CN111747874B - Ericoxib intermediate and preparation method and application thereof - Google Patents

Ericoxib intermediate and preparation method and application thereof Download PDF

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CN111747874B
CN111747874B CN201910253109.9A CN201910253109A CN111747874B CN 111747874 B CN111747874 B CN 111747874B CN 201910253109 A CN201910253109 A CN 201910253109A CN 111747874 B CN111747874 B CN 111747874B
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林巍
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Chengdu Tongxin Zongheng Biomedical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

Abstract

The invention provides an ereoxib intermediate and a preparation method and application thereof. The intermediate of the dapoxib is very stable; in the processes of preparing the intermediate of the ereoxib and preparing the ereoxib by using the intermediate of the ereoxib, the reaction condition is mild, the toxicity of the reagent is low, and the method is environment-friendly; in addition, the product is easy to separate and purify in the reaction process, has high yield, and is suitable for large-scale industrial production.

Description

Ericoxib intermediate and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to an erexib intermediate as well as a preparation method and application thereof.
Background
The chemical name of the imreoxib is 1-n-propyl-3- (4-methylphenyl) -4- (4-methylsulfonylphenyl) -2, 5-dihydro-1H-2-pyrrolidone, and the chemical structural formula is shown as the formula Y. Ereoxib is a non-steroidal anti-inflammatory drug used to relieve the pain symptoms of osteoarthritis and is currently approved by the national drug administration for marketing. Because the effect of the dapoxib on relieving pain is good, the dapoxib is widely regarded by research. At present, a plurality of patents report the synthesis of the ereoxib.
Figure BDA0002012876560000011
Patent CN108707100A discloses an ereoxib and an intermediate preparation method thereof, wherein in the modified preparation method, an α -aminoketone is adopted to react under an alkaline condition to prepare an ereoxib intermediate. However, it is produced by "Linear Applications of Named Reaction in Organic Synthesis: background and Detailed mechanics (L a szl Lo Kurti and Barbara Czak Lo), it can be known: alpha-aminoketones are unstable under alkaline conditions and readily undergo self-polymerization. If the more stable hydrochloride of the alpha-amino ketone is adopted to prepare the intermediate of the ereoxib, the subsequent steps can use stronger alkali, so that the reaction is more complicated, and the industrial production is not facilitated.
The preparation of the intermediate of the ereoxib by using patents CN1134413C, US20040029951, CN102206178B and CN104193664B and the like and the preparation of the ereoxib by using the intermediate have the problems of low yield, difficult separation and purification of products, expensive reagents, large toxicity of the reagents and three wastes generated by reaction, environmental friendliness and the like.
Disclosure of Invention
In order to solve the above problems, the present invention provides a compound represented by formula i, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
Figure BDA0002012876560000012
Figure BDA0002012876560000021
wherein R is selected from hydrogen, substituted or unsubstituted C1～C8An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Further, the compounds are of formula I-A:
Figure BDA0002012876560000022
the invention also provides a compound shown as a formula II, or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a prodrug or a metabolite thereof:
Figure BDA0002012876560000023
wherein R is selected from hydrogen, substituted or unsubstituted C1～C8An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Further, the compound is represented by formula II-A:
Figure BDA0002012876560000024
the invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0002012876560000025
reacting the compound shown in the formula III with propionyl chloride in the presence of alkali by taking an organic solvent as a solvent to obtain a compound shown in the formula I;
wherein R is selected from hydrogen, substituted or unsubstituted C1～C8An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Further, it comprises the following steps:
Figure BDA0002012876560000031
and reacting the compound 4 with propionyl chloride by taking an organic solvent as a solvent in the presence of alkali to obtain a compound 5.
Further, the base is triethylamine; the organic solvent is acetonitrile; the molar ratio of the compound 4 to the propionyl chloride to the triethylamine is 35: 32-52: 42-62; the mass-to-volume ratio of the compound 4 to acetonitrile is 1: 5-25 (w/v).
Further, the molar ratio of the compound 4, propionyl chloride and triethylamine is 35:42: 52; the mass-to-volume ratio of compound 4 to acetonitrile was 1:10 (w/v).
Further, the reaction is carried out at room temperature for 1-3 h, preferably at room temperature for 1-2 h.
Further, the method also comprises the following steps after the reaction with propionyl chloride: quenching and purifying the reaction solution; preferably, the quenching is adding water into the reaction liquid to quench the reaction; the purification is to remove acetonitrile and excess triethylamine, extract, wash and dry the organic phase.
Further, the purification was carried out by removing acetonitrile and excess triethylamine, followed by extraction with ethyl acetate, washing the organic phase with saturated brine, drying the organic phase with anhydrous sodium sulfate, and spin-drying the organic phase.
Further, the preparation method of the compound shown in the formula III comprises the following steps:
Figure BDA0002012876560000032
step 1: compound 1 and NH2Reacting OH & HCl in an aqueous solution of alkali to obtain a reaction solution, and purifying the reaction solution to obtain a compound 2;
step 2: reacting the compound 2, sulfonyl chloride compounds and alkali in an organic solvent to obtain reaction liquid, and purifying the reaction liquid to obtain a compound 3;
and step 3: reacting the compound 3 with potassium alcoholate in an anhydrous organic solvent to obtain a reaction solution, adding the organic solvent into the reaction solution to precipitate a solid, carrying out solid-liquid separation, introducing gaseous acid or an anhydrous organic solution of the acid into the filtrate, and purifying to obtain a compound shown in a formula III;
wherein R is selected from hydrogen, substituted or unsubstituted C1～C8An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Further, when the compound represented by the formula III is a compound 4, the preparation method of the compound 4 comprises the following steps:
Figure BDA0002012876560000041
step 1: compound 1 and NH2Reacting OH & HCl in an aqueous solution of alkali to obtain a reaction solution, and purifying the reaction solution to obtain a compound 2;
step 2: reacting the compound 2, sulfonyl chloride compounds and alkali in an organic solvent to obtain reaction liquid, and purifying the reaction liquid to obtain a compound 3;
and step 3: reacting the compound 3 with potassium alcoholate in an anhydrous organic solvent to obtain a reaction solution, adding the organic solvent into the reaction solution, separating out solids, carrying out solid-liquid separation, introducing gaseous acid or an anhydrous organic solution of the acid into the filtrate, and purifying to obtain a compound 4.
Further, the air conditioner is provided with a fan,
in step 1, the NH2OH & HCl is NH2OH & HCl aqueous solution; the compound 1 with NH2The mass-to-volume ratio of the OH & HCl aqueous solution is 1-5: 1 w/v; the mass volume ratio of the compound 1 to the aqueous solution of the alkali is 1: 1-5 w/v;
and/or in the step 2, the mass ratio of the compound 2 to the sulfonyl chloride compound to the alkali is 1: 0.5-2.5; the mass volume ratio of the compound 2 to the organic solvent is 1: 10-30 w/v;
and/or in the step 3, the mass ratio of the compound 3 to the potassium alkoxide is 1: 0.1-0.5; the mass volume ratio of the compound 3 to the anhydrous organic solvent is 1: 10-20 w/v; the mass volume ratio of the compound 3 to the organic solvent is 1: 10-20 w/v.
Further, the air conditioner is provided with a fan,
in step 1, the compound 1 is reacted with NH2The mass-volume ratio of the OH & HCl aqueous solution is 2:1 w/v; the mass-to-volume ratio of the compound 1 to the aqueous solution of the base is 1:3 w/v;
and/or in the step 2, the mass ratio of the compound 2 to the sulfonyl chloride compound to the base is 1:1.35: 1.25; the mass volume ratio of the compound 2 to the organic solvent is 1:20 w/v;
and/or in the step 3, the mass ratio of the compound 3 to the potassium alkoxide is 1: 0.23; the mass volume ratio of the compound 3 to the anhydrous organic solvent is 1:15 w/v; the mass volume ratio of the compound 3 to the organic solvent is 1:15 w/v.
Further, the air conditioner is provided with a fan,
in step 1, the aqueous solution of the alkali is NaOH, KOH, CsOH or K2CO3An aqueous solution of (a); the concentration of the aqueous solution of the alkali is 10-30% w/v; the NH2The concentration of the OH & HCl aqueous solution is 70-90% w/v;
and/or in the step 2, the sulfonyl chloride compound is p-methyl benzene sulfonyl chloride; the alkali is organic alkali or inorganic alkali; the organic solvent is dichloromethane;
and/or, in the step 3, the potassium alcoholate is potassium methylate; the anhydrous organic solvent is absolute ethyl alcohol; the organic solvent is methyl tert-butyl ether; the acid in the gaseous acid or the anhydrous organic solution of the acid is hydrochloric acid.
Further, the air conditioner is provided with a fan,
in the step 1, the aqueous solution of the alkali is an aqueous solution of NaOH; the concentration of the aqueous alkali solution is 20% w/v; the NH2The concentration of the OH & HCl aqueous solution is 84% w/v;
and/or, in the step 2, the alkali is potassium hydroxide.
Further, the air conditioner is provided with a fan,
in the step 1, the reaction is carried out in an ice bath for 1-4 h; after the reaction solution is extracted by ethyl acetate, combining organic phases and drying;
and/or in the step 2, the reaction is carried out at room temperature for 3-6 h; the purification is to filter, wash and dry the reaction solution;
and/or in the step 3, the reaction is carried out for 3-6 h at the temperature of 60-80 ℃; introducing gaseous acid or an anhydrous organic solution of the acid until the pH value of the filtrate is 2-4; and the purification comprises the steps of drying the filtrate, adding ethyl acetate, adjusting the pH value to 9-11, extracting, drying an organic phase, and inverting acid and alkali.
Further, the air conditioner is provided with a fan,
in the step 1, the reaction is carried out in an ice bath for 2 hours; after the reaction liquid is extracted by ethyl acetate, organic phases are combined and are extracted by anhydrous NaSO4Drying and spin-drying;
and/or in the step 2, the reaction is carried out for 4-5 hours at room temperature; the purification is to pump and filter the reaction solution, wash and spin dry;
and/or in the step 3, the reaction is carried out for 4-5 h at 70 ℃; introducing gaseous acid or an anhydrous organic solution of the acid until the pH value of the filtrate is 3; the purification comprises spin-drying the filtrate, adding ethyl acetate, adjusting pH to 10 with NaOH, extracting, spin-drying the organic phase, and inverting with acid and alkali.
The invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0002012876560000051
under the protection of nitrogen, reducing the compound to obtain a compound shown as a formula II;
wherein R is selected from hydrogen, substituted or unsubstituted C1～C8An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Further, it comprises the following steps:
Figure BDA0002012876560000061
and reducing the compound under the protection of nitrogen to obtain a compound 6.
Further, the reduction is carried out by reducing the compound with a reducing agent in an organic solvent; preferably, the reducing agent is borane tetrahydrofuran solution; the organic solvent is tetrahydrofuran; the mass-to-volume ratio of the compound to the borane tetrahydrofuran solution is 1: 1-10 (w/v); the mass-to-volume ratio of the compound to tetrahydrofuran is 1: 1-5 (w/v); wherein the concentration of the alkane tetrahydrofuran solution is 1-5 mol/L.
Further, the mass-to-volume ratio of the compound to the borane-tetrahydrofuran solution is 1:5.8 (w/v); the mass-to-volume ratio of the compound to tetrahydrofuran is 1:2 (w/v); wherein the concentration of the alkane tetrahydrofuran solution is 1 mol/L.
Further, the reduction is reflux reaction for 1-3 h at the temperature of 60-100 ℃; the reaction is preferably carried out at 80 ℃ under reflux for 1 h.
Further, the method also comprises the following steps after the reduction of the compound: quenching and purifying the reaction solution; preferably, the quenching is adding MeOH to the reaction solution to quench the reaction; and the purification is to spin-dry the reaction solution, add dilute hydrochloric acid, wash, adjust the pH of the water phase to 9-11, extract, wash and dry the organic phase.
Further, the purification is to spin-dry the reaction solution, add dilute hydrochloric acid with a concentration of 1mol/L, wash with ethyl acetate 3 times, adjust the pH of the aqueous phase to 10 with 20% NaOH solution, extract with ethyl acetate 3 times, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, and spin-dry the organic phase.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing the ereoxib as an intermediate.
In the invention, w/v is a mass-to-volume ratio and has a unit of g/mL.
In the invention, v/w is a volume-to-mass ratio and has a unit of mL/g.
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C8The alkyl group is a straight-chain or branched alkyl group having 1 to 8 carbon atoms.
"substituted" in the present invention means that a hydrogen atom in a molecule is replaced with another different atom or molecule.
The invention provides an ereoxib intermediate and a preparation method thereof. The intermediate of the dapoxib is very stable; in the processes of preparing the intermediate of the ereoxib and preparing the ereoxib by using the intermediate of the ereoxib, the reaction condition is mild, the toxicity of the reagent is low, and the method is environment-friendly; in addition, the product is easy to separate and purify in the reaction process, has high yield, and is suitable for large-scale industrial production.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
Figure 1 is a nuclear magnetic spectrum of an ereoxib intermediate (compound 4) prepared in the present invention.
Figure 2 is a nuclear magnetic spectrum of an ereoxib intermediate (compound 5) prepared in accordance with the present invention.
Figure 3 is a nuclear magnetic spectrum of an ereoxib intermediate (compound 6) prepared in accordance with the present invention.
Figure 4 is a nuclear magnetic spectrum of ereoxib (compound 8) prepared according to the invention.
Detailed Description
The raw materials used in the examples of the present invention are all common raw materials in the art, and the methods used in the examples are all conventional methods in the art, unless otherwise specified.
Abbreviations:
PE: petroleum ether (60-900C); EA: ethyl acetate; DCM: dichloromethane; KOMe (potassium methoxide); MTBE: methyl tert-butyl ether; et (Et)3N: triethylamine; THF: tetrahydrofuran; EDCI: a carbodiimide; HOBT: 1-hydroxybenzotriazole; DMAP: 4-dimethylaminopyridine.
Example 1 preparation of an intermediate of the present invention, Compound 4
The synthetic route of the intermediate (compound 4) of the invention is as follows:
Figure BDA0002012876560000071
step 1: preparation of the intermediate (Compound 2) of the present invention
Measuring 20% NaOH solution (60mL), adding the NaOH solution into a 250mL round-bottom flask, and cooling to 0 ℃; then weighing NH2OH & HCl (8.4g, 1.2mol) was dissolved in 10mL of water and added to a round bottom flask, and finally 4-methylsulfoxide acetophenone (20g, 1mol) was added and reacted for 2h in ice bath. TLC (PE: EA 1:1) monitors the progress of the reaction, and the reaction solution is obtained after the reaction is finished.
EA extractTaking the reaction solution for 4 times, wherein the dosage of EA is 100mL each time, combining organic phases, and anhydrous NaSO4The organic phase was dried and then spin-dried to give 20g of a white solid (Compound 2). The yield was 93%.
Step 2: preparation of the intermediate (Compound 3) of the present invention
To a 500mL round bottom flask were added sequentially compound 2(20g, 94mmol), p-toluenesulfonyl chloride (27g, 140mmol), 85% KOH (25g, 375mmol), and finally 400mL DCM was added and reacted at room temperature for 4-5 h. The progress of the reaction was monitored by TLC (PE: EA: 1). After the reaction is finished, the mixture is directly filtered and washed, and the filtrate is dried in a spinning mode to obtain 31g of light yellow solid (a compound 3), wherein the yield is 90%.
And step 3: preparation of the intermediate (Compound 4) of the present invention
Weighing the compound 3(20g, 54mmol), adding the compound into a 1L round-bottom flask, adding 300mL of absolute ethyl alcohol, fully stirring, finally weighing KOMe (4.6g, 65mmol), dissolving the KOMe in 50mL of absolute ethyl alcohol, and reacting for 4-5 h at 70 ℃. TLC (DCM: MeOH ═ 10:1) monitored the progress of the reaction. After the reaction is finished, adding 300mL of MTBE into the reaction solution, separating out solids, performing suction filtration, removing the solids, removing part of filtrate by rotation, and introducing HCl gas into the filtrate for half an hour until the pH value is 3; finally, the filtrate was spin-dried. 100mL of ethyl acetate was added, the pH was adjusted to 10 with NaOH, extracted with EA and the organic phase was spin-dried. Inversion with acid base once more gave 12g (compound 4) as a pale yellow solid in 75% yield.
The nuclear magnetic spectrum of the compound 4 prepared by the invention is shown in figure 1:1H NMR(400MHz,CDCl3)：δ7.89(d,J＝8.5Hz,2H),7.69(d,J＝8.6Hz,2H),3.43(m,2H),3.32(m,2H),3.02(s,3H),2.96(s,2H),1.18(t,J＝7.1Hz,6H).
the basic structure of the compound 4 prepared by the invention is as follows:
Figure BDA0002012876560000081
when the solvent in step 3 is absolute ethanol, the compound 4 of the present invention is obtained. When absolute ethyl alcohol is replaced by other alcohol solvent, different substituent groups can be obtainedTo obtain more intermediates of the ereoxib. Wherein R is1、R2Each independently selected from hydrogen, substituted or unsubstituted C1～C6An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino; preferably R1And R2And is simultaneously hydrogen, substituted or unsubstituted C1～C6An alkyl group; the substituent is halogen, hydroxyl, cyano, nitro or amino.
Example 2 preparation of an Iresib intermediate (Compound 5) of the present invention
Figure BDA0002012876560000091
Weighing Compound 4(10g, 35mmol) into a 250mL round-bottom flask, adding 100mL acetonitrile to the flask, followed by Et3N (7.3mL, 52mmol), finally propionyl chloride (3.7mL, 42mmol) was added dropwise at room temperature, and the reaction was continued at room temperature for 1-2 h. TLC (DCM: MeOH ═ 20:1) monitored the progress of the reaction. After the reaction is finished, adding water into the reaction solution to quench the reaction, removing acetonitrile and excessive triethylamine by spinning, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, and drying by using anhydrous sodium sulfate. The organic phase was spin-dried to give 12g (Compound 5) as a brown-yellow oily liquid in 100% yield.
The nuclear magnetic spectrum of the compound 5 prepared by the invention is shown in figure 2:1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.1Hz,2H),7.70(d,J＝8.3Hz,2H),5.22(s,1H),3.67(d,J＝5.8Hz,2H),3.48(m,2H),3.34(m,2H),3.03(s,3H),1.99(q,J＝7.5Hz,2H),1.19(t,J＝7.0Hz,6H),0.94(t,J＝7.9Hz,3H).
example 3 preparation of an intermediate of the present invention, Compound 6
Figure BDA0002012876560000092
Compound 5(10g, 29mmol) was weighed into a 250mL round bottom flask under N2Under the protection condition, 20mL of THF solvent is added into the flask, the mixture is refluxed at 80 ℃, and finally the reaction is performed againA1 mol/L borane-tetrahydrofuran solution (58mL, 58mmol) was added to the system, and the reaction was continued at reflux for 1 h. TLC (DCM: MeOH ═ 10:1) monitored the progress of the reaction. After the reaction, the reaction solution was quenched by adding MeOH, the reaction solution was spin-dried, 30mL of dilute hydrochloric acid (1mol/L) was added, the reaction solution was washed with ethyl acetate 3 times (30 mL each time), the aqueous phase was adjusted to pH 10 with 20% NaOH solution, the aqueous phase was extracted with EA 3 times (50 mL each time), the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was spin-dried to give 8g (Compound 6) as a pale yellow oily liquid in 83% yield.
The nuclear magnetic spectrum of the compound 6 prepared by the invention is shown in figure 3:1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.5Hz,2H),7.74(d,J＝8.6Hz,2H),3.46(m,2H),3.39-3.28(m,2H),3.05(s,4H),2.98(s,2H),2.41-2.34(m,2H),1.36–1.26(m,2H),1.21(t,J＝7.1Hz,6H),0.74(t,J＝7.4Hz,3H).
example 4 preparation of the invention
The synthetic route of the ereoxib (compound 8) of the invention is as follows:
Figure BDA0002012876560000101
step 6: preparation of the intermediate (Compound 7) of Ericoxib of the present invention
To a 250mL round bottom flask were added successively p-methylphenylacetic acid (4.5g, 30mmol), EDCI (5.8g, 30mmol), HOBT (4.0g, 30mmol), DMAP (183mg, 1.5mmol), DCM (100mL), Et3N (12.4mL, 90mmol), stirring at room temperature for half an hour, finally adding compound 6(5.0g, 15mmol), and continuing the reaction at room temperature for 1-2 h. The progress of the reaction was monitored by TLC (PE: EA: 1). After the reaction was complete, the reaction mixture was washed with water (100mL), 1N HCl (100mL), and saturated NaHCO in that order3(100mL), the reaction mixture was washed with saturated brine (100mL), the organic phase was dried over anhydrous sodium sulfate, the organic phase was spin-dried, concentrated hydrochloric acid (15mL) was added to hydrolyze the product (a large amount of white solid precipitated), filtered, washed with water (150mL), and recrystallized from ethanol. 4.5g (Compound 7) of an off-white solid was obtained in 78% yield.
And 7: preparation of Ehrexib (Compound 8) of the present invention
A50 mL round-bottom flask was charged with compound 7(3g, 7.8mmol), ethanol 90mL, water 100mL, and potassium carbonate (2.1g, 15.6mmol) in that order, and heated to 80-120 ℃ with stirring for dissolution under reflux. And reacting for 2 h. The progress of the reaction was monitored by TLC (PE: EA: 1). After the reaction is finished, the reaction solution is cooled to 60 ℃ slightly, poured into 150mL of ice water, neutralized to neutrality (pH is 6.5-7.0) by using 1N hydrochloric acid, stirred and cooled to 10 ℃, kept stand for 3h, and filtered to obtain 2.3g of an off-white solid product (compound 8, namely the erexib) with the yield of 79%.
The nuclear magnetic spectrum of the compound 8 prepared by the invention is shown in figure 4:1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.5Hz,2H),7.47(d,J＝8.5Hz,2H),7.27(d,J＝6.4Hz,2H),7.15(d,J＝8.0Hz,2H),4.29(s,2H),3.60–3.51(t,J＝7.2Hz 2H),3.05(s,3H),2.35(s,3H),1.70(m,2H),0.98(t,J＝7.4Hz,3H).[M+H]+calcd.for C21H23NO3S,370.1；Found,370.1.
comparative example 1
When HCl gas is introduced into step 3 in example 1 of the present invention, a stable compound cannot be obtained, that is, an intermediate of the present invention cannot be obtained, and the present invention cannot be used to prepare apparatuses.
In conclusion, the invention provides an ereoxib intermediate and a preparation method thereof. The intermediate of the dapoxib is very stable; in the processes of preparing the intermediate of the ereoxib and preparing the ereoxib by using the intermediate of the ereoxib, the reaction condition is mild, the toxicity of the reagent is low, and the method is environment-friendly; in addition, the product is easy to separate and purify in the reaction process, has high yield, and is suitable for large-scale industrial production.

Claims (32)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE001
wherein R is selected from unsubstituted C1~C8An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound is shown as a formula I-A:
Figure 363964DEST_PATH_IMAGE002
。
3. a compound of formula II, or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE003
wherein R is selected from unsubstituted C1~C8An alkyl group.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: the compound is shown as a formula II-A:
Figure 858268DEST_PATH_IMAGE004
。
5. a process for the preparation of a compound according to claim 1, characterized in that: it comprises the following steps:
Figure DEST_PATH_IMAGE005
reacting the compound shown in the formula III with propionyl chloride in the presence of alkali by taking an organic solvent as a solvent to obtain a compound shown in the formula I;
wherein R is selected from unsubstituted C1~C8An alkyl group.
6. The method of claim 5, wherein: it comprises the following steps:
Figure 716634DEST_PATH_IMAGE006
the compound 4 reacts with propionyl chloride by taking an organic solvent as a solvent in the presence of alkali to obtain the formula I-A.
7. The method of claim 6, wherein: the alkali is triethylamine; the organic solvent is acetonitrile; the molar ratio of the compound 4 to the propionyl chloride to the triethylamine is 35: 32-52: 42-62; the mass-to-volume ratio of the compound 4 to acetonitrile is 1: 5-25 (w/v).
8. The method of claim 7, wherein: the molar ratio of the compound 4, propionyl chloride and triethylamine is 35:42: 52; the mass-to-volume ratio of compound 4 to acetonitrile was 1:10 (w/v).
9. The method of claim 6, wherein: the reaction is carried out for 1-3 h at room temperature.
10. The method of claim 9, wherein: the reaction is carried out for 1-2 h at room temperature.
11. The method of claim 6, wherein: the method also comprises the following steps after the reaction with propionyl chloride: quenching and purifying the reaction liquid.
12. The method of claim 11, wherein: the quenching is to add water into the reaction liquid for quenching reaction; the purification is to remove acetonitrile and excess triethylamine, extract, wash and dry the organic phase.
13. The method of manufacturing according to claim 12, wherein: the purification is to remove acetonitrile and excess triethylamine, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, and spin-dry the organic phase.
14. The method of claim 5, wherein: the preparation method of the compound shown in the formula III comprises the following steps:
Figure DEST_PATH_IMAGE007
step 1: compound 1 and NH2Reacting OH, HCl in an aqueous solution of alkali to obtain a reaction solution, and purifying the reaction solution to obtain a compound 2;
step 2: reacting the compound 2, sulfonyl chloride compounds and alkali in an organic solvent to obtain reaction liquid, and purifying the reaction liquid to obtain a compound 3;
and step 3: reacting the compound 3 with potassium alcoholate in an anhydrous organic solvent to obtain a reaction solution, adding the organic solvent into the reaction solution to precipitate a solid, carrying out solid-liquid separation, introducing gaseous acid or an anhydrous organic solution of the acid into the filtrate, and purifying to obtain a compound shown in a formula III;
wherein R is selected from unsubstituted C1~C8An alkyl group.
15. The method of claim 14, wherein: when the compound shown in the formula III is the compound 4, the preparation method of the compound 4 comprises the following steps:
Figure 439739DEST_PATH_IMAGE008
step 1: compound 1 and NH2Reacting OH, HCl in an aqueous solution of alkali to obtain a reaction solution, and purifying the reaction solution to obtain a compound 2;
step 2: reacting the compound 2, sulfonyl chloride compounds and alkali in an organic solvent to obtain reaction liquid, and purifying the reaction liquid to obtain a compound 3;
and step 3: reacting the compound 3 with potassium alcoholate in absolute ethyl alcohol to obtain reaction liquid, adding an organic solvent into the reaction liquid, separating out solids, carrying out solid-liquid separation, introducing gaseous acid or an anhydrous organic solution of the acid into the filtrate, and purifying to obtain a compound 4.
16. The method of claim 15, wherein:
in step 1, the NH2HCl is NH2Aqueous hcl; the compound 1 with NH2The mass-to-volume ratio of the OH.HCl aqueous solution is 1-5: 1 w/v; the mass volume ratio of the compound 1 to the aqueous solution of the alkali is 1: 1-5 w/v;
and/or in the step 2, the mass ratio of the compound 2 to the sulfonyl chloride compound to the alkali is 1: 0.5-2.5; the mass volume ratio of the compound 2 to the organic solvent is 1: 10-30 w/v;
and/or in the step 3, the mass ratio of the compound 3 to the potassium alkoxide is 1: 0.1-0.5; the mass volume ratio of the compound 3 to the absolute ethyl alcohol is 1: 10-20 w/v; the mass volume ratio of the compound 3 to the organic solvent is 1: 10-20 w/v.
17. The method of manufacturing according to claim 16, wherein:
in step 1, the compound 1 is reacted with NH2The mass-to-volume ratio of the OH.HCl aqueous solution is 2:1 w/v; the mass-to-volume ratio of the compound 1 to the aqueous solution of the base is 1:3 w/v;
and/or in the step 2, the mass ratio of the compound 2 to the sulfonyl chloride compound to the base is 1:1.35: 1.25; the mass volume ratio of the compound 2 to the organic solvent is 1:20 w/v;
and/or in the step 3, the mass ratio of the compound 3 to the potassium alkoxide is 1: 0.23; the mass-to-volume ratio of the compound 3 to the absolute ethyl alcohol is 1:15 w/v; the mass volume ratio of the compound 3 to the organic solvent is 1:15 w/v.
18. The method of claim 17, wherein:
in step 1The aqueous solution of the alkali is NaOH, KOH, CsOH or K2CO3An aqueous solution of (a); the concentration of the aqueous solution of the alkali is 10-30% w/v; the NH2The concentration of the OH.HCl aqueous solution is 70-90% w/v;
and/or in the step 2, the sulfonyl chloride compound is p-methyl benzene sulfonyl chloride; the alkali is organic alkali or inorganic alkali; the organic solvent is dichloromethane;
and/or, in the step 3, the potassium alcoholate is potassium methylate; the organic solvent is methyl tert-butyl ether; the acid in the gaseous acid or the anhydrous organic solution of the acid is hydrochloric acid.
19. The method of claim 18, wherein:
in the step 1, the aqueous solution of the alkali is an aqueous solution of NaOH; the concentration of the aqueous alkali solution is 20% w/v; the NH2Concentration of aqueous HCl 84% w/v;
and/or, in the step 2, the alkali is potassium hydroxide.
20. The method of claim 15, wherein:
in the step 1, the reaction is carried out in an ice bath for 1-4 h; after the reaction solution is extracted by ethyl acetate, combining organic phases and drying;
and/or in the step 2, the reaction is carried out at room temperature for 3-6 h; the purification is to filter, wash and dry the reaction solution;
and/or in the step 3, the reaction is carried out for 3-6 h at the temperature of 60-80 ℃; introducing gaseous acid or an anhydrous organic solution of the acid until the pH value of the filtrate is 2-4; and the purification comprises the steps of drying the filtrate, adding ethyl acetate, adjusting the pH value to 9-11, extracting, drying an organic phase, and inverting once by using acid-base.
21. The method of claim 20, wherein:
in the step 1, the reaction is carried out in an ice bath for 2 hours; after the purification is that the ethyl acetate extracts the reaction liquid, the organic phases are merged and the organic phase isAnhydrous NaSO for organic phase4Drying and spin-drying;
and/or in the step 2, the reaction is carried out for 4-5 hours at room temperature; the purification is to pump and filter the reaction solution, wash and spin dry;
and/or in the step 3, the reaction is carried out for 4-5 h at 70 ℃; introducing gaseous acid or an anhydrous organic solution of the acid until the pH value of the filtrate is 3; the purification comprises spin-drying the filtrate, adding ethyl acetate, adjusting pH to 10 with NaOH, extracting, spin-drying the organic phase, and inverting once with acid-base.
22. A process for the preparation of a compound according to claim 3 or 4, characterized in that: it comprises the following steps:
Figure DEST_PATH_IMAGE009
reducing the compound of claim 1 or 2 under the protection of nitrogen to obtain a compound shown as a formula II;
wherein R is selected from unsubstituted C1~C8An alkyl group.
23. The method of claim 22, wherein: it comprises the following steps:
Figure 834205DEST_PATH_IMAGE010
reducing the compound of claim 2 under the protection of nitrogen to obtain the compound of formula II-A.
24. The method of claim 23, wherein: the reduction is a reduction of the compound of claim 2 with a reducing agent in an organic solvent.
25. The method of claim 24, wherein: the reducing agent is borane tetrahydrofuran solution; the organic solvent is tetrahydrofuran; the mass-to-volume ratio of the compound of claim 2 to a borane-tetrahydrofuran solution is 1: 1-10 (w/v); the mass-to-volume ratio of the compound of claim 2 to tetrahydrofuran is 1: 1-5 (w/v); wherein the concentration of the borane tetrahydrofuran solution is 1-5 mol/L.
26. The method of claim 25, wherein: the mass to volume ratio of the compound of claim 2 to the borane tetrahydrofuran solution is 1:5.8 (w/v); the mass to volume ratio of the compound of claim 2 to tetrahydrofuran is 1:2 (w/v); wherein the concentration of the borane tetrahydrofuran solution is 1 mol/L.
27. The method of claim 23, wherein: the reduction is a reflux reaction at 60-100 ℃ for 1-3 h.
28. The method of manufacturing according to claim 27, wherein: the reduction is carried out for 1h at 80 ℃.
29. The method of claim 23, wherein: the method of claim 2, further comprising the step of, after reducing the compound: quenching and purifying the reaction liquid.
30. The method of claim 29, wherein: the quenching is to add MeOH into the reaction liquid to quench the reaction; and the purification is to spin-dry the reaction solution, add dilute hydrochloric acid, wash, adjust the pH of the water phase to 9-11, extract, wash and dry the organic phase.
31. The method of claim 30, wherein: the purification is to spin-dry the reaction solution, add dilute hydrochloric acid with concentration of 1mol/L, wash with ethyl acetate for 3 times, adjust pH of aqueous phase to 10 with 20% NaOH solution, extract with ethyl acetate for 3 times, wash organic phase with saturated saline solution, dry organic phase with anhydrous sodium sulfate, and spin-dry organic phase.
32. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an intermediate in the preparation of etoricoxib.
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