CN111732572A - Preparation method of chiral antitumor drug FLX475 and intermediate thereof - Google Patents
Preparation method of chiral antitumor drug FLX475 and intermediate thereof Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a preparation method of a chiral drug FLX475 and an intermediate thereof, which comprises the following steps: the compound 6 is subjected to catalytic hydrogenation under the action of a hydrogenation catalyst to prepare a key intermediate (compound 7), the preparation method of the invention provides a chiral preparation method of an anti-tumor drug FLX475 which is completely different from the prior art, and the method has the remarkable characteristics of economy, mildness, simplicity, convenience and large-scale production; in the preparation of important chiral intermediate compound 7, PtO is used2As a catalyst, the target product with high chiral purity can be obtained by catalytic hydrogenation at normal temperature and normal pressure.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a chiral preparation method of a chiral antitumor drug FLX475 and an intermediate thereof.
Background
Regulatory T cells (T)reg) Has important function in tumor immunity. T isregThe effect of (a) is to inhibit the activation of CD8 positive T cells, which and other immunosuppressive cells are important contributors to the immunosuppressive properties of the tumor microenvironment. At TregIn, CCR4(chemokine receptor 4) is the most important receptor, and its high affinity ligands are thymus and activation regulated chemokines (TARC, CCL17, CCL22, etc.) and macrophage-derived chemokines (MDC/CCL 22/STCP-1). CCR (specific binding factor)4Mainly through CCR4+ Treg cells and CCR4+ Th2 cells exert immune effects by chemotaxis of Treg cells through binding with their ligands CCL17, CCL22, recruiting TregCells migrate into the tumor immune microenvironment and promote their enrichment, causing immune escape, leading to adverse clinical outcomes. CCR (specific binding factor)4The high expression of (A) is closely related to the infiltration and poor prognosis of various solid tumors and hematological tumors.
The compound FLX475 is a chiral, orally effective CCR4The antagonist has ideal tumor inhibiting activity in vivo and in vitro models, can obviously increase the tumor inhibiting effect of PD-1/PD-L1 and CTLA-4 in rat/mouse transplantation tumor models, and is suitable for various tumors such as nasopharyngeal carcinoma, esophageal cancer, lung cancer, breast cancer and the like. The compound FLX475 is currently in phase II clinical studies.
At present, the compound FLX475 is obtained by preparing a pair of diastereomers with the content of 1:1 (WO2018/022992 and ZL201910244644.8) and then preparing the diastereomers by a chiral column (WO2018/022992 and P272-273), and has poor economy and environmental friendliness and low productivity.
Therefore, the chiral preparation method which is economical, mild, simple and convenient and can be produced in a large scale is developed, and has important practical value.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the invention provides a simple and convenient chiral preparation method of the antitumor drug FLX475, which is economic, mild in reaction conditions, high in product chiral purity.
Means for solving the problems
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for the preparation of intermediate 7 of the chiral drug FLX475, comprising: the compound 6 is catalytically hydrogenated under the action of a hydrogenation catalyst to prepare an intermediate 7, and the synthetic route is as follows:
preferably, the hydrogenation catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd(NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, preferably PtO2。
Preferably, the reaction solvent for the catalytic hydrogenation is one or more selected from the group consisting of acetic acid, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water, cyclohexane, dichloroethane, toluene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone, preferably acetic acid; the catalytic hydrogenation pressure is 1atm to 200atm, and the reaction temperature is room temperature to 130 ℃.
The invention also provides a preparation method of the chiral drug FLX475, which comprises the following steps:
(1) salifying the compound 5 with hydrochloric acid to obtain a compound 6;
(2) the compound 6 is subjected to catalytic hydrogenation in the presence of a hydrogenation catalyst to prepare a chiral compound 7;
(3) reacting the compound 7 with iodoethanol in the presence of alkali to obtain a compound 8;
(4) removing Boc protecting group from the compound 8 in the presence of acid to obtain a compound 9;
(5) reacting compounds 9 and 10 in the presence of a base to obtain a compound FLX 475;
the synthetic route is as follows:
preferably, the solvent in step (1) is selected from one or more of acetonitrile, n-hexane, n-pentane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran;
the hydrogenation catalyst in the step (2) is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And are andthe pressure of catalytic hydrogenation is 1atm to 200atm, and the reaction temperature of catalytic hydrogenation is room temperature to 130 ℃.
Preferably, the base in step (3) is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine and di (isopropyl) ethylamine; the reaction temperature is between room temperature and 130 ℃;
preferably, the acid in step (4) is selected from one or more of sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, and the solvent used in the reaction in step (4) is selected from one or more of 1, 4-dioxane, water, dichloromethane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran; preferably, the acid and the solvent in step (4) are selected from hydrochloric acid and 1, 4-dioxane or water, respectively;
preferably, the base in step (5) is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine and di (isopropyl) ethylamine, and the reaction temperature is-20 ℃ to 100 ℃.
Preferably, the method further comprises the following steps for preparing compound 5:
under the catalysis of [ Pd ] and/or [ Ni ] catalyst, compounds 1 and 2 undergo a Negishi reaction to prepare a compound 3;
the compound 3 and the chiral ligand compound 4 are subjected to coupling reaction under the catalysis of [ Pd ] and/or [ Pt ] catalysts to prepare a compound 5;
the synthetic route is as follows:
preferably, in step (one), [ Pd ] is]The catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd(OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, the [ Pd ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%; said [ Ni ]]The catalyst is selected from NiCl2、Ni(PPh3)4、NiCl2glyme、NiBr2glyme and Ni (PPh)3)2Cl2Said [ Ni ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%, and the reaction temperature is-20 ℃ to 100 ℃;
in the second step, the [ Pd ]]The catalyst is Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd(NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, the [ Pd ]]The mass ratio of the catalyst to the compound 3 is 0.05-100%; the [ Pt ] is]The catalyst is selected from PtO2Pt-C, platinum tetrachloride, chloroplatinic acid, (1, 5-cyclooctadiene) platinum (II) dichloride, potassium chloroplatinite, platinum acetylacetonate, platinum dichloride, bis (2, 4-pentanedionate) platinum, bis (tri-tert-butylphosphine) platinum, cis-diaminedichloroplatinum (II), tetrakis (triphenylphosphine) platinum, cis-1, 1-cyclobutanedicarboxylic acid bis (II)Ammoplatin, [ Pt ] as]The mass ratio of the catalyst to the compound 3 is 0.05-100%, and the reaction temperature in the coupling reaction is-20 ℃ to 130 ℃.
Preferably, the reaction temperature in step (one) is room temperature;
the reaction temperature in the coupling reaction of the step (II) is 50 ℃ to 100 ℃.
Preferably, the hydrogenation catalyst in step (2) is PtO2The catalytic hydrogenation pressure is 1atm to 60atm, preferably 1atm, and the catalytic hydrogenation reaction temperature is room temperature to 100 ℃, preferably room temperature;
the reaction temperature in the step (3) is 50 to 100 ℃;
the reaction temperature in step (5) is-20 ℃ to 100 ℃, preferably room temperature.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a chiral preparation method of an anti-tumor drug FLX475 which is completely different from the prior art for the first time, and the method has the remarkable characteristics of economy, mildness, simplicity and convenience and large-scale production;
the invention creatively discovers that PtO is used in the preparation of important chiral intermediate (compound 7)2As a catalyst, carrying out catalytic hydrogenation at normal temperature and normal pressure to obtain a target product (compound 7) with high chiral purity;
the invention also surprisingly discovers that in the preparation of the key chiral intermediate (compound 7), the salification of the substrate is very important, and if the compound 6 exists in a free base form, the hydrogenation catalytic reaction cannot be carried out;
the invention also finds that the chiral purity of the target product is obviously superior to that of a reaction system using other solvents (such as methanol) by selecting acetic acid as the solvent in the step 4.
Detailed Description
The invention provides a preparation method of an intermediate 7 of a chiral drug FLX475, which comprises the following steps: the compound 6 is catalytically hydrogenated under the action of a hydrogenation catalyst to prepare a chiral compound 7, and the synthetic route is as follows:
in a preferred embodiment, the hydrogenation catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd(PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, preferably PtO2. The mass ratio of the hydrogenation catalyst to the compound 6 is 1-20%, preferably 2-10%.
In a preferred embodiment, the reaction solvent for catalytic hydrogenation is a solvent suitable for catalytic hydrogenation reaction commonly used in the art, preferably one or more of acetic acid, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water, cyclohexane, dichloroethane, toluene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, more preferably acetic acid; the pressure of the catalytic hydrogenation is 1atm to 200atm, and the reaction temperature is room temperature to 130 ℃.
In a preferred embodiment, the method comprises the steps of:
(1) salifying the compound 5 with hydrochloric acid to obtain a compound 6;
(2) the compound 6 is subjected to catalytic hydrogenation in the presence of a hydrogenation catalyst to prepare a chiral compound 7;
(3) reacting the compound 7 with iodoethanol in the presence of alkali to obtain a compound 8;
(4) removing Boc protecting group from the compound 8 in the presence of acid to obtain a compound 9;
(5) reacting compounds 9 and 10 in the presence of a base to obtain a compound FLX 475;
the synthetic route is as follows:
in a preferred embodiment, the solvent in step (1) is an organic solvent commonly used in the art, and may be selected from one or more of acetonitrile, n-hexane, n-pentane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, and the like;
the hydrogenation catalyst in the step (2) is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And a solvate of the above catalyst, the pressure of catalytic hydrogenation is 1atm to 200atm, and the reaction temperature of catalytic hydrogenation is room temperature to 130 ℃.
In a preferred embodiment, the base in step (3) is an organic or inorganic base commonly used in the art, preferably, the base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine, di (isopropyl) ethylamine, and the like; the reaction temperature is between room temperature and 130 ℃;
the acid in step (4) is organic acid or inorganic acid commonly used in the art, preferably, the acid is selected from one or more of sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and the solvent used in the reaction in step (4) is selected from one or more of 1, 4-dioxane, water, dichloromethane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran; preferably, the acid and the solvent in step (4) are respectively selected from hydrochloric acid and 1, 4-dioxane or water;
the base in step (5) is an organic base or an inorganic base commonly used in the art, and preferably, the base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine, di (isopropyl) ethylamine, and the like, and the reaction temperature is-20 ℃ to 100 ℃.
In a preferred embodiment, the process further comprises the following steps for preparing compound 5:
under the catalysis of [ Pd ] and/or [ Ni ] catalyst, compounds 1 and 2 undergo a Negishi reaction to prepare a compound 3;
the compound 3 and the chiral ligand 4 are subjected to coupling reaction under the catalysis of [ Pd ] and/or [ Pt ] catalysts to prepare a compound 5;
the synthetic route is as follows:
in a preferred embodiment, the [ Pd ] in step (one)]The catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, the [ Pd ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%; said [ Ni ]]The catalyst is selected from NiCl2、Ni(PPh3)4、NiCl2glyme、NiBr2glyme and Ni (PPh)3)2Cl2Said [ Ni ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%, and the reaction temperature is-20 ℃ to 100 ℃;
the [ Pd ] in the coupling reaction of step (II)]The catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd(OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And a solvate of the catalyst, wherein the mass ratio of the catalyst to the compound 3 is 0.05-100%; the [ Pt ] is]The catalyst is selected from PtO2Pt-C, platinum tetrachloride, chloroplatinic acid, (1, 5-cyclooctadiene) platinum (II) dichloride, potassium chloroplatinite, platinum acetylacetonate, platinum dichloride, bis (2, 4-pentanedionate) platinum, bis (tri-tert-butylphosphine) platinum, cis-diaminedichloroplatinum (II), tetrakis (triphenylphosphine) platinum, cis-1, 1-cyclobutanedicarboxylic acid diammineplatinum, wherein [ Pt-C ], [ platinum tetrachloride ], chloroplatinic acid, [ 1, 5-cyclooctadiene ] platinum (II) dichloride, potassium chloroplatinite, platinum dichloride, bis (2]The mass ratio of the catalyst to the compound 3 is 0.05-100%, and the reaction temperature in the coupling reaction is-20 ℃ to 130 ℃.
In a preferred embodiment, the reaction temperature in step (one) is room temperature;
the reaction temperature in the coupling reaction in the step (II) is 50-100 ℃;
in a preferred embodiment, the hydrogenation catalyst in step (2) is PtO2The catalytic hydrogenation pressure is 1atm to 60atm, preferably 1atm, and the reaction temperature of the catalytic hydrogenation is room temperature to 100 ℃, preferably room temperature;
the reaction temperature in the step (3) is 50 to 100 ℃;
the reaction temperature in step (5) is-20 ℃ to 100 ℃, preferably room temperature.
The following examples are for illustrative purposes only and do not limit the scope of the claims provided herein.
Summary of the invention1H-NMR spectra Bruker-400 NMR spectrometer with chemical shifts in parts per million and internal standard tetramethylsilane. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s, single multiplet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak. Mass spectrometry a Quattro microtapi triple quadrupole mass spectrometer was used.
Example 1
Preparation of Compound 3
Mixing compound 1(18.6g, 77.7mmoL), compound 2(20.0g, 70.6mmoL), zinc powder (23g, 0.353moL), iodine (3.6g, 14.2mmoL), Pd2(dba)3(3.2g, 3.54moL) and tri (o-tolyl) phosphine (2.2g, 7.06mmoL) were added to DMF (200mL) and reacted at room temperature for 1 hour under nitrogen. The reaction was complete by TLC. The solvent was evaporated under reduced pressure and the residue was extracted with water and dichloromethane. Separating liquid, decompressing and steaming to remove the solvent, separating the residue by using flash column chromatography, and eluting ethyl acetate: petroleum ether (1: 15-1: 3) to obtain 15.2g of target product with a yield of 72%.
1H NMR (400 MHz,CDCl 3 )8.29 (d,J= 2.5 Hz, 1H), 7.70 (dd,J= 8.3,2.6 Hz, 1H), 7.35 (d,J= 8.3 Hz, 1H), 4.37 (t,J= 8.7 Hz, 2H), 3.91 (dd,J=8.7, 5.7 Hz, 2H), 3.76-3.69 (m, 1H), 1.46 (s, 9H)。
ESI-MS:269.3 [M+H]+。
Example 2
Preparation of Compound 5
Mixing compound 3(12.8g, 47.7mmoL), compound 4(12.4g, 95.5mmoL), Pd2(dba)3(8.7g,9.55moL), XPhos (4.07g, 9.55mmoL) and cesium carbonate (8.75g, 9.55mmoL) were added to toluene (100mL) and reacted overnight at 100 ℃ under nitrogen. The reaction was complete by TLC. Filtering, and adding water and ethyl acetate into the filtrate. Separating liquid, decompressing and steaming to remove the solvent, separating the residue by using flash column chromatography, and eluting ethyl acetate: petroleum ether (10:1-2:1) was used to obtain 9.8g of the desired product in 56% yield.
1H NMR (400 MHz,CDCl 3 )8.23 (d,J= 2.4 Hz, 1H), 8.17 (d,J= 8.7Hz, 1H), 7.72 (dd, J = 8.7, 2.5 Hz, 1H), 4.87-4.83 (m, 1H), 4.41 – 4.25 (m,4H), 3.95-3.91 (m, 2H), 3.74-3.67 (m, 1H), 2.52-2.45 (m, 1H), 1.46 (s, 9H),0.93 (d,J= 7.0 Hz, 3H), 0.83 (d,J= 6.9 Hz, 3H)。
ESI-MS:362.4[M+H]+。
Example 3
Preparation of Compound 6
Compound 5(5.16g, 14.3mmoL) was added to 1, 4-dioxane (50mL), HCl/1, 4-dioxane (1M, 40mL) was added, and the mixture was stirred at room temperature for 30 minutes. N-hexane (100mL) and methyl tert-butyl ether (50mL) were added, a large amount of solid appeared, filtered, washed, and dried under high vacuum to give the desired product 5.5g with a yield of 97%.
Example 4
Preparation of Compound 7
Mixing Compound 6(550mg, 1.38mmoL) and PtO2(55mg) was added to methanol (5.0mL), and the mixture was catalytically hydrogenated at room temperature under 1 atmosphere for overnight reaction. The reaction was complete by TLC. Filtering, washing, vacuum evaporating to remove solvent, and high vacuum drying. 316mg of product are obtained with a yield of 83%.
ESI-MS:241.4 [M+H]+。
ee value: 78 percent.
Example 5
Preparation of Compound 7
Example 5 was performed as in example 4, except that acetic acid was used instead of methanol.
The yield thereof was found to be 89%. ee value: 93 percent.
Example 6
Preparation of Compound 7
Example 6 was performed as in example 4, except that acetic acid was used instead of methanol, and 100 atmospheres was used instead of 1 atmosphere.
The yield thereof was found to be 85%. ee value: 94 percent.
Example 7
Preparation of Compound 7
Example 7 was operated as example 4 except that 100 atmospheres was used instead of 1 atmosphere.
The yield thereof was found to be 80%. ee value: 91 percent.
Example 8
Preparation of Compound 7
Except for using Pd (OH)2Substitution of PtO2Example 8 was performed as in example 4, replacing methanol with acetic acid, replacing 1 atmosphere with 100 atmospheres, and replacing RT with 100 ℃.
The yield thereof was found to be 81%. ee value: 93 percent.
Example 9
Preparation of Compound 8
Compound 7(4.0g, 16.7mmoL), iodoethanol (2.6mL, 33.4mmoL) and potassium carbonate (7.0g, 50.1mmoL) were added to acetonitrile (100mL) and reacted at 80 ℃ overnight. The reaction was complete by TLC. Filtration and evaporation of the solvent under reduced pressure, the residue was extracted with water and dichloromethane. Separating, drying with a drying agent, evaporating the solvent under reduced pressure, and directly using the residue for the next reaction without purification. 3.1g of the target product was obtained in a yield of 67%.
1H NMR(400MHz,CDCl 3 )3.98-3.93(m, 2H) , 3.78-3.71(m, 2H) , 3.69-3.65(m, 3H) , 3.11-3.02(m, 2H) , 2.76-2.73(m, 2H) , 2.30-1.77 (m, 8H), 1 .43(s,9H) 。
ESI-MS: 285.2[M+H]+。
EXAMPLE 10 preparation of Compound 9
Compound 8(9.8g, 34.5mmoL) was added to a mixed solution of trifluoroacetic acid (40mL) and dichloromethane (40mL), and stirred at room temperature for 2 hours. The reaction was complete by TLC. The solvent was evaporated under reduced pressure and the residue was dried under high vacuum in an oil bath at 45 ℃ for more than 3 hours to give 5.2g of an oil in 81% yield. The product was used in the next reaction without purification.
1H NMR(400MHz,DMSO-d 6 )4.71(t,J=8.0 Hz, 1H), 3.98- 3.70(m, 6H),3.50-3.35(m, 2H), 3.12-3.07(m, 1H), 2.93-2.78(m, 1H), 2.65-2.49(m, 3H) ,2.09-2 .00(m, 1H) , 1.90-1.82(m, 1H) , 1.73-1.64(m, 2H), 1.02-0.92(m, 1H) 。
ESI-MS:185.0[M+H]+。
EXAMPLE 11 preparation of Compound 9
Example 10 was performed as in example 9, except that HCl/1, 4-dioxane was used instead of trifluoroacetic acid/DCM, and the residue was added to water in the work-up and neutralized with aqueous ammonia and then water was removed by rotary evaporation. The yield thereof was found to be 92%.
EXAMPLE 12 preparation of FLX475
Compound 9(13.6g, 74mmoL), compound 10(13g, 37mmoL, homemade according to WO 2018/022992) and DIPEA (11g, 111mmoL) were added to DMF (200 mL). Stir at rt overnight and check by TLC for reaction completion. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with dichloromethane: methanol (10: 1) gave 15.0g of a white solid in 82% yield.
1H NMR(400MHz,CD 3 OD)7.95(s, 1H), 7.49(d,J=4.0Hz, 1H) , 7.38(d,J=4.0 Hz, 1H), 7.30(dd,J=4.0, 8.0 Hz , 1H), 6.46(q,J=4.0 Hz, 1H), 4.32-4.27(m, 2 H), 4.01-3.97(m, 2H), 3.74(t,J=4.0 Hz, 2H) , 3.60(q,J=8.0 Hz, 1H),3.13-3.01(m, 3H), 2.68-2.62(m, 3H), 2.25-2.19(m, 1H), 1.92-1.64(m, 8H), 1.20-1.16(m, 1H), 1.00-0.92(m, 1H)。
ESI-MS:500.0 [M+H]+。
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. Modifications and variations may be made by those skilled in the art without departing from the spirit and scope of the invention, which should be limited only by the appended claims.
Claims (10)
2. the method of claim 1, wherein the hydrogenation catalyst is selected from the group consisting of Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts.
3. The method according to claim 1, wherein the reaction solvent for catalytic hydrogenation is selected from one or more of acetic acid, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water, cyclohexane, dichloroethane, toluene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone; the catalytic hydrogenation pressure is 1atm to 200atm, and the reaction temperature is room temperature to 130 ℃.
4. A process for the preparation of the chiral drug FLX475, comprising the steps of:
(1) salifying the compound 5 with hydrochloric acid to obtain a compound 6;
(2) the compound 6 is subjected to catalytic hydrogenation in the presence of a hydrogenation catalyst to prepare a chiral compound 7;
(3) reacting the compound 7 with iodoethanol in the presence of alkali to obtain a compound 8;
(4) removing Boc protecting group from the compound 8 in the presence of acid to obtain a compound 9;
(5) reacting compounds 9 and 10 in the presence of a base to obtain a compound FLX 475;
the synthetic route is as follows:
5. the method according to claim 4,
the solvent in the step (1) is selected from one or more of acetonitrile, n-hexane, n-pentane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran;
the hydrogenation catalyst in the step (2) is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd (NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And a solvate of the above catalyst, the pressure of catalytic hydrogenation is 1atm to 200atm, and the reaction temperature of catalytic hydrogenation is room temperature to 130 ℃.
6. The method according to claim 4,
the alkali in the step (3) is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine and di (isopropyl) ethylamine; the reaction temperature is between room temperature and 130 ℃;
the acid in the step (4) is selected from one or more of sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, and the solvent used in the reaction in the step (4) is selected from one or more of 1, 4-dioxane, water, dichloromethane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran;
the alkali in the step (5) is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine and di (isopropyl) ethylamine, and the reaction temperature is-20 ℃ to 100 ℃.
7. The method of claim 4, further comprising the step of preparing compound 5 by:
under the catalysis of [ Pd ] catalyst and/or [ Ni ] catalyst, compounds 1 and 2 undergo a Negishi reaction to prepare a compound 3;
the compound 3 and the chiral ligand compound 4 are subjected to coupling reaction under the catalysis of a [ Pd ] catalyst and/or a [ Pt ] catalyst to prepare a compound 5;
the synthetic route is as follows:
8. the method according to claim 7,
in the step (one), the [ Pd ] is]The catalyst is selected from Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd(NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, the [ Pd ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%; said [ Ni ]]The catalyst is selected from NiCl2、Ni(PPh3)4、NiCl2glyme、NiBr2glyme and Ni (PPh)3)2Cl2Said [ Ni ]]The mass ratio of the catalyst to the compound 1 is 0.05-100%, and the reaction temperature is-20 ℃ to 100 ℃;
in the second step, the [ Pd ]]The catalyst is Pd-C, Pd-BaSO4、Pd-CaCO3、Pd(OH)2、Pd (OAc)2、Pd(NO3)2、Pd(But)2Bis (cyclohexylphosphine) palladium, Pd (CF)3CO2)2Palladium on alumina, PdCN2、Pd (PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(PPh3)Cl2、Pd(PPh3)2Cl2、PdCl2、PdCl2(dppf)、PdCl2(CH3CN)2、PdI2、Pd[(P(O-Tol)3]2Cl2、Pd(Amphos)2Cl2And PtO2And solvates of the above catalysts, the [ Pd ]]The mass ratio of the catalyst to the compound 3 is 0.05-100%; the [ Pt ] is]The catalyst is selected from PtO2Pt-C, platinum tetrachloride, chloroplatinic acid, (1, 5-cyclooctadiene) platinum (II) dichloride, potassium chloroplatinite, platinum acetylacetonate, platinum dichloride, bis (2, 4-pentanedionate) platinum, bis (tri-tert-butylphosphine) platinum, cis-diaminedichloroplatinum (II), tetrakis (triphenylphosphine) platinum, cis-1, 1-cyclobutanedicarboxylic acid diammineplatinum, wherein [ Pt-C ], [ platinum tetrachloride ], chloroplatinic acid, [ 1, 5-cyclooctadiene ] platinum (II) dichloride, potassium chloroplatinite, platinum dichloride, bis (2]The mass ratio of the catalyst to the compound 3 is 0.05-100%, and the reaction temperature in the coupling reaction is-20 ℃ to 130 ℃.
9. The method according to claim 7,
the reaction temperature in the step (one) is room temperature;
the reaction temperature in the coupling reaction of the step (II) is 50 ℃ to 100 ℃.
10. The method according to claim 7,
the hydrogenation catalyst in the step (2) is PtO2The catalytic hydrogenation pressure is 1atm to 60atm, and the catalytic hydrogenation reaction temperature is room temperature to 100 ℃;
the reaction temperature in the step (3) is 50 to 100 ℃;
the reaction temperature in the step (5) is-20 ℃ to 100 ℃.
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