CN115043895A - PNU-159682 and preparation method of intermediate thereof - Google Patents
PNU-159682 and preparation method of intermediate thereof Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms
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Abstract
The invention discloses a preparation method of PNU-159682 and an intermediate thereof, which comprises the steps of preparing an intermediate compound I, an intermediate compound II and an intermediate compound III, wherein the intermediate I is prepared from doxorubicin hydrochloride, the intermediate II is prepared from the intermediate I, the intermediate III is prepared from the intermediate II, and finally, the intermediate III is prepared to obtain the PNU-159682; compared with the prior art, the method solves the problems of limited raw materials and high cost, takes relatively cheap and easily-obtained adriamycin as the initial raw material, and improves the stability of each intermediate by introducing the protective group, thereby realizing stable and reliable process, being easy for scale-up production and reducing the operation difficulty of scale-up production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a PNU-159682 and a preparation method of an intermediate thereof.
Background
The antibody drug conjugate is a novel anti-tumor drug, ADC for short, and the principle is that cytotoxin is connected to the antibody, and the cytotoxin is transported to a target point through the recognition of the antibody to a specific antigen on the surface of a cancer cell and the entry of the antibody into the cancer cell through endocytosis, so that the aim of targeted therapy of malignant tumor is achieved.
Compared with the traditional micromolecular antitumor drugs, the ADC has the advantages that the target recognition performance of the antibody and the high activity of toxin can be utilized, so that the ADC has higher specificity and effectiveness; the ADC comprises three different components, namely an antibody, a linker and cytotoxin, the antibody realizes targeting, the linker ensures the stability of the ADC in blood transportation, and the cytotoxin plays a role in killing cancer cells after reaching an action target point, wherein the toxin suitable for the ADC is divided into a microtubule inhibitor, a DNA damaging agent and an RNA polymerase inhibitor according to different action mechanisms.
PNU-159682 is a highly potent anthracycline metabolite, DNA topoisomerase II inhibitor, PNU-159682 is remarkably cytotoxic and is a potent ADC cytotoxin, and PNU-159682 has the following structure.
The compound patent of PNU-159682 is a patent applied by Pharmacia & Upjohn S.P.A. on 1997, 6/20, and the compound patent is due.
PNU-159682 is a metabolite of Nemorubicin (Nemorubicin), a morpholinyl anthracycline derivative, and thus literature methods have all been published for modifying and derivatizing the structure of Nemorubicin to obtain PNU-159682, such as: the compound of PNU-159682, WO9802446, discloses a process for preparing PNU-159682 by reacting an N-oxidized derivative (4) of a morpholinyl anthracycline derivative with an iron salt in the presence of an iron complexing agent, but this process has the disadvantages of very low yield and very unstable process; patent CN103270043, applied by Nelervera medical science and technology Limited, Italy, 2011, 12, 1, discloses a method for preparing PNU-159682 by reacting an N-oxidized derivative of a morpholinyl anthracycline derivative with cyanuric chloride; patent CN10776501 applied by Binning (Suzhou) biopharmaceutical Co., Ltd in 2019, 8, month 22 discloses that hydroxyl of Nemouubicin is protected by a protecting group, and then PNU-159682 is obtained through oxidation, dehydration, ring closure and deprotection reactions.
The methods all use nemorubicin as a raw material, but the preparation method of the nemorubicin is complex, expensive, difficult to commercialize and purchase, and not very beneficial to mass production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a PNU-159682 and a preparation method of an intermediate thereof.
In order to achieve the purpose, the PNU-159682 and the preparation method of the intermediate thereof are designed, and the molecular structure of the intermediate compound I is as follows:
wherein R1 and R2 are ketal protecting groups.
The molecular structure of an intermediate compound II prepared by the intermediate compound I is as follows:
wherein R1 and R2 are ketal protecting groups.
The molecular structure of an intermediate compound III prepared by adopting the intermediate compound II is as follows:
wherein R1 and R2 are ketal protecting groups.
The invention also comprises the following preferred technical scheme.
Further, a method for preparing PNU-159682 comprises the following specific steps:
s1, adding doxorubicin hydrochloride into a solvent A, and reacting under the action of a reaction reagent B and a catalyst C to generate a ketal-protected ketocarbonyl intermediate; then adding a solvent A, 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde and a reducing agent D to perform reductive amination reaction to generate an intermediate compound I;
s2, adding the intermediate compound I and a reaction reagent F into the solvent E to react to generate an intermediate compound II;
s3, adding an intermediate compound II and a reaction reagent H into the solvent G to react to generate an intermediate compound III;
s4, adding the intermediate compound III and the reaction reagent K into the solvent J, and reacting to generate PNU-159682.
Further, the solvent A is selected from dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, benzene, toluene, xylene, water, acetonitrile, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, methyl chloride, ethyl acetate, methyl acetate, toluene, xylene, water, ethyl acetate, methyl acetate, benzene, toluene, xylene, water, acetonitrile, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 2-methyl-1, 3-propanediol, 2-isopropyl-2-ethyl-1, 3-propanediol, 2-tert-butyl propane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-methoxy-propane diol, 2-methoxy-1, 3-methoxy-propane diol, 2-methoxy-2-methoxy-1, 2-methoxy-hydroxy, 2-methoxy-hydroxy, 2, 3, 2, or a, 2, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, diphenyl ether, 1, 4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.
Further, the reactant B is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, trimethyl orthopropionate, triethyl orthopropionate, trimethyl orthoisopropionate, triethyl orthoisopropionate, trimethyl orthobutyrate, triethyl orthobutyrate, trimethyl pivalate, triethyl orthovalerate and 2-methoxy-1, 3-dioxolane.
Further, the catalyst C is selected from one or more of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, methanesulfonic acid, ethylsulfonic acid, propylsulfonic acid, butylsulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid, perfluorooctylsulfonic acid, and metal salts, pyridine salts, imidazole salts, and N-methylimidazole salts corresponding to the above acids.
Further, the agent D is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and 2-methylpyridine borane complex.
Further, the solvent E is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide.
Further, the reaction reagent F is selected from one or more of 2-iodoxybenzoic acid, manganese dioxide, Jones reagent, Coriolis reagent, pyridinium chlorochromate, pyridinium dichromate, dess-martin oxidant, potassium permanganate, periodic acid, osmium tetroxide, hydrogen peroxide, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, acetone peroxide, methyl trifluoromethyl dioxirane, dimethyl sulfoxide and oxalyl chloride.
Further, the solvent G is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide.
Further, the reaction reagent F is selected from one or more of 1-propyl phosphoric anhydride, a Burgis reagent, dicyclohexylcarbodiimide, polyphosphoric acid, ferrous chloride tetrahydrate, cyanuric chloride, tartaric acid, malic acid, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, n-butyl lithium, lithium diisopropylamide and cyanuric chloride.
Further, the solvent J is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide.
Further, the reactant K is selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, ethylsulfonic acid, propylsulfonic acid, butylsulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid, and perfluorooctylsulfonic acid.
Compared with the prior art, the invention has the advantages that: the problems of limited raw materials and high cost are solved, the relatively cheap and easily available adriamycin is used as the initial raw material, and the stability of each intermediate is improved by introducing the protective group, so that the stable and reliable process is realized, the large-scale production is easy, and the operation difficulty of the large-scale production is reduced.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of the present invention.
Detailed Description
The technical solution of the present invention will be further described in non-limiting detail with reference to the following embodiments.
Referring to FIG. 1, a schematic diagram of a synthetic route of the present invention is shown, and the present invention is illustrated with reference to the accompanying drawings.
The first step is that the raw material adriamycin hydrochloride (CAS: 25316-40-9) has a structural formula shown in the specification.
Adding doxorubicin hydrochloride (also known as doxorubicin hydrochloride, CAS: 25316-40-9) into a solvent A, and reacting under the action of a reaction reagent B and a catalyst C to generate an intermediate of which the ketocarbonyl group is protected by ketal; then adding a solvent A, 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde and a reducing agent D to perform reductive amination reaction to generate an intermediate compound I, wherein the structural formula of the intermediate compound I is shown in the specification.
Wherein R1, R2 are ketal protecting groups derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like.
Solvent A is selected from dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, benzene, toluene, xylene, water, acetonitrile, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, one or more of 3-propanediol, 2-ethyl-1, 3-propanediol, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, diphenyl ether, 1, 4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran; preferred are dichloromethane, methanol, ethanol, toluene, acetonitrile.
The reaction reagent B is selected from one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, trimethyl orthopropionate, triethyl orthopropionate, trimethyl orthoisopropionate, triethyl orthoisopropionate, trimethyl orthobutyrate, triethyl orthobutyrate, trimethyl orthovalerate, triethyl orthovalerate and 2-methoxy-1, 3-dioxolane; preferably trimethyl formate and triethyl orthoformate.
The catalyst C is selected from one or more of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, methanesulfonic acid, ethylsulfonic acid, propylsulfonic acid, butylsulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid, perfluorooctylsulfonic acid, and metal salts, pyridine salts, imidazole salts and N-methylimidazole salts corresponding to the acids; preferred are indium trifluoromethanesulfonate and N-methylimidazole trifluoromethanesulfonate.
The reducing agent D is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and 2-methylpyridine borane complex. Preferably sodium cyanoborohydride.
The reaction temperature for the formation of ketal by ketone carbonyl is-30 to 50 ℃, and the reaction temperature for reductive amination is-30 to 30 ℃.
This patent also provides intermediate compounds I of the formula.
Wherein R1, R2 are ketal protecting groups derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like, and the following compounds are preferred.
And in the second step, the intermediate compound I and the reaction reagent F are added into the solvent E to react to generate the intermediate compound II, and the structural formula of the intermediate compound II is shown in the specification.
Wherein R1, R2 are ketal protecting groups derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like.
The solvent E is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide; preferred are dichloromethane and acetone.
The reaction reagent F is selected from one or more of 2-iodoxybenzoic acid, manganese dioxide, Jones reagent, corins reagent, pyridinium chlorochromate, pyridinium dichromate, Dis-Martin oxidant, potassium permanganate, periodic acid, osmium tetroxide, hydrogen peroxide, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, acetone peroxide (DMDO), methyltrifluoromethyl dioxirane (TFDO), dimethyl sulfoxide and oxalyl chloride; preferred reagents are m-chloroperoxybenzoic acid, t-butyl hydroperoxide and acetone peroxide (DMDO).
The reaction temperature is-30-35 ℃, and the preferable temperature is-10 ℃.
This patent also provides an intermediate compound ii of the formula.
Wherein R1 and R2 are ketal protecting groups and are derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like, and the following compounds are preferred.
And thirdly, adding a compound II and a reaction reagent H into a solvent G to react to generate an intermediate compound III, wherein the structural formula of the intermediate compound III is shown in the specification.
Wherein R1, R2 are ketal protecting groups derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like.
The solvent G is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide; preferred are dichloromethane, acetone, tetrahydrofuran, acetonitrile.
The reaction reagent H is selected from one or more of 1-propyl phosphoric anhydride, a Burgis reagent, dicyclohexyl carbodiimide, polyphosphoric acid, ferrous chloride tetrahydrate, cyanuric chloride, tartaric acid, malic acid, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, n-butyl lithium, lithium diisopropylamide and cyanuric chloride; preference is given to 1-propylphosphoric anhydride, Burgis reagent, cyanuric chloride and cesium carbonate.
The reaction temperature is-30 to 50 ℃, preferably-10 to 30 DEG C
This patent also provides an intermediate compound iii of the formula.
Wherein R1, R2 are ketal protecting groups derived from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropylpropane-1, 3-diol, 2-tert-butylpropane-1, 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol and the like, and the following compounds are preferred.
And fourthly, adding the intermediate compound III and the reaction reagent K into the solvent J to react to generate the PNU-159682 with the structural formula shown in the specification.
The solvent J is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide, preferably dichloromethane and acetone.
The reaction reagent K is selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, ethylsulfonic acid, propylsulfonic acid, butylsulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid and perfluorooctylsulfonic acid, and is preferably hydrobromic acid and p-toluenesulfonic acid.
The reaction temperature is-30 to 50 ℃, and preferably-30 to 30 ℃.
The reaction raw materials and reagents related to the present invention can be obtained commercially or prepared according to the methods described in the prepared literature, and the methods for controlling and detecting include TLC (thin layer chromatography), LCMS (liquid chromatography-mass spectrometry), HPLC (high performance liquid chromatography) and NMR (nuclear magnetic resonance) detection.
The present invention is further illustrated by the following examples, which are set forth below.
Example 1
Synthesis of Compound (Ia): DCM (120 mL), 1, 3-propanediol (7.60 g, 100 mmol), and doxorubicin hydrochloride (5.80 g, 10 mmol) were added to the reaction flask and the solution was stirred at RT. Trimethyl orthoformate (21.22 g, 200 mmol) was added, stirred at room temperature for 30 min, indium triflate (225 mg, 0.4 mmol) was added, stirred at room temperature for 24-30 h, TLC (DCM/MeOH = 7: 1) and HPLC were controlled and the starting material essentially disappeared. Acetonitrile was added, the temperature was reduced to 0-10 deg.C, sodium bicarbonate (1.68 g, 20 mmol) was added in portions, and stirring was carried out for 0.5 hour. Most of the dichloromethane was distilled off under reduced pressure at an external temperature of 30 ℃ or less, the remaining acetonitrile solution was cooled to 0 to 10 ℃ and a solution of 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde in acetonitrile (0.5M, 40 mL) was added and stirring was continued for 30 minutes. Sodium cyanoborohydride (1.26 g, 20 mmol) was added, the temperature was controlled below 10 ℃ and stirring was continued for 16-24 hours. TLC (DCM/MeOH = 10: 1) and HPLC, the starting material essentially disappeared. Evaporating most of the reaction solution at the temperature below 30 ℃ under reduced pressure, adding DCM to the residue for dissolving, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, stirring the mixture by using 100-mesh silica gel and 200-mesh silica gel, passing the mixture through a 200-mesh silica gel column, and DCM: MeOH = 50: 1-30: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 3.64g of red solid with the yield of 52 percent.
Example 2
Synthesis of Compound (Ib): DCM (120 mL), 2, 2-dimethyl-1, 3-propanediol (10.40 g, 100 mmol) and doxorubicin hydrochloride (5.80 g, 10 mmol) were added to the reaction flask and the solution was stirred at room temperature. Trimethyl orthoformate (21.22 g, 200 mmol) was added, stirred at room temperature for 30 min, indium triflate (225 mg, 0.4 mmol) was added, stirred at room temperature for 24-30 h, TLC (DCM/MeOH = 7: 1) and HPLC were controlled and the starting material essentially disappeared. Acetonitrile was added, the temperature was reduced to 0-10 deg.C, sodium bicarbonate (1.68 g, 20 mmol) was added in portions, and stirring was carried out for 0.5 hour. Most of the dichloromethane was distilled off under reduced pressure at an external temperature of 30 ℃ or less, the remaining acetonitrile solution was cooled to 0 to 10 ℃ and a solution of 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde in acetonitrile (0.5M, 40 mL) was added and stirring was continued for 30 minutes. Sodium cyanoborohydride (1.26 g, 20 mmol) was added, the temperature was controlled below 10 ℃ and stirring was continued for 16-24 hours. TLC (DCM/MeOH = 10: 1) and HPLC, the starting material essentially disappeared. Evaporating most of the reaction solution at the temperature below 30 ℃ under reduced pressure, adding DCM to the residue for dissolving, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, stirring the mixture by using 100-mesh silica gel and 200-mesh silica gel, passing the mixture through a 200-mesh silica gel column, and DCM: MeOH = 50: 1-30: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 3.73g of red solid with the yield of 51 percent.
Example 3
Synthesis of Compound (Ic): the reaction flask was charged with anhydrous methanol (300 mL, moisture less than 80 ppm), doxorubicin hydrochloride (5.80 g, 10 mmol) and trimethyl orthoformate (212.2 g, 2000 mmol), stirred at room temperature for 30 minutes, indium triflate (450 mg, 0.8 mmol) was added, stirred at room temperature for 24-30 hours, TLC (DCM/MeOH = 7: 1) and HPLC were monitored and the starting material essentially disappeared. After cooling to 0-10 deg.C, sodium bicarbonate (3.36 g, 40 mmol) was added in portions and stirred for 0.5 h. A solution of 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde in acetonitrile (0.5M, 40 mL) was added and stirring was continued for 30 minutes. Sodium cyanoborohydride (1.26 g, 20 mmol) was added, the temperature was controlled below 10 ℃ and stirring was continued for 16-24 hours. TLC (DCM/MeOH = 10: 1) and HPLC, the starting material essentially disappeared. Evaporating most of the reaction solution at the temperature below 30 ℃ under reduced pressure, adding DCM to the residue for dissolving, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, stirring the mixture by using 100-mesh silica gel and 200-mesh silica gel, passing the mixture through a 200-mesh silica gel column, and DCM: MeOH = 50: 1-30: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 3.12g of red solid with the yield of 45 percent.
Example 4
Synthesis of Compound (Id): the reaction flask was charged with ethanol (300 mL, moisture less than 80 ppm), doxorubicin hydrochloride (5.80 g, 10 mmol) and triethyl orthoformate (148.2 g, 1000 mmol), stirred at room temperature for 30 minutes, indium triflate (450 mg, 0.8 mmol) was added, stirred at room temperature for 24-30 hours, TLC (DCM/MeOH = 7: 1) and HPLC were controlled and the starting material essentially disappeared. After cooling to 0-10 deg.C, sodium bicarbonate (3.36 g, 40 mmol) was added in portions and stirred for 0.5 h. A solution of 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde in acetonitrile (0.5M, 40 mL) was added and stirring was continued for 30 minutes. Sodium cyanoborohydride (1.26 g, 20 mmol) was added, the temperature was controlled below 10 ℃ and stirring was continued for 16-24 hours. TLC (DCM/MeOH = 10: 1) and HPLC medium, the starting material essentially disappeared. Evaporating most of the reaction solution at the temperature below 30 ℃ under reduced pressure, adding DCM to the residue for dissolving, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, stirring the mixture by using 100-mesh silica gel and 200-mesh silica gel, passing the mixture through a 200-mesh silica gel column, and DCM: MeOH = 50: 1-30: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 3.27g of red solid with a yield of 46 percent.
Example 5
Synthesis of Compound (IIb): compound (Ib) (3.65 g, 5.0 mmol) and DCM (70 mL) were added to a reaction flask, stirred at room temperature to dissolve, cooled to-20 to-15 degrees, DMDO in acetone (0.13M, 77mL, 10 mmol) was added rapidly, warmed to room temperature naturally, TLC (DCM/MeOH = 15: 1) and HPLC were controlled and the starting material essentially disappeared. Methylphenylsulfide (621 mg, 5 mmol) was added thereto, and the mixture was stirred for 5 minutes. The reaction solution was concentrated under reduced pressure and mixed with 100-mesh 200-mesh silica gel, 200-mesh 300-mesh silica gel was passed through a column, DCM: MeOH = 30: 1-10: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 3.17g of red solid with the yield of 87%.
Example 6
Synthesis of Compound (IIIb): adding the compound (IIb) (2.98 g, 4.0 mmol) and acetone (300 mL, the water content is less than 150 ppm) into a reaction bottle, stirring and dissolving the mixture at room temperature under the protection of argon, cooling the mixture to 15-20 ℃, sequentially adding powdered cesium carbonate (3.91 g, 12mmol, 200 meshes and 300 meshes) and cyanuric chloride (1.48 g, 8.0 mmol), and performing TLC (DCM/MeOH = 15: 1) for neutralization, wherein the raw materials disappear in 15-30 minutes. Purified water (720 mg, 40 mmol) was added dropwise, and stirring was continued for 5 minutes. The reaction solution was concentrated under reduced pressure, and the sample was stirred with 100-200 mesh silica gel, passed through 200-300 mesh silica gel column, DCM: MeOH = 40: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 1.95g of red solid with the yield of 67 percent.
Example 7
Synthesis of Compound (PNU-159682): compound (IIIb) (1.46 g, 2.0 mmol) and acetone (30 mL) were added to the reaction flask, argon blanketed, stirred at room temperature, added p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol), controlled by TLC (DCM/MeOH = 20: 1), and the starting material disappeared 15-30 min. Sodium bicarbonate (252 mg, 3.0 mmol) was added and stirring continued for 5 min. The reaction solution was concentrated under reduced pressure, and the sample was stirred with 100-200 mesh silica gel, passed through 200-300 mesh silica gel column, DCM: MeOH = 40: 1, collecting the product, and concentrating the product to dryness at a temperature of below 40 ℃ to obtain 1.20g of red solid with the yield of 93 percent.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be within the technical scope of the present invention, and the technical solutions and novel concepts according to the present invention should be covered by the scope of the present invention.
Claims (14)
1. An intermediate for use in the preparation of PNU-159682, characterized in that the molecular structure of the intermediate compound I is as follows:
wherein R1 and R2 are ketal protecting groups.
2. An intermediate for preparing PNU-159682, characterized in that an intermediate compound II is prepared from the intermediate compound I as claimed in claim 1, the molecular structure of the intermediate compound II is as follows:
wherein R1 and R2 are ketal protecting groups.
3. An intermediate for preparing PNU-159682, characterized in that an intermediate compound III is prepared from an intermediate compound II according to claim 2, the molecular structure of the intermediate compound III is as follows:
wherein R1 and R2 are ketal protecting groups.
4. A method for preparing PNU-159682 is characterized in that
S1, adding doxorubicin hydrochloride into a solvent A, and reacting under the action of a reaction reagent B and a catalyst C to generate an intermediate with ketocarbonyl protected by ketal; subsequently adding solvent A, 2- [ (1S) -1-methoxy-2-oxoethoxy ] acetaldehyde and reducing agent D to perform reductive amination reaction to generate intermediate compound I as claimed in claim 1;
s2, adding the intermediate compound I and a reaction reagent F into a solvent E, and reacting to generate an intermediate compound II according to claim 2;
s3, adding an intermediate compound II and a reaction reagent H into a solvent G to react to generate an intermediate compound III as claimed in claim 3;
s4, adding the intermediate compound III and the reaction reagent K into the solvent J, and reacting to generate PNU-159682.
5. The method of claim 4 wherein solvent A is selected from the group consisting of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, benzene, toluene, xylene, water, acetonitrile, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, ethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 2-methyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 2-n-propyl-1, 3-propanediol, 2-ethyl-2-methyl-1, 3-propanediol, 2-isopropyl propane-1, 3-diol, 2-tert-butyl propane-1, one or more of 3-diol, 2-methoxy-1, 3-propanediol, 2-dimethyl-1, 3-propanediol, 2-ethyl-1, 3-propanediol, 1-cyclopropanedimethanol, 1-bis (hydroxymethyl) cyclobutane, 1-bis (hydroxymethyl) cyclopentane, 1-bis (hydroxymethyl) cyclohexane, 1, 3-butanediol, 2-methyl-1, 3-butanediol, 1, 3-pentanediol, 2, 4-pentanediol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, diphenyl ether, 1, 4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.
6. A method of making PNU-159682 as set forth in claim 4 wherein reagent B is selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, trimethyl orthopropionate, triethyl orthopropionate, trimethyl orthoisopropanoate, triethyl orthopropionate, trimethyl orthobutyrate, triethyl orthobutyrate, trimethyl orthovalerate, triethyl orthovalerate, and one or more of 2-methoxy-1, 3-dioxolane.
7. A method of making PNU-159682 as set forth in claim 4 wherein said catalyst C is selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, propylsulfonic acid, butylsulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid, perfluorooctylsulfonic acid, and one or more of the corresponding metal, pyridine, imidazole, and N-methylimidazolium salts of these acids.
8. A process for the preparation of PNU-159682 as claimed in claim 4, wherein the reducing agent D is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-methylpyridine borane complex.
9. A method of making PNU-159682 as claimed in claim 4, wherein solvent E is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide.
10. A method of making PNU-159682 as claimed in claim 4, wherein said reagent F is selected from one or more of 2-iodoxybenzoic acid, manganese dioxide, Jones reagent, corins reagent, pyridinium chlorochromate, pyridinium dichromate, dess-martin oxidant, potassium permanganate, periodic acid, osmium tetroxide, hydrogen peroxide, m-chloroperoxybenzoic acid, t-butyl hydroperoxide, acetone peroxide, methyltrifluoromethyldioxirane, dimethyl sulfoxide, oxalyl chloride.
11. The method of claim 4 wherein the solvent G is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide.
12. A method of making PNU-159682 as claimed in claim 4 wherein the reactant H is selected from one or more of 1-propylphosphoric anhydride, Burgis reagent, dicyclohexylcarbodiimide, polyphosphoric acid, ferrous chloride tetrahydrate, cyanuric chloride, tartaric acid, malic acid, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, n-butyllithium, lithium diisopropylamide, cyanuric chloride.
13. The method of claim 4 wherein solvent J is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, acetone, water, ethyl acetate, methyl acetate, methanol, ethanol, 1-propanol, 1-butanol, isopropanol, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide.
14. A process for the preparation of PNU-159682 as set forth in claim 4, wherein reagent K is selected from the group consisting of one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, propylsulfonic acid, butyl sulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, perfluorobutylsulfonic acid, perfluorohexylsulfonic acid, perfluoroheptylsulfonic acid, perfluorooctylsulfonic acid.
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