposes of definition in the specification, the preparation method comprises the following steps: cyclizing the compound shown in the formula 6 in a solvent in the presence of a catalyst and a halosilane reagent to obtain the compound shown in the formula 7. The intermediate obtained by the invention can be used for further preparing the irinotecan product, and has the advantages of less reaction steps and high product yield.

Description

Eptification intermediate and preparation method thereof
Technical Field
The invention relates to an irinotecan intermediate and a preparation method thereof.
Background
The chemical name of isatecan (execan) is (1 s,9 s) -9-ethyl-5-fluoro-1-amino-9-hydroxy-4-methyl-10, 13-dioxo-2,3,9,10,13,15-hexahydro-1 h,12 h-benzo [ de ] pyrano [3',4':6,7] indolizino [1,2-b ] quinoline, developed by the first co (Daiichi Sankyo) corporation, and the ADC drug Enhertu (fam-trastuzumab deruxtecan-nxki) consisting of trastuzumab was approved for adult treatment of HER2 (human epidermal growth factor receptor, human epithelial growth factor receptor 2) positive breast cancer by the FDA in the united states at 20 days of 2019 via the accelerated approval procedure approved by the FDA.
The synthesis of the irinotecan is prepared by splicing a key intermediate 1 with chiral tricyclic lactone (2) and then deprotecting, wherein the synthesis of the key intermediate 1 is prepared in the compound patent EP0495432 by using 2-fluoro-toluene as a starting material through more than ten steps of reactions such as acylation, reduction, esterification, nitration, hydrolysis, decarbonylation, repeated oxidization of carbonyl and the like, and the total yield is only 2.3%.
In patent WO1996026181, the synthesis of intermediate 1 takes 2-fluoro-toluene as a starting material, and is prepared through more than ten steps of reactions such as acylation, reduction, cyclization, amination, beckmann rearrangement, repeated ring-opening cyclization and the like, and the total yield is 2.6%.
In the recent patent WO2019044946, the synthesis of the intermediate 1 takes 2-fluoro-4-nitrotoluene as a starting material and is prepared by eight steps of reactions such as bromination, reduction, acetylation, heck reaction, double bond reduction, cyclization, nitrosation and reduction, and the total yield is 14%.
Compared with the prior literature route, the synthesis of the intermediate 1 in the WO2019044946 patent has the advantages that the process steps and the yield are greatly improved, but the process still has great limitation, for example, the first-step bromination selectivity is poor, the generated byproducts are not easy to remove, the crystallization is removed when the intermediate 3 is needed to be subjected to three-step reaction, the yield of the first three-step reaction is lower (37%), and the three hydrogenation reduction reactions of nitro reduction, double bond reduction and nitroso reduction occur in sequence in the whole route, so that the process is repeated and the efficiency is reduced. Aiming at the two points, the invention improves the yield and the efficiency.
Disclosure of Invention
The invention aims to solve the technical problems that the existing irinotecan has long preparation path and low yield, and therefore, the invention provides an irinotecan intermediate and a preparation method thereof. The preparation method can be used for efficiently preparing the intermediate of the irinotecan, and can be used for improving the yield of the irinotecan product.
The invention provides a preparation method of a compound shown as a formula 7, which comprises the following steps: in a solvent, in the presence of a catalyst and a halosilane reagent, carrying out cyclization reaction shown in the following formula 6 to obtain a compound shown in the formula 7;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the cyclization reaction, the solvent is a reaction solvent which is conventional in the art, for example, a halogenated hydrocarbon solvent, preferably 1, 2-dichloroethane.
In the cyclization reaction, the catalyst is a conventional reaction catalyst in the field, such as indium halide, preferably indium trichloride or indium tribromide, and indium tribromide is more preferably indium trichloride.
In the cyclization reaction, the halosilane reagent may be a conventional halosilane reagent in this type of reaction in the art, for example Wherein X may be halogen, such as Cl or Br, preferably Cl; r is R a Can be H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, R b And R is c Can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halosilane reagent is preferably HSi (CH) 3 ) 2 Cl。
In the cyclization reaction, the molar ratio of the compound of formula 6 to the catalyst may be from 1:0.5 to 1:4, for example 1:1, 1:2 or 1:3, preferably from 1:1.5 to 1:3.5, further preferably 1:2.
In the cyclization reaction, the molar ratio of the compound represented by formula 6 to the halosilane reagent may be 1:1.0 to 1:3.5, for example 1:1.2, 1:2.3 or 1:2.9, preferably 1:2.3 to 1:2.9, further preferably 1:2.3.
In the cyclization reaction, the mass-to-volume ratio of the compound represented by formula 6 to the solvent may be a mass-to-volume ratio conventionally used in such a reaction in the art, and is preferably 10g/L to 150g/L, for example, 20g/L, 50g/L and 100g/L, and more preferably 50g/L.
In the cyclization reaction, the temperature of the reaction is a reaction temperature which is conventional in the art such as room temperature (10-30 ℃) to 110 ℃, preferably the reaction is carried out by maintaining the room temperature for 4 hours after the start of the reaction and then heating to reflux; the heating to reflux conditions may be to 70-110 ℃, preferably 90 ℃.
The progress of the cyclization reaction can be detected using conventional monitoring methods (e.g., LCMS) of such reactions in the art, typically with the compound of formula 6 as the end point of the reaction when it disappears or no longer reacts. The reaction time of the reaction may be 8 to 48 hours, for example 24 hours.
The cyclization reaction may be performed in an inert atmosphere, which may be nitrogen, argon.
The preparation method can also comprise the following post-treatment steps: after the cyclization reaction, adding water, extracting the aqueous phase with an organic solvent (for example, extracting with dichloromethane three times), mixing the organic phases, washing (for example, sequentially using water and saturated saline), drying (for example, drying with anhydrous sodium sulfate), and concentrating (for example, concentrating under reduced pressure); obtaining the compound shown in the formula 7; or further recrystallizing to obtain the compound shown in the formula 7. The solvent for recrystallization can be a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:1.
In one embodiment, the cyclizing reaction is carried out using a compound of formula 6, dimethylchlorosilane, indium trichloride, and the solvent.
In one embodiment, the compound of formula 6 may be prepared by a method comprising the steps of: carrying out amidation reaction on a compound shown in a formula 5-B and an acetylating reagent in a solvent to obtain a compound shown in a formula 6;
Wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the amidation reaction, the solvent is a reaction solvent which is conventional in this type of reaction in the art, for example, an ether solvent, preferably tetrahydrofuran.
In the amidation reaction, the acetylating agent is an acetylating agent conventional in this type of reaction in the art, such as acetic acid and/or acetic anhydride, preferably acetic acid and acetic anhydride.
In the amidation reaction, when the acetylating reagent is acetic acid and acetic anhydride, the volume ratio of acetic acid to acetic anhydride may be a volume ratio conventional in this type of reaction in the art, for example, 1:0.1 to 1:10, preferably 1:1 to 1:3, more preferably 3:4.
In the amidation reaction, when the acetylating reagent is acetic acid and acetic anhydride, the mass-to-volume ratio of the compound represented by formula 5-B to the acetic anhydride may be a mass-to-volume ratio conventional in such a reaction in the art, for example, 40g/L to 150g/L, preferably 120g/L.
In the amidation reaction, the temperature of the reaction may be a conventional reaction temperature for such a reaction in the art, for example, 20 to 40 ℃, preferably 30 ℃.
In the amidation reaction, the progress of the reaction can be detected by methods conventional in the art for monitoring such reactions (e.g., LCMS, TLC, HPLC or NMR), typically with the end point of the reaction when the starting material 5-B is lost or no longer reacted. The amidation reaction time may be 8 to 48 hours, for example 20 hours or 24 hours.
The amidation reaction may further comprise the following post-treatment steps: after the reaction, the reaction mixture is filtered, neutralized with an alkali (e.g., 5N sodium hydroxide solution), extracted (e.g., three times with 2-methyltetrahydrofuran), the organic phases are combined and washed (e.g., with saturated brine), dried (e.g., with anhydrous sodium sulfate), and concentrated (e.g., under reduced pressure); obtaining the compound shown in the formula 6; or further purifying to obtain the compound shown in the formula 6. The purification can be performed by ethyl acetate/petroleum ether column chromatography.
In one embodiment, the materials for the amidation reaction are the compound of formula 5-B, an acetylating agent (acetic acid and acetic anhydride), and the solvent.
In one embodiment, the compound of formula 5-B may be prepared by a method comprising the steps of:
(1) In a solvent, in the presence of alkali, carrying out nitrosation reaction of a compound shown in a formula 5 and isoamyl nitrite as shown below to obtain a substance 5-A;
(2) In the presence of a catalyst, carrying out reduction reaction on a substance 5-A and a reducing reagent to obtain a compound shown in a formula 5-B;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the nitrosation reaction, the solvent is a reaction solvent which is conventional in the art, for example, an ether solvent, preferably tetrahydrofuran.
The temperature of the nitrosation reaction is a reaction temperature conventional in this type of reaction in the art, for example from 0 ℃ to-40 ℃, preferably from-12 ℃ to-40 ℃, more preferably-20 ℃.
The nitrosation reaction may be carried out in an inert atmosphere, which may be nitrogen, argon.
In the nitrosation reaction, the base is a base conventional in this type of reaction in the art, for example an alkali metal alkoxide, preferably potassium tert-butoxide.
In the nitrosation reaction, the molar ratio of the isoamyl nitrite to the compound of formula 5 may be a molar ratio conventional in this type of reaction in the art, preferably from 2.0:1 to 1.0:1, for example 1.4:1, 1.8:1 or 1.1:1, more preferably 1.4:1.
In the nitrosation reaction, the molar ratio of the base to the compound of formula 5 may be a molar ratio conventional in this type of reaction in the art, for example 1.5:1, 1.3:1 or 1.1:1, preferably 1.5:1 to 1.1:1, more preferably 1.3:1.
In the nitrosation reaction, the mass to volume ratio of the compound of formula 5 to the solvent may be a mass to volume ratio as is conventional in this type of reaction in the art, for example 5g/L to 500g/L, preferably 50g/L.
In the nitrosation reaction, the progress of the reaction can be detected using methods conventional in the art for monitoring such reactions (e.g. LCMS, TLC, HPLC or NMR), typically with the compound of formula 5 as an endpoint of the reaction when it disappears or no longer reacts. The reaction time of the reaction may be 0.5 to 3 hours, for example 1 hour.
In one embodiment, the nitrosation reaction is carried out using a compound of formula 5, isoamyl nitrite, a base (e.g., potassium tert-butoxide), and the solvent.
In a certain scheme, the reaction liquid obtained after the nitrosation reaction is finished can directly participate in the reduction reaction of the step (2) without post-treatment.
The reaction temperature of the reduction reaction is a reaction temperature conventional in this type of reaction in the art, for example, 20 to 50 ℃, preferably 30 to 40 ℃.
The catalyst for the reduction reaction is a conventional reaction catalyst in this type of reaction in the art, for example, platinum carbon or palladium carbon, preferably platinum carbon, more preferably 5% platinum carbon.
In the reduction reaction, the mass ratio of the catalyst to the compound represented by formula 5 may be 1:1 to 1:10, for example, 1:5, 1:10 or 3:10, preferably 1:5 to 3:10, and more preferably 1:5.
The reducing agent of the reduction reaction is a conventional reducing agent in this type of reaction in the art, for example a reducing gas, preferably hydrogen.
The pressure of the reduction reaction is a reaction pressure conventional in this type of reaction in the art, for example, 0.5atm, 1atm, 2atm or 3atm, preferably 1atm to 3atm, and most preferably 1atm.
In the reduction reaction, the progress of the reaction can be detected using methods conventional in the art for monitoring such reactions (e.g., LCMS, TLC, HPLC or NMR), typically with the end point of the reaction when the substance 5-A is lost or no longer reacted. The reaction time of the reduction reaction may be 8 to 48 hours, for example 24 hours.
In a certain scheme, the reaction liquid obtained after the reduction reaction is finished can directly participate in the amidation reaction without post-treatment.
In one embodiment, the compound of formula 6 may be obtained by sequentially reacting the compound of formula 5 via the above step (1), the above step (2) and the above amidation reaction.
In one embodiment, the compound of formula 5 may be prepared by a process comprising the steps of: in a solvent, under the action of a catalyst or a catalyst and a ligand, carrying out the coupling reaction of a compound shown in a formula 4 and an alkenoic acid ester shown in a formula (I) under the action of alkali to obtain the compound shown in a formula 5;
Wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the coupling reaction, the solvent is a reaction solvent which is conventional in the art, such as an ether solvent or a mixed solvent of an ether solvent and water; preferably, the ether solvent is tetrahydrofuran; more preferably, the solvent is a mixed solvent of an ether solvent and water, for example, a mixed solvent of tetrahydrofuran and water.
In the coupling reaction, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to the water may be a conventional volume ratio in the art, preferably 1:1 to 10:1, for example 5:1 or 4.7:1, further preferably 4:1 to 5:1, most preferably 4:1.
In the coupling reaction, the mass-to-volume ratio of the compound represented by formula 4 to the solvent may be a mass-to-volume ratio conventional in such a reaction in the art, and is preferably 100g/L to 200g/L, for example, 111.1g/L, 100g/L or 164.7g/L, more preferably 111.1g/L to 133.3g/L, and most preferably 133.3g/L.
In the coupling reaction, the catalyst is a conventional reaction catalyst in the art, for example, a transition metal catalyst, preferably palladium acetate.
In the coupling reaction, the ligand is phosphine ligand conventional in the reaction, such as tri-o-tolylphosphine; more preferably the mass ratio of the tri-o-tolylphosphine to the palladium acetate may be from 1:1 to 4:1, preferably from 8:3 to 55:23, most preferably 8:3.
In the coupling reaction, the mass ratio of the catalyst to the compound represented by formula 4 may be a mass ratio conventional in this type of reaction in the art, preferably 1:100 to 5:100, for example 2.5:100, 1.6:100,3.8:100, more preferably 2.5:100 to 3.8:100, most preferably 2.5:100.
In the coupling reaction, the base may be an organic base conventional in this type of reaction in the art, preferably, the base is diisopropylethylamine.
In the coupling reaction, the molar ratio of the compound of formula 4 to the base may be a molar ratio conventional in this type of reaction in the art, for example 1:4.4, 1:3.1 or 1:2.9, preferably 1:1 to 1:5.5, more preferably 1:2.9 to 1:4.4, most preferably 1:4.4.
In the coupling reaction, the alkenoic acid ester shown in the formula (I) is selected from tert-butyl 3-butenoate, isopropyl 3-butenoate, allyl 3-butenoate and benzyl 3-butenoate, preferably tert-butyl 3-butenoate.
In the coupling reaction, the molar ratio of the compound of formula 4 to the enoate of formula (I) may be a molar ratio conventional in this type of reaction in the art, preferably 1:1.2 to 1:2.0, for example 1:1.8 or 1:1.9, more preferably 1:1.8.
In the coupling reaction, the temperature of the reaction is a reaction temperature which is conventional in such reactions in the art, preferably 50℃to 65℃such as 50℃or 60℃and more preferably 60 ℃.
In the coupling reaction, the progress of the reaction can be detected by conventional monitoring methods (e.g., LCMS, TLC, HPLC or NMR) of such reactions in the art, typically with the compound of formula 4 as an endpoint of the reaction when it disappears or no longer reacts. The reaction time of the reaction may be 8 to 48 hours, for example 24 hours.
In the coupling reaction, the reaction may be performed in an inert atmosphere, which may be nitrogen or argon.
The coupling reaction can also comprise the following post-treatment steps after finishing: after the reaction is completed, the reaction solution is cooled to room temperature (for example, 10 ℃ to 30 ℃), filtered, a filter cake (for example, ethyl acetate rinse) is washed, a filtrate is collected and washed (for example, half saturated saline and saturated saline are sequentially washed), the filtrate is dried (for example, dried with anhydrous sodium sulfate), and concentrated (for example, reduced pressure concentration); obtaining the compound shown in the formula 5; or further recrystallizing to obtain the compound shown in the formula 5. The solvent for recrystallization can be a mixed solvent with a volume ratio of ethyl acetate/petroleum ether of 1:15.
In one embodiment, the materials for the coupling reaction are the compound of formula 4, the alkenoate of formula (I) (t-butyl 3-butenoate), the base (diisopropylethylamine), the ligand (tri-o-tolylphosphine), the catalyst (palladium acetate) and the solvent.
In one embodiment, the compound of formula 4 may be prepared by a process comprising the steps of: in a solvent, carrying out halogenation reaction on 2-fluoro-4-nitrotoluene and an iodination reagent as shown below to obtain a compound shown in a formula 4;
in the halogenation reaction, the solvent is a reaction solvent which is conventional in this type of reaction in the art, for example concentrated sulfuric acid.
In the halogenation reaction, the mass to volume ratio of the 2-fluoro-4-nitrotoluene to the solvent may be a mass to volume ratio conventional in this type of reaction in the art, preferably 50g/L to 200g/L, for example 80g/L, 100g/L and 200g/L, preferably 50g/L to 80g/L, most preferably 80g/L.
In the halogenation reaction, the iodinating agent is a conventional iodinating agent in this type of reaction in the art, such as periodic acid and iodine molecule composition.
In the halogenation reaction, when the iodinating agent is a combination of periodic acid and iodine molecules, the molar ratio of periodic acid to iodine molecules is preferably 3.1:10 to 3.5:10, for example 3.3:10.
The iodinated reagent can be prepared by a method conventional in the art, and the following steps are preferable in the invention: adding (e.g., adding in batches) sodium periodate into a mixed solution of concentrated sulfuric acid and iodine molecules, and mixing (e.g., stirring and mixing) to obtain an iodinated reagent;
in the step, the temperature of the addition may be 0 ℃ to 20 ℃, for example 5 ℃ to 10 ℃;
in the step, the temperature of the mixing may be 20 ℃ to 40 ℃, for example 25 ℃ to 30 ℃.
In the halogenation reaction, the molar ratio of the 2-fluoro-4-nitrotoluene to the iodine molecule in the iodinating agent may be a molar ratio conventional in this type of reaction in the art, preferably from 2.5:1 to 1.3:1, further preferably from 2.1:1 to 1.3:1, most preferably 2:1.
In the halogenation reaction, the temperature of the reaction is a reaction temperature conventional in this type of reaction in the art, for example, 20℃to 40℃and preferably 25℃to 30 ℃.
In the halogenation reaction, the progress of the reaction can be detected using conventional monitoring methods for such reactions in the art (e.g., TLC), preferably comprising the steps of: (1) Adding a sample into saturated sodium bicarbonate to obtain a mixed system; (2) Ethyl acetate was added to the mixture, and the organic phase was taken and analyzed by TLC. The 2-fluoro-4-nitrotoluene is generally taken as the end point of the reaction when it disappears or is no longer produced. The reaction time of the reaction may be 0.5 hours to 3 hours, for example 1 hour.
The halogenation reaction can also comprise the following post-treatment steps: after the reaction is finished, pouring the reaction solution into water containing sodium thiosulfate (for example, sodium thiosulfate ice water with the volume being 4 times that of concentrated sulfuric acid) to quench the reaction, stirring, filtering, washing a filter cake (for example, washing with water and petroleum ether in sequence), and drying; the compound shown in the formula 4 is obtained.
In one embodiment, the materials for the halogenation reaction are the 2-fluoro-4-nitrotoluene, the sodium periodate and iodine molecule composition and the solvent.
The invention provides a compound shown as a formula 5, a formula 5-B or a formula 6;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
The invention provides a preparation method of a compound shown as a formula 6, which comprises the following steps: carrying out amidation reaction on a compound shown in a formula 5-B and an acetylating reagent in a solvent to obtain a compound shown in a formula 6;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the preparation method, the reaction conditions and operations can be shown in any one of the methods for preparing the compound shown in the formula 6 in the preparation method of the compound shown in the formula 7.
The invention provides a preparation method of a compound shown in a formula 5-B, which comprises the following steps:
(1) In a solvent, in the presence of alkali, carrying out nitrosation reaction of a compound shown in a formula 5 and isoamyl nitrite as shown below to obtain a substance 5-A;
(2) In the presence of a catalyst, carrying out reduction reaction on a substance 5-A and a reducing reagent to obtain a compound shown in a formula 5-B;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the preparation method, the reaction conditions and the operation can be shown in any one of the methods for preparing the compound shown in the formula 5-B in the preparation method of the compound shown in the formula 7.
The invention provides a preparation method of a compound shown in a formula 5, which comprises the following steps: in a solvent, under the existence of a catalyst or a catalyst and a ligand, carrying out the coupling reaction of a compound shown in a formula 4 and an alkenoic acid ester shown in a formula (I) under the action of alkali to obtain a compound shown in a formula 5;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
In the preparation method, the reaction conditions and operations can be shown in any one of the methods for preparing the compound shown in the formula 5 in the preparation method of the compound shown in the formula 7.
The invention provides a preparation method of a compound shown in a formula 4, which comprises the following steps: in a solvent, carrying out halogenation reaction on 2-fluoro-4-nitrotoluene and an iodination reagent as shown below to obtain a compound shown in a formula 4;
in the preparation method, the reaction conditions and operations can be shown in any one of the methods for preparing the compound shown in the formula 4 in the preparation method of the compound shown in the formula 7.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the intermediate of the irinotecan disclosed by the invention can be used for further preparing the irinotecan product, and has the advantages of few reaction steps and high product yield.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 preparation of Compounds of formula 4
Sodium periodate (8.8 g,0.041 mol) was added in portions to a mixture of concentrated sulfuric acid (400 ml) and iodine (31 g,0.122 mol) at 5-10℃and stirred for 1 hour at 25-30℃to prepare an oxidizing agent solution. The mixture was slowly added to a mixture of 2-fluoro-4-nitrotoluene (40 g,0.25 mol) and concentrated sulfuric acid (100 ml), and the reaction was continued for 1 hour at a temperature of 25 to 30 ℃. The reaction solution is slowly poured into ice water containing 25g of sodium thiosulfate, stirred, filtered, and the filter cake is washed with petroleum ether and dried to obtain 50.5g of the compound shown in the formula 4, and the yield is: 69.7% and 93.20% purity.
EXAMPLE 2 preparation of the Compound of formula 5
A solution of a compound represented by formula 4 (60.0 g,0.213 mol) in tetrahydrofuran (360 ml) and water (90 ml) was successively added with tert-butyl 3-butenoate (55.0 g, 0.383 mol), diisopropylethylamine (120 g, 0.328 mol), triphenylphosphine (4 g) and palladium acetate (1.5 g), and the mixture was heated to 60℃under nitrogen for 24 hours.
The reaction mixture was cooled to room temperature, suction-filtered, the cake was rinsed with ethyl acetate, and the filtrate was washed with half-saturated brine and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The volume ratio of the obtained concentrate was 1: the ethyl acetate 15/petroleum ether is recrystallized to obtain 52g of the compound shown in the formula 5, and the yield is 82.4%.
1 H-NMR(400MHz,DMSO-d6)δ8.10(1H,s),7.95(1H,dd,J＝9.4,2.1Hz),6.81(1H,d,J＝15.8Hz),6.42(1H,dt,J＝15.6,7.0Hz),3.31(2H,dd,J＝7.0,1.1Hz),2.31(3H,d,J＝2.1Hz),1.45(9H,s)
EXAMPLE 3 preparation of the Compound of formula 6
A reaction flask was charged with the compound of formula 5 (5 g,16.9 mmol), tetrahydrofuran (100 ml), and cooled to-20℃under nitrogen, and isoamyl nitrite (2.8 g,23.9 mmol) and potassium tert-butoxide (2.4 g,21.3 mmol) were added and reacted for 1 hour.
5% platinum carbon (1 g) is added into the reaction solution, hydrogen is filled, and hydrogenation reaction is carried out for 24 hours at the temperature of between 30 and 40 ℃ under 1atm, so as to obtain the compound shown in the formula 5-B. MS (m/z): 283.1[ M+H ] +
Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction mixture, and the reaction was continued at about 30℃for 20 hours. The reaction solution was filtered to remove platinum carbon, the filtrate was neutralized with 5N sodium hydroxide solution, extracted three times with 2-methyltetrahydrofuran, the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate/petroleum ether column chromatography to give 4.2g of the compound of formula 6 in 67.7% yield.
MS(m/z)：367.0[M+H]+
1 H-NMR(600MHz,CD 3 OD)δ7.20(1H,d,J＝11.7Hz),6.96(1H,s),4.26-4.10(1H,m),2.58(2H,t,J＝7.9Hz),2.05(3H,s),2.00(3H,s),1.98-1.92(2H,m),1.91(3H,s),1.38(9H,s)
EXAMPLE 4 preparation of the Compound of formula 7
The compound represented by formula 6 (2.0 g,5.4 mmol) was added to 1, 2-dichloroethane (40 mL), and indium trichloride (2.4 g,10.8 mmol) and dimethylchlorosilane (1.2 g,12.6 mmol) were added under nitrogen atmosphere, reacted at room temperature for 4 hours, and then heated to reflux (about 90 ℃ C.) for 24 hours. The reaction solution was poured into water, the solution was separated, the aqueous phase was extracted three times with methylene chloride, the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:1 to give 1.2g of the compound of formula 7 in 75.2% yield.
MS(m/z)：293.1[M+H]+,315.0[M+Na]+.
EXAMPLE 5 preparation of Compounds of formula 1
The compound represented by formula 7 (2.2 g,7.5 mmol) was added to 2N hydrochloric acid/ethanol (30 ml), and the mixture was heated to 50℃under nitrogen atmosphere to react for 5 hours. The reaction solution was cooled to 0 to 5℃and water (50 ml) was added thereto, and triethylamine (10 ml) was added dropwise thereto and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with cold 50% aqueous ethanol and dried under reduced pressure to give 1.7g of crude compound 1. The crude product of the compound shown in the formula 1 is pulped for 5 hours at the temperature of 20ml of acetone and 50 ℃, cooled to room temperature, filtered, and a filter cake is dried under reduced pressure to obtain 1.5g of the compound shown in the formula 1, and the yield is 79.6%.
MS(m/z)：251.1[M+H]+
1 H-NMR(400MHz,DMSO-d6)δ8.07(1H,d,J＝7.9Hz),7.41(2H,brs),6.39(1H,d,J＝12.5Hz),4.51-4.44(1H,m),3.01-2.74(2H,m),2.20-2.10(1H,m),1.98(3H,d,J＝1.1Hz,),1.91(3H,s),1.86(1H,dd,J＝13.0,5.0Hz).
EXAMPLE 6 preparation of the Compound of formula 4
Sodium periodate (21 g,98.2 mmol) was added in portions to a mixture of concentrated sulfuric acid (1000 ml) and iodine (75 g,0.295 mol) at 0-10 c, and stirred for 1h at 20-30 c to prepare an oxidizer solution. The mixture was slowly added to a mixture of 2-fluoro-4-nitrotoluene (60 g,0.387 mol) and concentrated sulfuric acid (200 ml), and the reaction was continued for 3 hours at a temperature of 20 to 30 ℃. Slowly pouring the reaction solution into ice water containing 25g of sodium thiosulfate, stirring, suction-filtering, washing a filter cake with petroleum ether, and drying to obtain 68g of a compound shown in formula 4, wherein the yield is as follows: 62.5%.
EXAMPLE 7 preparation of the Compound of formula 4
Sodium periodate (7.1 g,33.2 mmol) was added in portions to a mixture of concentrated sulfuric acid (300 ml) and iodine (25.4 g,0.100 mol) at 10-20℃and stirred for 1h at 30-40℃to prepare an oxidizer solution. The mixture was slowly added to a mixture of 2-fluoro-4-nitrotoluene (40 g,0.25 mol) and concentrated sulfuric acid (100 ml), and the reaction was continued for 0.5h at a temperature of 30 to 40 ℃. The reaction solution is slowly poured into ice water containing 25g of sodium thiosulfate, stirred, filtered, and the filter cake is washed with petroleum ether and dried to obtain 41.5g of the compound shown in the formula 4, and the yield is: 57.3%.
EXAMPLE 8 preparation of the Compound of formula 5
The compound (6.0 g,21.3 mmol) shown in formula 4 was dissolved in tetrahydrofuran (60 ml), and tert-butyl 3-butenoate (5.5 g,38.6 mmol), diisopropylethylamine (12 g,92.8 mmol), tri-o-tolylphosphine (0.4 g) and palladium acetate (0.15 g) were added in this order, and the mixture was heated to 50℃under nitrogen atmosphere to react for 24 hours.
The reaction mixture was cooled to room temperature, suction-filtered, the cake was rinsed with ethyl acetate, and the filtrate was washed with half-saturated brine and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:15 to give 4.8g of the compound of formula 5 in a yield of 76.1%.
EXAMPLE 9 preparation of the Compound of formula 5
The compound (14 g,49.8 mmol) represented by formula 4 was dissolved in a solution of tetrahydrofuran (70 ml) and water (15 ml), tert-butyl 3-butenoate (8.4 g,59.2 mmol), diisopropylethylamine (35 g, 0.271mol), trioctylphosphine (0.9 g) and palladium acetate (0.33 g) were added in this order, and the mixture was heated to 65℃under nitrogen atmosphere to react for 24 hours.
The reaction mixture was cooled to room temperature, suction-filtered, the cake was rinsed with ethyl acetate, and the filtrate was washed with half-saturated brine and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:15 to give 8.9g of the compound of formula 5 in 73.6% yield.
EXAMPLE 10 preparation of the Compound of formula 5
A solution of the compound of formula 4 (6.0 g,21.3 mmol) in tetrahydrofuran (45 ml) and water (9 ml) was added in sequence with tert-butyl 3-butenoate (5.5 g,38.6 mmol), diisopropylethylamine (8 g,61.9 mmol), tri-o-tolylphosphine (0.55 g) and palladium acetate (0.23 g), nitrogen-protected, and heated to 60℃for 24 hrs.
The reaction mixture was cooled to room temperature, suction-filtered, the cake was rinsed with ethyl acetate, and the filtrate was washed with half-saturated brine and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:15 to give 5.0g of the compound of formula 5 in 79.3% yield.
EXAMPLE 11 preparation of the Compound of formula 6
A reaction flask was charged with the compound of formula 5 (5 g,16.9 mmol), tetrahydrofuran (100 ml), nitrogen-purged, cooled to 0℃and then isoamyl nitrite (2.8 g,23.9 mmol) and potassium tert-butoxide (2.4 g,21.3 mmol) were added to react for 1h.
5% platinum carbon (0.5 g) was added to the reaction mixture, followed by hydrogen charging and hydrogenation at 20 to 30℃under 2atm for 24 hours to obtain a compound represented by the formula 5-B.
Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction mixture, and the reaction was continued at about 20℃for 24 hours. The reaction solution was filtered to remove platinum carbon, the filtrate was neutralized with 5N sodium hydroxide solution, extracted three times with 2-methyltetrahydrofuran, the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate/petroleum ether column chromatography to give 4.2g of the compound of formula 6 in 45.1% yield.
EXAMPLE 12 preparation of the Compound of formula 6
Into the reaction flask were charged the compound of formula 5 (5 g,16.9 mmol), tetrahydrofuran (100 ml), nitrogen-purged, cooled to-20℃and isoamyl nitrite (3.6 g,30.7 mmol) and potassium tert-butoxide (2.8 g,24.9 mmol) were added to react for 1h.
5% platinum carbon (1.5 g) was added to the reaction mixture, followed by hydrogen charging and hydrogenation at 30 to 40℃under 3atm for 24 hours to obtain a compound represented by the formula 5-B. Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction mixture, and the reaction was continued at about 40℃for 24 hours. The reaction solution was filtered to remove platinum carbon, the filtrate was neutralized with 5N sodium hydroxide solution, extracted three times with 2-methyltetrahydrofuran, the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate/petroleum ether column chromatography to give 3.5g of the compound of formula 6 in a yield of 56.4%.
EXAMPLE 13 preparation of the Compound of formula 6
A reaction flask was charged with the compound of formula 5 (5 g,16.9 mmol), tetrahydrofuran (100 ml), nitrogen-purged, cooled to-40℃and isoamyl nitrite (2.2 g,18.7 mmol) and potassium tert-butoxide (2.1 g,18.7 mmol) were added to react for 1h.
5% platinum carbon (1 g) is added into the reaction solution, hydrogen is filled, and hydrogenation reaction is carried out for 24 hours at the temperature of between 40 and 50 ℃ under 1atm, so as to obtain the compound shown in the formula 5-B. Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction mixture, and the reaction was continued at about 30℃for 24 hours. The reaction solution was filtered to remove platinum carbon, the filtrate was neutralized with 5N sodium hydroxide solution, extracted three times with 2-methyltetrahydrofuran, the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate/petroleum ether column chromatography to give 3.0g of the compound of formula 6 in a yield of 48.3%.
EXAMPLE 14 preparation of the Compound of formula 7
The compound represented by formula 6 (2.0 g,5.4 mmol) was added to 1, 2-dichloroethane (100 mL), and indium trichloride (3.6 g,16.3 mmol) and dimethylchlorosilane (1.5 g,15.8 mmol) were added under nitrogen atmosphere, reacted at room temperature for 4 hours, and heated to about 90℃again for 48 hours. The reaction solution was poured into water, the solution was separated, the aqueous phase was extracted three times with methylene chloride, the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:1 to give 1.1g of the compound of formula 7 in a yield of 68.9%.
EXAMPLE 15 preparation of the Compound of formula 7
The compound represented by formula 6 (2.0 g,5.4 mmol) was added to 1, 2-dichloroethane (20 mL), and indium trichloride (1.2 g,5.4 mmol) and dimethylchlorosilane (0.62 g,6.55 mmol) were added under nitrogen atmosphere, reacted at room temperature for 4 hours, and then heated to about 110℃for 24 hours. The reaction solution was poured into water, the solution was separated, the aqueous phase was extracted three times with methylene chloride, the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:1 to give 0.55g of the compound of formula 7 in 34.5% yield.
EXAMPLE 16 preparation of the Compound of formula 7
The compound represented by formula 6 (1.0 g,2.7 mmol) was added to 1, 2-dichloroethane (20 mL), and indium tribromide (1.9 g,5.4 mmol) and dimethylchlorosilane (0.6 g,6.3 mmol) were added under nitrogen, reacted at room temperature for 4 hours, and heated to about 70℃for 8 hours. The reaction solution was poured into water, the solution was separated, the aqueous phase was extracted three times with methylene chloride, the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate/petroleum ether at a volume ratio of 1:1 to give 0.56g of the compound of formula 7 in a yield of 70.2%.

Claims (15)

1. A process for the preparation of a compound of formula 7, comprising the steps of: in a solvent, cyclizing a compound shown in a formula 6 in the presence of a catalyst and a halogenated silane reagent to obtain a compound shown in a formula 7;
wherein R is 1 Is isopropyl, allyl, benzyl or tert-butyl.
2. The method of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the cyclization reaction, the R 1 Is tert-butyl;
(2) In the cyclization reaction, the solvent is a halogenated hydrocarbon solvent, preferably 1, 2-dichloroethane;
(3) In the cyclization reaction, the catalyst is indium halide, preferably indium trichloride or indium tribromide, more preferably indium trichloride;
(4) In the cyclization reaction, the halosilane reagent isWherein X is halogen, such as Cl or Br, preferably Cl; r is R a Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, R b And R is c Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halosilane reagent is preferably HSi (CH) 3 ) 2 Cl；
(5) In the cyclization reaction, the molar ratio of the compound represented by formula 6 to the catalyst is 1:0.5 to 1:4, for example 1:1, 1:1.15, 1:2 or 1:3;
(6) In the cyclization reaction, the molar ratio of the compound shown in the formula 6 to the halosilane reagent is 1:10 to 1:3.5, such as 1:1.2, 1:2.3 or 1:2.9;
(7) In the cyclization reaction, the mass-to-volume ratio of the compound represented by formula 6 to the solvent is 10g/L to 150g/L, for example, 20g/L, 50g/L and 100g/L;
(8) In the cyclization reaction, the temperature of the reaction is from room temperature to 110 ℃, preferably the reaction is carried out by keeping the room temperature for 4 hours after the start of the reaction and then heating the reaction to reflux; the heating to reflux conditions is to 70-110 ℃, preferably 90 ℃;
(9) The cyclization reaction can be performed in an inert atmosphere, wherein the inert atmosphere is nitrogen or argon;
(10) The preparation method also comprises the following post-treatment steps: after the cyclization reaction is finished, adding water, extracting, combining organic phases, washing, drying and concentrating to obtain the compound shown in the formula 7;
or further comprises recrystallizing in a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:1 to obtain the compound shown in the formula 7;
(11) The materials of the cyclization reaction are the compound shown in the formula 6, a catalyst, a halogenated silane reagent and the solvent.
3. The preparation method according to claim 1 or 2, characterized in that the preparation method further comprises the steps of: carrying out amidation reaction on a compound shown in a formula 5-B and an acetylating reagent in a solvent to obtain a compound shown in a formula 6;
wherein R is 1 As shown in claim 1 or 2.
4. The method of claim 3, wherein the amidation reaction satisfies one or more of the following conditions:
(1) In the amidation reaction, the solvent is an ether solvent, preferably tetrahydrofuran;
(2) In the amidation reaction, the acetylating reagent is acetic acid and/or acetic anhydride, preferably acetic acid and acetic anhydride; more preferably, the volume ratio of the acetic acid to the acetic anhydride is from 1:0.1 to 1:10, even more preferably from 1:1 to 1:3, most preferably 3:4;
(3) In the amidation reaction, when the acetylating reagent is acetic acid and acetic anhydride, the mass-volume ratio of the compound shown in the formula 5-B to the acetic anhydride is 40g/L to 150g/L, preferably 120g/L;
(4) The temperature of the amidation reaction is 20 ℃ to 30 ℃, preferably 30 ℃;
(5) The amidation reaction further comprises the following post-treatment steps: after the reaction is finished, filtering, neutralizing, extracting, combining organic phases, washing, drying and concentrating the reaction liquid; obtaining the compound shown in the formula 6;
or further purifying by ethyl acetate/petroleum ether column chromatography to obtain the compound shown in the formula 6;
(6) The amidation reaction material is the compound shown in the formula 5-B, an acetylating reagent and the solvent.
5. A method of preparing as claimed in claim 3, further comprising the steps of:
(1) Nitrosation reaction is carried out on a compound shown in a formula 5 and isoamyl nitrite in a solvent in the presence of alkali, so as to obtain a substance 5-A;
(2) In the presence of a catalyst, carrying out reduction reaction on a substance 5-A and a reducing reagent to obtain a compound shown in a formula 5-B;
wherein R is 1 As shown in claim 3.
6. The method of claim 5, wherein the method of preparation satisfies one or more of the following conditions:
(1) In the nitrosation reaction, the solvent is an ether solvent, preferably tetrahydrofuran;
(2) In the nitrosation reaction, the temperature of the reaction is from 0 ℃ to-40 ℃, preferably from-12 ℃ to-40 ℃, more preferably from-20 ℃;
(3) The nitrosation reaction can be carried out in an inert atmosphere, wherein the inert atmosphere is nitrogen or argon;
(4) In the nitrosation reaction, the base is an alkali metal alkoxide, preferably potassium tert-butoxide;
(5) In the nitrosation reaction, the molar ratio of the isoamyl nitrite to the compound represented by the formula 5 is from 2:1 to 1:1, for example 1.4:1, 1.8:1 or 1.1:1;
(6) In the nitrosation reaction, the molar ratio of the base to the compound of formula 5 is from 2:1 to 1:1, for example 1.5:1, 1.3:1 or 1.1:1;
(7) In the nitrosation reaction, the mass-volume ratio of the compound shown in the formula 5 to the solvent is 5g/L to 500g/L, preferably 50g/L;
(8) The materials of the nitrosation reaction are the compound shown in the formula 5, isoamyl nitrite, alkali and the solvent;
(9) In the reduction reaction, the temperature of the reaction is 20 ℃ to 50 ℃, preferably 30 ℃ to 40 ℃;
(10) In the reduction reaction, the catalyst of the reduction reaction is platinum carbon or palladium carbon, preferably 5% platinum carbon;
(11) In the reduction reaction, the mass ratio of the catalyst to the compound represented by formula 5 is 1:3 to 1:10, for example, 1:10, 2:10 or 3:10;
(12) The reducing agent of the reduction reaction is a reducing gas, preferably hydrogen;
(13) The pressure of the reduction reaction is 1atm to 3atm, for example 1atm or 2atm;
(14) The reaction liquid obtained after the nitrosation reaction in the step (1) is directly involved in the reduction reaction in the step (2) without post-treatment;
(15) The reaction liquid obtained after the completion of the reduction reaction directly participates in the amidation reaction of claim 3 or 4 without post-treatment.
7. The method of claim 5, further comprising the steps of: in a solvent, under the action of a catalyst or a catalyst and a ligand, under the action of alkali, carrying out a coupling reaction on a compound shown in a formula 4 and an olefine acid ester shown in a formula (I) to obtain the compound shown in a formula 5;
wherein R is 1 The method of claim 5.
8. The method of claim 7, wherein the coupling reaction satisfies one or more of the following conditions:
(1) In the coupling reaction, the solvent is an ether solvent or a mixed solvent of an ether solvent and water; preferably, the ether solvent is tetrahydrofuran; the mixed solvent of the ether solvent and the water is preferably a mixed solvent of tetrahydrofuran and the water;
(2) In the coupling reaction, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to the water is 1:1 to 10:1, preferably 4:1, 5:1 or 4.7:1;
(3) In the coupling reaction, the mass-volume ratio of the compound shown in the formula 4 to the solvent is 100g/L to 200g/L, preferably 111.1g/L to 164.7g/L, and more preferably 133.3g/L;
(4) In the coupling reaction, the catalyst is a transition metal catalyst, such as palladium acetate;
(5) In the coupling reaction, the ligand is a phosphine ligand, such as tri-o-tolylphosphine;
(6) The ligand to transition metal catalyst mass ratio is 1:1 to 4:1, preferably 8:3 to 55:23;
(7) In the coupling reaction, the mass ratio of the catalyst to the compound represented by formula 4 is 1:100 to 5:100, for example, 2.5:100, 1.6:100, or 3.8:100;
(8) In the coupling reaction, the base is an organic base, preferably diisopropylethylamine;
(9) In the coupling reaction, the molar ratio of the compound of formula 4 to the base is 1:1 to 1:5.5, for example 1:4.4, 1:3.1 or 1:2.9;
(10) In the coupling reaction, the alkenoic acid ester shown in the formula (I) is selected from tert-butyl 3-butenoate, isopropyl 3-butenoate, allyl 3-butenoate and benzyl 3-butenoate, preferably tert-butyl 3-butenoate;
(11) In the coupling reaction, the molar ratio of the compound shown in the formula 4 to the enoate shown in the formula (I) is 1:1.2 to 1:2.0, such as 1:1.8 or 1:1.9;
(12) In the coupling reaction, the temperature of the reaction is 50 ℃ to 65 ℃, for example 50 ℃ or 60 ℃;
(13) In the coupling reaction, the reaction is carried out in an inert atmosphere, wherein the inert atmosphere is nitrogen and argon;
(14) The coupling reaction further comprises the following post-treatment steps: after the reaction is finished, cooling the reaction liquid to room temperature, filtering, washing, collecting filtrate, washing, drying and concentrating; obtaining the compound shown in the formula 5;
or recrystallizing in a mixed solvent with a volume ratio of ethyl acetate to petroleum ether of 1:15 to obtain the compound shown in the formula 5;
(15) The materials of the coupling reaction are the compound shown in the formula 4, the alkenoic acid ester shown in the formula (I), the base, the catalyst, the ligand and the solvent.
9. The method of claim 7, further comprising the steps of: carrying out halogenation reaction on 2-fluoro-4-nitrotoluene and an iodination reagent in a solvent to obtain a compound shown in a formula 4;
10. the method of claim 9, wherein,
the halogenation reaction satisfies one or more of the following conditions:
(1) In the halogenation reaction, the solvent is concentrated sulfuric acid;
(2) In the halogenation reaction, the mass-volume ratio of the 2-fluoro-4-nitrotoluene to the solvent is 50g/L to 200g/L, for example 200g/L, 100g/L, 80g/L;
(3) In the halogenation reaction, the iodination reagent is a composition of periodic acid and iodine molecules;
(4) In the halogenation reaction, when the iodinating agent is a combination of periodic acid and iodine molecules, the molar ratio of periodic acid to iodine molecules is 3.1:10 to 3.5:10, for example 3.3:10;
(5) The iodinated reagent can be prepared by a method comprising the steps of: adding sodium periodate into a mixed solution of concentrated sulfuric acid and iodine molecules, and mixing to obtain the iodized reagent;
wherein the temperature at the time of addition is 0 ℃ to 20 ℃, for example 5 to 10 ℃; the temperature of the mixing is from 20 ℃ to 40 ℃, e.g., from 25 ℃ to 30 ℃;
(6) In the halogenation reaction, the molar ratio of the iodine molecules in the 2-fluoro-4-nitrotoluene and the iodinating agent is 2.5:1 to 1.3:1, preferably 2.1:1 to 1.3:1;
(7) In the halogenation reaction, the temperature of the reaction is 20 ℃ to 40 ℃, preferably 25 ℃ to 30 ℃;
(8) The method further comprises the following post-treatment steps after the halogenation reaction is finished: after the reaction is finished, pouring the reaction solution into water containing sodium thiosulfate for quenching, filtering, washing a filter cake and drying; obtaining the compound shown in the formula 4;
(9) In the halogenation reaction, the materials of the reaction are the 2-fluoro-4-nitrotoluene, the sodium periodate and iodine molecule composition and the solvent.
11. A compound represented by formula 5, formula 5-B or formula 6;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.
12. A method for preparing a compound of formula 6, comprising the steps of: carrying out amidation reaction on a compound shown in a formula 5-B and an acetylating reagent in a solvent to obtain a compound shown in a formula 6;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl;
the reaction conditions and operations of the preparation method can be as defined in any one of claims 3 to 10.
13. A process for the preparation of a compound of formula 5-B comprising the steps of:
(1) Nitrosation reaction is carried out on a compound shown in a formula 5 and isoamyl nitrite in a solvent in the presence of alkali, so as to obtain a substance 5-A;
(2) In the presence of a catalyst, carrying out reduction reaction on a substance 5-A and a reducing reagent to obtain a compound shown in a formula 5-B;
wherein R is 1 Isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl;
the reaction conditions and operations of the preparation method can be as defined in any one of claims 5 to 10.
14. A method for preparing a compound represented by formula 5, comprising the steps of: in a solvent, in the presence of a catalyst or a catalyst and a ligand, carrying out coupling reaction on a compound shown in a formula 4 and an olefine acid ester shown in a formula (I) under the action of alkali to obtain a compound shown in a formula 5;
wherein R is 1 Isopropyl, allyl, benzyl and tert-butyl, preferably tert-butyl;
the reaction conditions and operations of the preparation method can be as defined in any one of claims 7 to 10.
15. A method for preparing a compound represented by formula 4, comprising the steps of: in a solvent, carrying out halogenation reaction on 2-fluoro-4-nitrotoluene and an iodination reagent to obtain a compound shown in a formula 4;
In the preparation method, the reaction conditions and the operation can be as described in claim 9 or 10.
CN202210521012.3A 2022-05-12 2022-05-12 Eptification intermediate and preparation method thereof Pending CN117088786A (en)

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