Disclosure of Invention
A first object of the present invention is to provide a compound I having the following structure:
the present invention further provides a process for preparing compound I, comprising the steps of:
X is Cl, br or I.
Compound II is reacted with 1-amino ring Ding Jiasuan or a salt thereof in the presence of a catalyst, a base, and a reaction solvent to prepare compound I.
Wherein the molar ratio of the compound II to the 1-amino ring Ding Jiasuan or the salt thereof is 1:1.0-2.0. Preferably 1:1.2.
Wherein the catalyst is one or more selected from copper powder, cuprous iodide, cuprous bromide, cuprous chloride and cuprous oxide. Preferably copper iodide or a mixed catalytic system consisting of copper powder and copper iodide. More preferred are mixed catalytic systems having a molar ratio of copper powder to copper iodide of 1:1.
Wherein the molar ratio of the compound II to the catalyst is 1:0.1-0.3. Preferably 1:0.15.
Wherein the ligand of the catalyst is selected from dimethylglycine, proline or N, N' -dimethyl-1, 2-cyclohexanediamine. Dimethylglycine is preferred.
Wherein the molar ratio of the catalyst to the catalyst ligand is 1:1.0-1.5. Preferably 1:1.2.
Wherein the base is selected from inorganic bases including, but not limited to, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, and the like. Potassium carbonate is preferred.
Wherein the molar ratio of the compound II to the alkali is 1:2.5-3.5. Preferably 1:3.0.
Wherein the reaction solvent is a mixed solvent composed of an organic solvent and water, wherein the organic solvent is one or more selected from N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and water. Preferably, a mixed solvent of N, N-dimethylacetamide and water or a mixed solvent of N-methylpyrrolidone and water.
Wherein the mass ratio of the organic solvent to water in the mixed solvent is 1:0.10-0.20. Preferably 1:0.14.
Wherein the reaction temperature is 90-110 ℃. Preferably 95 ℃.
In some specific embodiments, compound II is reacted with 1-amino ring Ding Jiasuan or a salt thereof at 95 ℃ in a mixed catalytic system having a 1:1 molar ratio of copper powder to cuprous iodide, dimethylglycine as the catalyst ligand, potassium carbonate as the base, and a mixed solvent of N, N-dimethylformamide and water to form compound I.
A second object of the present invention is to provide a compound IV having the following structure:
r is C1-C6 alkyl, C1-C6 aryl or heteroaryl. Preferably methyl, ethylallyl or benzyl. More preferably methyl or ethyl.
The present invention further provides a process for preparing compound IV comprising the steps of:
R is C1-C6 alkyl, C1-C6 aryl or heteroaryl. Preferably methyl, ethyl, allyl or benzyl. More preferably methyl.
Compound I is reacted with RX '(X' is Cl, br or I) or ROH in the presence of an auxiliary reagent to prepare compound IV.
Wherein, when compound I is reacted with RX '(X' is Cl, br or I), the auxiliary reagent is selected from, but not limited to: triethylamine, pyridine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate. Potassium carbonate or cesium carbonate is preferred.
Wherein, when compound I is reacted with RX ' (X ' is Cl, br or I), the molar ratio of compound I to RX ' is 1:2.0-3.0, preferably 1:2.5; the molar ratio of compound I to auxiliary agent is 1:2.0-5.0, preferably 1:3.0.
Wherein, when compound I is reacted with ROH, the auxiliary reagent is selected from, but not limited to: thionyl chloride, oxalyl chloride, hydrochloric acid, sulfuric acid. Preferably thionyl chloride or oxalyl chloride.
Wherein the molar ratio of the compound I to the auxiliary reagent is 1:2.0-5.0, preferably 1:3.0.
Wherein the reaction temperature is 20-80 ℃, preferably 40-60 ℃.
In some specific embodiments, compound I is reacted with RX '(X' is Cl, br, or I) in the presence of potassium carbonate at 40-60℃to form compound IV. In some specific embodiments, compound I is reacted with ROH in the presence of thionyl chloride at 40-60 ℃ to form compound IV.
A third object of the present invention is to provide a process for preparing compound VI from compound IV and 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine, which comprises the steps of:
R is C1-C6 alkyl, C1-C6 aryl or heteroaryl. Preferably methyl, ethyl, allyl or benzyl. More preferably methyl.
Compound iv is reacted with 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine in the presence of an organic solvent to prepare compound VI.
Wherein the molar ratio of the compound IV to the 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine is 1:1.3-2.0. Preferably 1:1.5.
Wherein the organic solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, isopropyl acetate and toluene. N-methylpyrrolidone, N-dimethylacetamide or dimethylsulfoxide are preferred.
Wherein the reaction temperature is 80-120 ℃. Preferably 90-100 ℃.
In some specific embodiments, compound IV is reacted with 5-isothiocyano-2-cyano-3-trifluoromethylpyridine in N-methylpyrrolidone at 90-100deg.C to form compound VI.
The present invention provides a process for preparing compound VII apatamide from compound VI, comprising the steps of:
R is C1-C6 alkyl, C1-C6 aryl or heteroaryl. Preferably methyl, ethyl, allyl or benzyl. More preferably methyl.
Compound VI was prepared with methylamine reagent in the presence of organic solvent.
Among them, methylamine reagents include, but are not limited to, methylamine gas, aqueous methylamine solution, methanolic methylamine solution, ethanolic methylamine solution, tetrahydrofuran methylamine solution, methylamine hydrochloride, and the like. Aqueous methylamine solutions are preferred.
Wherein the molar ratio of the compound VI to the aqueous solution of methylamine is 1:8-12. Preferably 1:10.
Wherein the organic solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, isopropyl acetate, tetrahydrofuran and acetonitrile. Tetrahydrofuran or acetonitrile are preferred.
Wherein the reaction temperature is 10-50 ℃. Preferably 20-30 ℃.
In some specific embodiments, compound VI is reacted with aqueous methylamine in tetrahydrofuran at 20-30 ℃ to form compound VII apatamide.
The invention provides a method for preparing VII apatamide, which comprises the following steps:
x is Cl, br or I;
R is C1-C6 alkyl, C1-C6 aryl or heteroaryl. Preferably methyl, allyl or benzyl. More preferably methyl.
1) The compound II, 1-amino ring Ding Jiasuan or salt thereof, potassium carbonate, dimethyl glycine, copper powder and cuprous iodide react in a mixed solvent of N, N-dimethylformamide and water at the temperature of 90-110 ℃ to generate a compound I;
2) The compound I and R-X' or R-OH undergo substitution or esterification reaction to obtain a compound IV;
3) The compound IV and 5-isothiocyanato-2-cyano-3-trifluoromethyl pyridine are subjected to ring closure to obtain a compound VI;
4) The compound VI and methylamine undergo ammonolysis reaction to obtain the compound VII apatamide.
The method adopts 4-bromo-2-fluorobenzoic acid as a raw material, and the target product apatamide is obtained through 4 steps of reactions; compared with the existing methods for preparing the apatamide, the method has the advantages of simple and easily purchased initial raw materials, lower cost, mild reaction conditions in each step, simple operation and high yield, and avoids the use of thiophosgene with higher toxicity; meanwhile, the purity of the product obtained by the preparation method is more than 99 percent, and the total yield is as high as 50 to 60 percent, so that the method is beneficial to realizing industrial production.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
EXAMPLE 1 preparation of Compound I4- (1-carboxy-cyclobutylamino) -2-fluoro-benzoic acid
Under the protection of inert gas at room temperature, 40ml of N, N-dimethylacetamide, 6.5ml of water, 5g of 4-bromo-2-fluorobenzoic acid, 5.26g of compound III, 1.06g of dimethylglycine, 0.44g of copper powder, 1.30g of cuprous iodide and 11.03g of potassium carbonate are sequentially added into a reaction bottle, and the temperature is raised to 90 ℃ for reaction for 20 hours. Cooled to room temperature, 100ml of water was added and stirred for 0.5 hour. Suction filtration, pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and extraction was performed 4 times with 50ml of ethyl acetate. The organic phases were combined, washed with saturated brine and concentrated under reduced pressure to remove the organic solvent. To the residue was added 100ml of water, stirred at room temperature for 2 hours, and filtered to give a crude product of compound I. And (5) refluxing, pulping and purifying by acetonitrile, and drying. 5.40g of pure compound I (HPLC purity 97.32%, yield 93.4%) were obtained.
MS+[M+1]254.1。
1H NMR(400MHz,DMSO)δ12.49(s,2H),7.60(t,J=8.3Hz,1H),7.43(s,1H),6.22(d,J=8.3Hz,1H),6.00(d,J=13.9Hz,1H),2.64–2.57(m,2H),2.30–2.07(m,2H),2.06–1.76(m,2H).13C NMR(101MHz,DMSO)δ175.4,165.0,164.9,161.9,152.3,133.2,108.4,105.3,98.6,58.8,30.4,14.8.
EXAMPLE 2 preparation of Compound I4- (1-carboxy-cyclobutylamino) -2-fluoro-benzoic acid
40Ml of N-methylpyrrolidone, 8.0ml of water, 5g of 4-bromo-2-fluorobenzol, 3.28g of compound III, 0.26g of proline, 0.15g of copper powder, 0.43g of cuprous iodide and 2.28g of sodium hydroxide are sequentially added into a reaction flask under the protection of inert gas at room temperature, and the mixture is heated to 110 ℃ for reaction for 20 hours. Cooled to room temperature, 100ml of water was added and stirred for 0.5 hour. Suction filtration, pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and extraction was performed 4 times with 50ml of ethyl acetate. The organic phases were combined, washed with brine and concentrated under reduced pressure to remove the organic solvent. To the residue was added 100ml of water, stirred at room temperature for 2 hours, and filtered to give a crude product of compound I. And (5) refluxing, pulping and purifying by acetonitrile, and drying. 5.24g of pure compound I (HPLC purity 96.48%, yield 90.7%) were obtained.
EXAMPLE 3 preparation of Compound I4- (1-carboxy-cyclobutylamino) -2-fluoro-benzoic acid
Under the protection of inert gas at room temperature, 40ml of N, N-dimethylformamide, 3.8ml of water, 5g of 4-bromo-2-fluorobenzoic acid, 3.94g of compound III, 0.42g of dimethylglycine, 0.22g of copper powder, 0.65g of cuprous iodide and 10.40g of potassium carbonate are added into a reaction bottle in sequence, and the temperature is raised to 95 ℃ for reaction for 20 hours. Cooled to room temperature, 100ml of water was added and stirred for 0.5 hour. Suction filtration, pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and extraction was performed 4 times with 50ml of ethyl acetate. The organic phases were combined, washed with brine and concentrated under reduced pressure to remove the organic solvent. To the residue was added 100ml of water, stirred at room temperature for 2 hours, and filtered to give a crude product of compound I. And (5) refluxing, pulping and purifying by acetonitrile, and drying. 5.31g of pure compound I (HPLC purity 96.85%, yield 91.9%) are obtained.
EXAMPLE 4 preparation of Compound I4- (1-carboxy-cyclobutylamino) -2-fluoro-benzoic acid
Under the protection of inert gas at room temperature, 40ml of N, N-dimethylacetamide, 6.5ml of water, 5g of compound II, 3.94g of compound III, 0.58g of N, N' -dimethyl-1, 2-cyclohexanediamine, 0.65g of cuprous iodide and 10.40g of potassium carbonate are added into a reaction bottle in sequence, and the temperature is raised to 95 ℃ for reaction for 20 hours. Cooled to room temperature, 100ml of water was added and stirred for 0.5 hour. Suction filtration, pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and extraction was performed 4 times with 50ml of ethyl acetate. The organic phases were combined, washed with brine and concentrated under reduced pressure to remove the organic solvent. To the residue was added 100ml of water, stirred at room temperature for 2 hours, and filtered to give a crude product of compound I. And (5) refluxing, pulping and purifying by acetonitrile, and drying. 5.19g of pure compound I (HPLC purity 95.46%, yield 89.8%) were obtained.
EXAMPLE 5 preparation of Compound I4- (1-carboxy-cyclobutylamino) -2-fluoro-benzoic acid
400Ml of N, N-dimethylacetamide, 65ml of water, 50g of a compound II, 39.4g of a compound III, 4.2g of dimethylglycine, 2.2g of copper powder, 6.5g of cuprous iodide and 104.0g of potassium carbonate are sequentially added into a reaction bottle at room temperature under the protection of inert gas, and the mixture is heated to 95 ℃ for reaction for 20 hours. Cooled to room temperature, 1000ml of water is added and stirred for 0.5 hour. Suction filtration, pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and extraction was performed 4 times with 500ml of ethyl acetate. The organic phases were combined, washed with brine and concentrated under reduced pressure to remove the organic solvent. 1000ml of water was added to the residue, stirred at room temperature for 2 hours, and filtered to give a crude product of compound I. And (5) refluxing, pulping and purifying by acetonitrile, and drying. 54.63g of pure compound I (HPLC purity 98.11%, yield 94.5%) are obtained.
EXAMPLE 6 preparation of the Compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester
500Ml of methanol and 50g of compound I are added into a reaction flask under the protection of inert gas at room temperature, and 51.73g of oxalyl chloride is added dropwise at 5-15 ℃. The reaction was carried out at 40℃for 5 hours. The organic solvent was concentrated under reduced pressure, 500ml of water was added to the residue, which was stirred at room temperature for 2 hours, filtered and dried to give 50.10g of methyl 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoate (HPLC purity 98.72%, yield 90.2%).
MS+[M+1]282.2。
1H NMR(400MHz,DMSO)δ7.70–7.46(m,2H),6.22(d,J=8.3Hz,1H),6.01(d,J=14.0Hz,1H),3.73(s,3H),3.63(s,3H),2.72–2.55(m,2H),2.28–2.11(m,2H),2.11–1.79(m,2H).13C NMR(101MHz,DMSO)δ174.1,164.2,163.9,161.7,152.2,133.0,108.5,104.5,98.7,58.9,52.39,51.4,30.5,14.8.
EXAMPLE 7 preparation of the Compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester
100Ml of methanol and 10g of compound I are added into a reaction bottle under the protection of inert gas at room temperature, and 23.50g of thionyl chloride is added dropwise at 5-15 ℃. The reaction was carried out at 60℃for 2 hours. The organic solvent was concentrated under reduced pressure, 100ml of water was added to the residue, and the mixture was stirred at room temperature for 2 hours, filtered and dried to give 10.95g of methyl 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoate (HPLC purity 98.36%, yield 98.6%).
EXAMPLE 8 preparation of the Compound 4- (1-ethoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid ethyl ester
100Ml of ethanol and 10g of compound I are added into a reaction bottle under the protection of inert gas at room temperature, and 14.10g of thionyl chloride is added dropwise at 5-15 ℃. The reaction was carried out at 60℃for 2 hours. The organic solvent was concentrated under reduced pressure, 100ml of water was added to the residue, and the mixture was stirred at room temperature for 2 hours, filtered and dried to give 10.46g of 4- (1-ethoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid ethyl ester (purity by HPLC: 97.25%, yield: 94.2%).
EXAMPLE 9 preparation of the Compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester
280Ml of DMF, 90.07g of cesium carbonate and 35g of compound I are added to a reaction flask at room temperature under the protection of inert gas, and 39.25g of methyl iodide is added dropwise at 5-15 ℃. The reaction was carried out at 40℃for 5 hours. Cooling to room temperature, adding the system into 1400ml of water, stirring at room temperature for 2 hours, filtering, and drying to obtain 35.46g of compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester (HPLC purity 96.36%, yield 91.2%).
EXAMPLE 10 preparation of the Compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester
Under the protection of inert gas at room temperature, 280ml of DMF, 95.37g of potassium carbonate and 35g of compound I are added into a reaction bottle, and 58.87g of methyl iodide is added dropwise at 5-15 ℃. The reaction was carried out at 60℃for 3 hours. Cooling to room temperature, adding the system into 1400ml of water, stirring at room temperature for 2 hours, filtering, and drying to obtain 35.89g of compound 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoic acid methyl ester (HPLC purity 97.57%, yield 92.3%).
EXAMPLE 11 preparation of Compound I V methyl 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoate
1000Ml of methanol and 100g of compound I are added into a reaction bottle under the protection of inert gas at room temperature, and 141.0g of thionyl chloride is added dropwise at 5-15 ℃. The reaction was carried out at 50℃for 2 hours. The organic solvent was concentrated under reduced pressure, 100ml of water was added to the residue, and the mixture was stirred at room temperature for 2 hours, filtered and dried to give 108.7g of methyl 4- (1-methoxycarbonyl-cyclobutylamino) -2-fluoro-benzoate (HPLC purity 98.88%, yield 97.9%).
EXAMPLE 12 preparation of the Compound 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoic acid methyl ester
45Ml of dimethyl sulfoxide, 45g of compound IV and 47.66g of 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine are added into a reaction flask at room temperature under the protection of inert gas, and the temperature is raised to 80 ℃ for reaction for 24 hours. 180ml of ethyl acetate was added, 180ml of water was used for extraction and separation, and the aqueous phase was extracted twice with 90ml of ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, and 90ml of isopropanol was added to the residue to crystallize, which was filtered and dried to give 52.35g of the compound methyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoate (HPLC purity 99.12%, yield 68.4%).
MS+[M+1]479.2。
1H NMR(400MHz,DMSO)δ9.21(d,J=1.9Hz,1H),8.74(d,J=1.9Hz,1H),8.14(t,J=8.3Hz,1H),7.55(dd,J=11.0,1.8Hz,1H),7.46(dd,J=8.3,1.8Hz,1H),3.91(s,3H),2.74–2.58(m,2H),2.58–2.41(m,2H),2.03–1.91(m,1H),1.64–1.54(m,1H).13C NMR(101MHz,DMSO)δ179.6,174.3,163.3,159.7,153.4,140.8,135.5,133.0,129.0,126.6,122.9,119.3,119.0,114.2,67.7,52.7,31.1,13.4.
EXAMPLE 13 preparation of the Compound 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoic acid methyl ester
45Ml of N, N-dimethylacetamide, 45g of compound IV and 73.33g of 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine were added to a reaction vessel at room temperature under the protection of inert gas, and the reaction was carried out at 120℃for 20 hours. 180ml of ethyl acetate was added, 180ml of water was used for extraction and separation, and the aqueous phase was extracted twice with 90ml of ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, and 90ml of isopropanol was added to the residue to crystallize, which was filtered and dried to give 54.65g of the compound methyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoate (HPLC purity 98.98%, yield 71.4%).
EXAMPLE 14 preparation of the Compound 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoic acid methyl ester
45Ml of NMP, 45g of compound IV and 55g of 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine are added into a reaction flask at room temperature under the protection of inert gas, and the mixture is heated to 95 ℃ for reaction for 20 hours. 180ml of ethyl acetate was added, 180ml of water was used for extraction and separation, and the aqueous phase was extracted twice with 90ml of ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the organic solvent, and 90ml of isopropanol was added to the residue to crystallize, which was filtered and dried to give the compound methyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl) -2-fluoro-N-methylbenzoate 60.24g (HPLC purity 99.24%, yield 78.7%).
EXAMPLE 15 preparation of Compound VII (apatamide)
102Ml of tetrahydrofuran and 34g of the compound VI are introduced into a reaction flask at room temperature under the protection of inert gas, and 55.2g (content: about 40%) of an aqueous methylamine solution is added dropwise at 5-15 ℃. The reaction was carried out at 50℃for 16 hours. The organic solvent was concentrated under reduced pressure, 100ml of isopropanol was added to the residue to crystallize, and the crystals were filtered and dried to obtain 28.16g of compound VII apatamide (HPLC purity 99.65%, yield 83.0%).
MS+[M+1]478.1,
1H NMR(400MHz,DMSO)δ9.21(d,J=1.9Hz,1H),8.75(d,J=1.9Hz,1H),8.49(d,J=4.3Hz,1H),7.83(t,J=8.0Hz,1H),7.47(dd,J=10.5,1.8Hz,1H),7.38(dd,J=8.1,1.8Hz,1H),2.81(d,J=4.3Hz,3H),2.73–2.57(m,2H),2.57–2.35(m,2H),1.94-1.99(m,1H),1.70–1.45(m,1H).13C NMR(101MHz,DMSO)δ174.3,163.4,153.4,135.5,133.2,131.1,126.4,125.4,118.3,67.6,31.1,26.2,13.4.
EXAMPLE 16 preparation of Compound VII (apatamide)
102Ml of acetonitrile and 34g of compound VI are added to a reaction flask at room temperature under the protection of inert gas, and 55.2g (content about 40%) of aqueous methylamine solution is added dropwise at 5-15 ℃. The reaction was carried out at 10℃for 36 hours. The organic solvent was concentrated under reduced pressure, 100ml of isopropanol was added to the residue to crystallize, and the crystals were filtered and dried to obtain 27.95g of compound VII (HPLC purity 99.68%, yield 82.4%).
EXAMPLE 17 preparation of Compound VII (apatamide)
102Ml of tetrahydrofuran and 34g of the compound VI are introduced into a reaction flask at room temperature under the protection of inert gas, and 55.2g (content: about 40%) of an aqueous methylamine solution is added dropwise at 5-15 ℃. The reaction was carried out at 25℃for 20 hours. The organic solvent was concentrated under reduced pressure, 100ml of isopropanol was added to the residue to crystallize, and the crystals were filtered and dried to obtain 28.04g of compound VII (HPLC purity 99.36%, yield 82.6%).