CN113527237A - Method for preparing abemostat, intermediate and preparation method of intermediate - Google Patents

Method for preparing abemostat, intermediate and preparation method of intermediate Download PDF

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CN113527237A
CN113527237A CN202110689076.XA CN202110689076A CN113527237A CN 113527237 A CN113527237 A CN 113527237A CN 202110689076 A CN202110689076 A CN 202110689076A CN 113527237 A CN113527237 A CN 113527237A
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methyl
acetate
benzofuran
dimethylamino
phenoxy
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陆晟
王晗
朱晓磊
李波
许志勇
蒋顺
康琳琳
茆勇军
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Shanghai University of Engineering Science
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms

Abstract

The invention provides a preparation method of abersat, which comprises the following steps: (1) performing amide condensation on a first intermediate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid and a second intermediate 4- (2-aminoethoxy) methyl benzoate to obtain a third intermediate 4- [2- (3-dimethylamino benzofuran-2-yl-carbonylamino) ethoxy ] methyl benzoate; (2) and (4) carrying out deesterification on the third intermediate, and then carrying out acid modulation to obtain the abeditat. The method has the advantages of easily available raw materials, simple process, mild reaction conditions, convenient operation, high yield, low cost and easy industrial production. The invention also provides a first intermediate and a second intermediate for preparing the abedit and a preparation method thereof.

Description

Method for preparing abemostat, intermediate and preparation method of intermediate
Technical Field
The invention relates to the technical field of organic synthesis and preparation of raw material medicines and intermediates, in particular to a method for preparing abersat, an intermediate and a preparation method of the intermediate.
Background
Abestat is a selective HDAC (histone deacetylase) inhibitor developed by the kno pharmaceutical industry. At present, the clinical trials of ebesistat on non-hodgkin lymphoma conducted in china have entered phase ii, and the clinical trials of renal cell carcinoma conducted globally have also entered phase iii.
The chemical structure of abersat is shown in formula I:
Figure BDA0003125155160000011
the preparation of the Ebesartan mainly comprises the following methods:
the synthetic route disclosed in WO 2004092115 a2(2004.10.28) is shown in formula II.
Figure BDA0003125155160000012
The method takes Tetrahydrofuran (THF) as a solvent, and oxalyl chloride, methanol-triethylamine and catalytic amount are dripped into 3-methyl-benzofuran-2-carboxylic acid (compound 6)At room temperature to obtain 3-methylbenzofuran-2-carboxylic acid methyl ester (3); dissolving Compound 3 in CCl4Further heating and refluxing for 3h under the action of AIBN and NBS to obtain 3-bromomethylbenzofuran-2-carboxylic acid methyl ester (4); dissolving the compound 4 in anhydrous DMF, adding a tetrahydrofuran solution of dimethylamine at room temperature, and purifying a crude product after reaction by using a silica gel column to obtain 3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (5); dissolving the compound 5 in methanol, adding NaOH aqueous solution to adjust the pH value to 13, reacting for 60-90min under the alkaline condition, and then adjusting the pH value to 3 by HCl aqueous solution acid to obtain benzofuran carboxylate (16); dissolving the compound 16 in anhydrous DMF, sequentially adding EDCI and HOBt, reacting at room temperature for 30-60 min, respectively adding (4- (2-ethoxyamine)) methyl benzoate hydrochloride (7) and TEA, and stirring at room temperature overnight to obtain 4- [2- (3-dimethylaminobenzofuran-2-yl-carbonylamino) ethoxy]Methyl benzoate (8); adding excessive hydroxylamine aqueous solution and NaOH aqueous solution into THF solution of a compound 8 until the pH value is 10-11, stirring the mixture at room temperature for reacting overnight, adding HCl to adjust the pH value to 7-8, concentrating, and purifying a crude product by preparative HPLC to finally obtain the target product, namely the abetas.
The synthetic route of the original research medicament directly takes the compound 6 as a raw material, and the substance is not provided by manufacturers on professional websites of the chemical industry, such as the seven days of China, is not easy to purchase, needs to be developed in a customized manner and is expensive; the post-treatment such as acid regulation, alkali regulation and the like is carried out for a plurality of times in the route, and the generated wastewater causes great burden to the environment; the original research route of the synthetic method of the compound 7 is not reported; the compound 8 after docking needs to be purified by column chromatography, and finally the ebetastat is prepared in a trace amount by HPLC, so that batch production cannot be realized.
There are also the following methods: the synthetic route disclosed in CN 102391222B (2004.4.6) is shown in formula III.
Figure BDA0003125155160000031
Dissolving a compound 6 and a compound 7 in acetonitrile, quickly adding pyridine at 0 ℃, then slowly dropwise adding an acetonitrile solution of phosphorus oxychloride, and reacting at room temperature to obtain 4- {2- [ (3-methylbenzofuran-2-carbonyl) amino ] ethoxy } methyl benzoate (9); AIBN and NBS are added into chlorobenzene solution dissolved with compound 9 and react at 80 ℃ to obtain 4- {2- [ (3-bromo-methylbenzofuran-2-carbonyl) amino ] ethoxy } methyl benzoate (10); dripping a chlorobenzene solution and DCM of the compound 10 into a tetrahydrofuran solution of dimethylamine at 0-5 ℃, and reacting for 1h at room temperature to obtain a compound 8; dissolving compound 8 in methanol solution, adding KOH aqueous solution, and heating at 60 ℃ to obtain white solid potassium 4- {2- [ (3-dimethylaminomethyl-benzofuran-2-carbonyl) amino ] ethoxy } benzoate (11); dissolving the compound 11 in DMF, adding dioxane, EDCI and HOBt respectively, stirring at room temperature, and acidifying and refluxing to obtain the target product of the abetas. Wherein the compound 7 is prepared by reacting 4-hydroxy-benzoic acid methyl ester (12) and (2-hydroxyethyl) carbamic acid tert-butyl ester (13) in THF solution with triphenylphosphine and DIDA at 0-5 ℃ overnight.
The reaction route still adopts the compound 6 as a raw material, and the target compound abestat is obtained after the reactions of acylation, bromination, amine substitution, salification and the like are sequentially carried out. As with the original route, the starting materials are not sold industrially, are not easily purchased, and are expensive to customize.
Therefore, it is necessary to improve the prior art to overcome the defects in the prior art, and to provide a preparation method with easily available raw materials, simple process, convenient operation and higher yield, so as to reduce the cost.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of the abersat, and the method has the advantages of easily obtained raw materials, simple process, convenient operation, high yield, low cost and easy industrial production.
The invention also provides an intermediate for preparing the abedit and a preparation method of the intermediate.
The invention is realized by the following technical scheme:
the preparation method of the abersat comprises the following steps:
(1) performing amide condensation on a first intermediate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid (compound 2) and a second intermediate 4- (2-aminoethoxy) methyl benzoate (compound 7) to obtain a third intermediate 4- [2- (3-dimethylamino benzofuran-2-yl-carbonylamino) ethoxy ] methyl benzoate (compound 8);
(2) and (3) carrying out base deesterification on the third intermediate, and then carrying out acid modulation to obtain the abedite (compound 1).
In the step (2), the conditions of the deesterification reaction are as follows: adding an alcohol solution containing alkali at 25-60 ℃ to react for 25-60 minutes;
after the ester is removed, the pH value is adjusted to be neutral by acid; the molar ratio of 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid to base is 1: 2-6.
The alcohol solution containing alkali is an alcohol solution containing hydroxylamine, and the preparation method comprises the steps of dissolving hydroxylamine hydrochloride in absolute methanol, adding KOH or NaOH, stirring, removing precipitate and drying; the molar ratio of 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid to hydroxylamine hydrochloride is 1:2 to 6.
In the step (1), the amide condensation reaction conditions are as follows: activating one of the first intermediate and the second intermediate by using a condensing agent and alkali under a protective atmosphere or without the protective atmosphere, adding the other intermediate, and reacting for 4-9 hours at 20-50 ℃; the organic solvent comprises N, N-dimethylformamide, acetonitrile, tetrahydrofuran or acetone, the condensing agent comprises EDCI/HOBt, DCI/DMAP or HATU, and the base comprises sodium hydroxide, potassium carbonate, sodium hydride or triethylamine; the activation time is 10-40 minutes; the molar ratio of the first intermediate to the second intermediate to the condensing agent to the base is 1: 0.9-1.1: 1-1.1: 1-2.5.
An intermediate for the synthesis of abersat is 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid (first intermediate).
The preparation method of the first intermediate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid comprises the following steps: 2- (2- (dimethylglycyl) phenoxy) methyl acetate (21) is taken as a raw material, alkali is added, and ring closure and ester hydrolysis are carried out under the anaerobic condition to generate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid.
The crude first intermediate can be directly used for the next reaction without purification.
Preferably, the reaction temperature is 65-75 ℃, the organic solvent used is methanol, anhydrous methanol, toluene, anhydrous toluene, ethanol, anhydrous ethanol, tetrahydrofuran, anhydrous tetrahydrofuran, N-dimethylformamide or anhydrous N, N-dimethylformamide, the base is potassium carbonate, sodium hydride, sodium bicarbonate, sodium hydroxide, sodium methoxide or sodium ethoxide, and the molar ratio of methyl 2- (2- (dimethylglycyl) phenoxy) acetate to base is 1: 1.8 to 2.3. The alkali is sodium alkoxide, preferably sodium methoxide.
An intermediate for synthesizing the albuterol is methyl 2- (2- (dimethylglycyl) phenoxy) acetate.
The preparation method of the methyl 2- (2- (dimethylglycyl) phenoxy) acetate comprises the following steps:
(A) preparing 2- (2-acetylphenoxy) methyl acetate (compound 20) from o-hydroxy phenyl ketone (compound 14) and 2-methyl chloroacetate (compound 26) through Williamson etherification reaction;
(B)2- (2-acetylphenoxy) methyl acetate (compound 20) is halogenated and substituted under the action of a catalyst to prepare 2- [2- (2-bromoacetyl) phenoxy ] methyl acetate (compound 27);
(C) substitution reaction of methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate (27) with dimethylamine at-5 to 0 ℃ to produce methyl 2- (2- (dimethylglycyl) phenoxy) acetate (compound 21).
Preferably, in the step (a), the o-hydroxy phenyl ketone (14) and methyl 2-chloroacetate (26) are etherified at 60-90 ℃ for 0.75-6 hours, the used organic solvent comprises acetonitrile, acetone, isopropanol or N, N-dimethylformamide, the used base comprises potassium hydroxide, sodium hydride, potassium carbonate or sodium carbonate, and the equivalent ratio of the base to the o-hydroxy phenyl ketone is 1: 1-3, wherein the molar ratio of the o-hydroxybenzophenone (14) to the methyl 2-chloroacetate (26) is 1: 1 to 1.7;
in the step (B), the halogenation reaction conditions of the methyl 2- (2-acetylphenoxy) acetate (20) are as follows: catalyzing a bromination reagent with a catalyst at room temperature in an organic solvent to finish bromination, wherein the used organic solvent comprises dichloromethane, acetone, methyl tert-butyl ether, acetonitrile or tetrahydrofuran, the used catalyst comprises aluminum trichloride or ferric trichloride, and the equivalent ratio of the 2- (2-acetylphenoxy) methyl acetate to the catalyst is 1: 0.05-0.13, wherein the used bromination reagent comprises copper bromide, liquid bromine or N-bromosuccinimide, and the molar ratio of the methyl 2- (2-acetylphenoxy) acetate to bromine in the bromination reagent is 1: 0.7 to 1.1;
in step (C), methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate (27) is prepared under the reaction conditions: respectively dissolving methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate and dimethylamine in an organic solvent and mixing at-5-0 ℃; the organic solvent used includes N, N-dimethylformamide, tetrahydrofuran, diethyl ether or acetone.
In the step (C), the molar ratio of methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate to dimethylamine is 1: 1.5-2, and adding an acid-binding agent, wherein the acid-binding agent is dimethylamine, triethylamine, sodium hydride, potassium carbonate, sodium hydroxide or sodium bicarbonate. The molar ratio of the 2- [2- (2-bromoacetyl) phenoxy ] methyl acetate to the acid-binding agent is 1: 0.5-1.5, preferably 1: 1-1.2.
When dimethylamine is used as an acid-binding agent, in the step (C), the molar ratio of the methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate to the dimethylamine is 1: 2-3.2; when an acid-binding agent other than dimethylamine is used, the molar ratio of methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate to dimethylamine is 1: 1.5-2.
Preferably, dimethylamine is used as an acid-binding agent, and the molar ratio of the methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate to the dimethylamine in the step (C) is 1: 2-3.5, more preferably 1: 2.5-3.
The solution of dimethylamine is an aqueous solution of dimethylamine, a methanol solution, an ethanol solution or a tetrahydrofuran solution.
An intermediate for synthesizing the ebesistat is methyl 4- (2-aminoethoxy) benzoate (a second intermediate).
The preparation method of the second intermediate methyl 4- (2-aminoethoxy) benzoate (compound 7) comprises the following steps:
s1, reacting methyl 4-hydroxybenzoate (12) with 2-bromoethylamine (namely tert-butyl (2-bromoethyl) carbamate) protected by Boc to prepare methyl 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) benzoate;
s2.4- (2- ((tert-butoxycarbonyl) amino) ethoxy) methyl benzoate is deprotected to obtain 4- (2-aminoethoxy) methyl benzoate.
The reaction conditions of step S1 were: mixing methyl 4-hydroxybenzoate with alkali and an organic solvent, adding 2-bromoethylamine (namely tert-butyl (2-bromoethyl) carbamate) protected by Boc at 60-105 ℃ for reaction for 5-12 hours, wherein the used organic solvent is acetonitrile, acetone or N, N-dimethylformamide, and the molar ratio of methyl 4-hydroxybenzoate to 2-bromoethylamine (namely tert-butyl (2-bromoethyl) carbamate is 1: 1.5-2.2, the used alkali comprises potassium hydroxide, sodium hydroxide, potassium carbonate, sodium hydride or sodium carbonate, and the molar ratio of the methyl 4-hydroxybenzoate to the alkali is 1: 1-3;
the reaction conditions of step S2 were: dissolving methyl 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) benzoate in an organic solvent, adding the organic solvent containing acid at the temperature of 25-75 ℃, and reacting for 1.5-12 hours; the acid is trifluoroacetic acid or hydrogen chloride; the organic solvent is dichloromethane, ethyl acetate or methanol solution, and the equivalent ratio of 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) methyl benzoate to acid is 1: 1 to 6.
The invention takes 2- (2- (dimethylglycyl) phenoxy) methyl acetate as raw material to prepare a first intermediate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid; preparing a second intermediate methyl 4- (2-aminoethoxy) benzoate by taking methyl 4-hydroxybenzoate as a raw material; performing amide condensation on the first intermediate and the second intermediate to obtain a third intermediate methyl 4- [2- (3-dimethylaminobenzofuran-2-yl-carbonylamino) ethoxy ] benzoate; the abetas is prepared by deesterification and acid modulation, the used raw materials are easy to obtain, the process is simple, the operation is convenient, and the yield of each step is high; the yield of the final product was 72.4% based on the first intermediate; the yield of the first intermediate was up to 66.8% based on methyl 2- (2- (dimethylglycyl) phenoxy) acetate.
Detailed Description
The technical solution of the present invention will be described below with reference to specific examples. The preparation route is shown as formula IV:
Figure BDA0003125155160000071
EXAMPLE 12 preparation of methyl- (2-Acetylphenoxy) acetate (Compound 20)
DMF (500mL), K was added to a 2L three-necked flask2CO3(101.5g, 0.734mol) and o-hydroxy-benzophenone (compound 14) (50g, 0.367mol), stirring for 30min at room temperature, gradually changing the reaction liquid from white turbidity to yellow turbidity, raising the temperature to 70 ℃ after stirring without obvious gravel sound, slowly dropwise adding 2-methyl chloroacetate (compound 26) (59.8g, 0.551mol), changing the reaction liquid from yellow to light orange along with the continuous reaction, and displaying the internal temperature at 70-80 ℃.
After 1h of reaction, no raw material remained, and the reaction was stopped. After the reaction solution is cooled to room temperature, 1.5L of water is directly poured into the reaction solution, stirred for 30min, kept stand for layering, filtered to obtain a solid, dried and weighed to obtain 75.1g of off-white solid. The yield was 98.3% and the HPLC purity was 99.6%.1H NMR(400MHz,DMSO-d6)δ7.59(dd,J＝7.6,1.7Hz,1H),7.55–7.47(m,1H),7.19–6.98(m,2H),4.97(s,2H),3.73(s,3H),2.62(s,3H).13C NMR(101MHz,DMSO)δ199.42,169.30,157.14,134.05,130.01,128.77,121.64,113.74,65.51,52.34,32.11.
EXAMPLE 22 preparation of methyl- [2- (2-bromoacetyl) phenoxy ] acetate (Compound 27)
Methyl 2- (2-Acetylphenoxy) acetate (Compound 20) (50g, 0.24mol) was weighed out and dissolved in a 1L three-necked flask containing methyl tert-butyl ether (300mL) and catalytic amount of AlCl was added3(3.5g, 26.42mmol) was stirred at room temperature and the diluted Br was added2(34.5g, 0.216mol) is slowly dripped in three batches, the reaction solution is changed into orange red from colorless clarification with generation of white smoke, the internal temperature is kept at 25-30 ℃, then the reaction solution is in yellow clarification state until three batches of Br2After all the dropwise addition was completed (about 1 hour), the reaction mixture was stirred for 10min and then startedTurbidity, which is a large amount of white solid precipitated with further reaction, accompanied by an acidic pungent odor, and absorbed gases. The TLC plate layer shows no obvious change, the auxiliary HPLC data show that the reaction is finished, a new substance is generated, the generated new substance has a polarity which is closer to that of the raw material 20, the reaction is carried out for 1h in total, the reaction solution is cooled under the ice bath condition, the reaction solution is stirred for 10min and then is kept stand, a solid is obtained by suction filtration, the white-like solid is dried and weighed to obtain 67.1g, the yield is 97.2%, and the HPLC purity is 99.6%.1H NMR(400MHz,DMSO-d6)δ7.73–7.52(m,2H),7.23–7.07(m,2H),5.00(s,2H),4.95(s,2H),3.74(s,3H).13C NMR(101MHz,DMSO)δ192.68,169.25,157.11,135.10,130.90,125.58,122.10,114.15,65.89,52.48,39.14.
Example 32 Synthesis of methyl- (2- (dimethylglycyl) phenoxy) acetate (Compound 21)
Weighing 2- [2- (2-bromoacetyl) phenoxy]Methyl acetate (compound 27) (30g, 0.104mol) was dissolved in a 1L three-necked flask with anhydrous THF (150mL) and stirred under ice-bath conditions until clear. Weighing a tetrahydrofuran solution (2M, 146.3mL, 0.293mol) of dimethylamine (also used as an acid-binding agent), slowly dripping the tetrahydrofuran solution into the tetrahydrofuran solution at the temperature of-5-0 ℃ at a speed of 4mL/min, gradually leading the solution to become yellow and turbid from clarification and generating a large amount of white solids, standing after dripping, removing white powdery solids by suction filtration after solid-liquid separation, carrying out vacuum rotary drying on the solvent at room temperature, and weighing to obtain 23.5g of light yellow viscous liquid. The yield was 89.5% and the HPLC purity was 98.5%.1H NMR(400MHz,DMSO-d6)δ7.57–7.46(m,2H),7.12–7.04(m,2H),4.93(s,2H),3.78(s,2H),3.74(s,3H),2.23(s,6H).13C NMR(101MHz,DMSO)δ199.99,169.25,156.66,133.85,129.98,128.08,121.78,113.64,69.20,65.67,52.36,45.46.
Or triethylamine, sodium hydride, potassium carbonate, sodium hydroxide or sodium bicarbonate can be added into the reaction system as an acid-binding agent, and the molar ratio of the 2- [2- (2-bromoacetyl) phenoxy ] methyl acetate to the acid-binding agent is 1: 1.1, the corresponding dimethylamine dosage was reduced to 1: 1.7, but the experimental yield using the acid-binding agent is only 50-80%.
Example 43 Synthesis of- ((dimethylamino) methyl) benzofuran-2-carboxylic acid (Compound 2, first intermediate)
Methyl 2- (2- (dimethylglycyl) phenoxy) acetate (compound 21) (20g, 79.59mmol) was weighed out and dissolved in a nitrogen-filled sealed tube containing 60mL of anhydrous methanol, and NaOCH was added3(1M, 167.1mL, 0.167mol), and reacted at 70 ℃ for 5 h. During the reaction, the solution gradually changed from clear to yellow suspension with the formation of a large amount of white solid. Cooling to room temperature, filtering to remove white solid, and spin-drying the solution to give crude light yellow powder 20.63g, which was purified by column chromatography (DCM: MeOH 1000:80) to give pure white 13.47g in 77.2% yield.
And experimental research and analysis show that the crude product obtained by ring closure and deesterification does not need to be treated, and can be directly delivered in the next reaction without influencing the subsequent reaction.
1H NMR(400MHz,DMSO-d6)δ14.37(s,1H),7.90(d,J＝7.7Hz,1H),7.70(d,J＝8.2Hz,1H),7.51(t,J＝7.6Hz,1H),7.40(t,J＝7.3Hz,1H),4.63(s,2H),2.87(s,6H).13C NMR(101MHz,DMSO)δ161.84,153.26,150.00,127.98,126.93,123.66,120.83,114.06,112.31,50.81,41.97.MS(ESI):m/z＝220.1[M+H]+.
Wherein the preparation of sodium methoxide: weighing 400mL of anhydrous methanol solution, placing in a 1L eggplant bottle, slowly adding the weighed solid sodium metal (9.2g, 0.4mol) into the solution, stirring in an ice bath, cooling to room temperature after the solid sodium metal reacts completely, and bottling for later use, wherein the prepared sodium methoxide solution is 1M.
EXAMPLE 54 preparation of methyl- (2-aminoethoxy) benzoate (Compound 7, second intermediate)
DMF (100mL), K was added to a 500mL three-necked flask2CO3(36.3g, 0.262mol) and methyl 4-hydroxybenzoate (12) (20g, 0.131mol), the reaction solution gradually turned from white turbidity to yellow-goose turbidity with no noticeable gritty stirring at room temperature for 30 min. Heating to 90 ℃, weighing the compound 24(58.9g, 0.262mol), slowly dripping, keeping the internal temperature at 90-100 ℃, wherein the solution is in a faint yellow turbid state and has white attachments on the container wall. During which time TLC plates were monitored and no starting material remained after 5 h. To-be-reacted liquidAfter cooling to room temperature, 300mL of water was poured into the reaction solution, stirred for 20min, and then allowed to stand for layering, and filtered to obtain a pale yellow solid, which was dried and weighed to obtain 38.3g of intermediate 25 in total, with a yield of 98.7% and an HPLC purity of 99.5%.1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.0Hz,2H),7.01(d,J＝8.1Hz,3H),4.03(s,2H),3.79(s,3H),3.32(d,J＝4.3Hz,2H),1.36(s,9H).13C NMR(101MHz,DMSO)δ166.32,162.80,156.15,131.67,122.38,114.91,78.27,67.19,52.22,28.65.
Further, the intermediate compound 25(38.3g, 0.13mol) obtained above was dissolved in 100mL of EA, 10% HCl/EA (237.3g, 0.65mol) was measured, and slowly added dropwise at 45 to 55 ℃, as the reaction proceeded, a large amount of white solid precipitated, the solution gradually became cloudy, finally, the reaction was complete as monitored by TLC plate, stopped, cooled to room temperature, filtered, washed with ice EA (3 × 30mL), dried, and weighed to obtain 25g of white solid, with a yield of 98.4%. The total yield of the two-step reaction was 97.1% and the HPLC purity was 99.6%.1H NMR(400MHz,DMSO-d6)δ8.45(s,3H),7.92(d,J＝8.7Hz,2H),7.08(d,J＝8.7Hz,2H),4.28(t,J＝4.8Hz,2H),3.80(s,3H),3.20(t,J＝4.9Hz,2H).13C NMR(101MHz,DMSO)δ166.29,162.17,131.70,122.85,115.14,65.01,52.32,38.57.
Wherein 10% HCl/EA is prepared by the reaction of acetyl chloride and absolute ethyl alcohol, and the specific experimental operation is as follows: anhydrous ethanol (38.2g, 0.829mol) was weighed into an eggplant bottle, acetyl chloride (65g, 82.8mol) was slowly added dropwise, and 199g of EA was added to obtain a final HCl (g)/EA solution with a content of 10% for future use.
EXAMPLE 6 preparation of tert-butyl (2-bromoethyl) carbamate (Compound 24)
Compound 24 was prepared as described: obtained by reacting 2-bromoethylamine hydrobromide (22) with TEA and BOC anhydride in anhydrous THF solution. Specific experimental operations: weighed compound 22(54g, 0.264mol) was placed in a three-necked flask, and 200mL of anhydrous THF and BOC anhydride (23) (63.3g, 0.290mol) were added thereto in N2Under protection, triethylamine TEA (32g, 0.316mol) was slowly added dropwise under ice-bath conditions, and the solution gradually turned from clear to white turbid. After the dropwise addition, the ice bath is removed, the mixture is stirred at room temperature for 12 hours and then filtered to remove solidsAnd (5) spin-drying the solvent to obtain a light yellow transparent liquid for later use.
Example 7 preparation of Ebesartan (Compound 1)
Compound 2(10g, 45.61mmol) purified by column chromatography prepared in example 4 and weighed HATU (O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 17.3g, 45.61mmol) were dissolved in 60mL of anhydrous tetrahydrofuran solution in N2Under protection, TEA (triethylamine, 9.2g, 91.22mmol) was slowly added at-5 to 0 ℃ and stirred, white smoke was generated during the reaction, and a white solid was precipitated. After activation for 30min, slowly adding compound 7(9g, 46.1mmol), reacting at 40-45 ℃ for 5h, stopping the reaction, filtering to remove solid impurities, collecting filtrate, and spin-drying to obtain 19.6g of compound 8 (third intermediate) as a yellow-brown viscous liquid.
The above untreated material was dissolved in a solution of hydroxylamine in methanol (75.9g, 0.23mol, 10%) and stirred at 35-40 ℃ for 30min, followed by adjusting the pH to 7 with acetic acid (about 90mL), concentration to give 19.3g of a brown solid mixture, column chromatography of the crude reaction product to give the final purified product, refining by methanol reflux, oven drying, and weighing to give 13.1g of a pink solid. The yield was 72.4% and the HPLC purity was 99.8%.
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.06(t,J＝4.8Hz,1H),8.92(s,1H),7.86(d,J＝7.8Hz,1H),7.75(d,J＝8.7Hz,2H),7.64(d,J＝8.3Hz,1H),7.46(t,J＝7.7Hz,1H),7.33(t,J＝7.5Hz,1H),7.04(d,J＝8.7Hz,2H),4.22(t,J＝5.2Hz,2H),3.82(s,2H),3.74–3.68(m,2H),2.19(s,6H).13C NMR(101MHz,DMSO)δ161.11,159.67,153.42,146.28,129.17,128.88,127.31,125.67,123.81,122.01,120.52,114.58,112.11,66.87,51.73,44.80,38.94.HRMS(ESI)calcd for:C21H23N3O5[M+Na]+420.1535,Found:420.15298.
Wherein, the preparation of the methanol solution of hydroxylamine comprises the following specific experimental operations: hydroxylamine hydrochloride (107.41g, 1.55mol) was dissolved in 568mL of anhydrous methanol solution, KOH (129.03g, 2.3mol) was slowly added at 0 deg.C, the reaction was stopped after stirring for 30min, the precipitate was filtered off, anhydrous sodium sulfate (3 x 10g) was added and dried to finally obtain 10% hydroxylamine in methanol solution for use.
Example 8 preparation of Ebesartan (Compound 1)
The crude compound 2 prepared in example 4 (41.1g, about 65% purity, 121.92mmol) and weighed amount of HATU (O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 46.3g, 121.84mmol) were dissolved in 150mL of anhydrous tetrahydrofuran solution in N2Under protection, TEA (triethylamine, 24.7g, 244.10mmol) was slowly added at-5 to 0 ℃ and stirred, white smoke was generated during the reaction, and a white solid was precipitated. After activation for 30min, slowly adding compound 7(24g, 122.94mmol), reacting at 40-45 ℃ for 5h, stopping the reaction, filtering to remove solid impurities, collecting filtrate, and spin-drying to obtain 52.3g of compound 8 (third intermediate) as a yellow-brown viscous liquid.
The above untreated material was dissolved in a solution of hydroxylamine in methanol (201.3g, 0.61mol, 10%) and stirred at 35-40 ℃ for 30min, followed by adjusting the pH to 7 with acetic acid (about 220mL), concentration to give 51.4g of a brown solid mixture, column chromatography of the crude reaction product to give the final purified product, refining by methanol reflux, oven drying, and weighing to give 34.11g of a pink solid. The yield was 70.4% and the HPLC purity was 99.8%. The characterization data are the same as in example 7.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (10)

1. A method of preparing abersat comprising the steps of:
(1) performing amide condensation on a first intermediate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid and a second intermediate 4- (2-aminoethoxy) methyl benzoate to obtain a third intermediate 4- [2- (3-dimethylamino benzofuran-2-yl-carbonylamino) ethoxy ] methyl benzoate;
(2) and (4) carrying out deesterification on the third intermediate, and then carrying out acid modulation to obtain the abeditat.
2. The process for preparing abersat according to claim 1 wherein in step (2) the deesterification reaction conditions are: adding an alcohol solution containing alkali at 25-60 ℃ to react for 25-60 minutes;
after the ester is removed, the pH value is adjusted to be neutral by acid; the molar ratio of 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid to base is 1: 2-6.
3. The process for preparing abersat according to claim 2, wherein the alcoholic solution containing a base is an alcoholic solution containing hydroxylamine, which is prepared by dissolving hydroxylamine hydrochloride in anhydrous methanol, adding KOH or NaOH, stirring, removing the precipitate and drying; the molar ratio of 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid to hydroxylamine hydrochloride is 1:2 to 6.
4. The process for preparing abersat according to claim 1, wherein in step (1), the amide condensation reaction conditions are: activating one of the first intermediate and the second intermediate by using a condensing agent and alkali under a protective atmosphere or without the protective atmosphere, adding the other intermediate, and reacting for 4-9 hours at 20-50 ℃; the organic solvent comprises N, N-dimethylformamide, acetonitrile, tetrahydrofuran or acetone, the condensing agent comprises EDCI/HOBt, DCI/DMAP or HATU, and the base comprises sodium hydroxide, potassium carbonate, sodium hydride or triethylamine; the activation time is 10-40 minutes; the molar ratio of the first intermediate to the second intermediate to the condensing agent to the base is 1: 0.9-1.1: 1-1.1: 1-2.5.
5. An intermediate for synthesizing abersat, which is characterized in that the intermediate is 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid.
6. The process for the preparation of 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid, an intermediate for the synthesis of abersat according to claim 4, comprising the steps of: 2- (2- (dimethylglycyl) phenoxy) methyl acetate (21) is taken as a raw material, alkali is added, and ring closure and ester hydrolysis are carried out under the anaerobic condition to generate 3- ((dimethylamino) methyl) benzofuran-2-carboxylic acid.
7. An intermediate for synthesizing Ebestatin, which is characterized in that the intermediate is 4- (2-aminoethoxy) methyl benzoate.
8. A process for the preparation of the intermediate methyl 4- (2-aminoethoxy) benzoate according to claim 7, which comprises the steps of:
s1, reacting methyl 4-hydroxybenzoate with 2-bromoethylamine protected by Boc and tert-butyl (2-bromoethyl) carbamate to prepare methyl 4- (2- ((tert-butoxycarbonyl) amino) ethoxy) benzoate;
s2, obtaining 4- (2-aminoethoxy) methyl benzoate through deprotection.
9. An intermediate for the synthesis of abersat, wherein said intermediate is methyl 2- (2- (dimethylglycyl) phenoxy) acetate (21).
10. A process for the preparation of the intermediate methyl 2- (2- (dimethylglycyl) phenoxy) acetate (21) as claimed in claim 9, comprising the steps of:
(A) preparing 2- (2-acetylphenoxy) methyl acetate (20) by carrying out Williamson etherification reaction on o-hydroxybenzophenone (14), 2-methyl chloroacetate (26) and alkali in an organic solvent;
(B)2- (2-acetylphenoxy) methyl acetate (20) is halogenated and substituted under the action of a catalyst to prepare 2- [2- (2-bromoacetyl) phenoxy ] methyl acetate (27);
(C) and (3) carrying out substitution reaction of methyl 2- [2- (2-bromoacetyl) phenoxy ] acetate (27) with dimethylamine at-5 to 0 ℃ to produce methyl 2- (2- (dimethylglycyl) phenoxy) acetate (21).
CN202110689076.XA 2021-06-21 2021-06-21 Method for preparing abemostat, intermediate and preparation method of intermediate Pending CN113527237A (en)

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