Preparation method for morpholinquinazoline compound and intermediates thereof

Abstract

The present disclosure relates to a preparation method morpholinquinazoline compound and a midbody thereof. The preparation method for morpholinquinazoline compound comprises the following steps: S1, performing a Suzuki reaction of compound S and compound IV as represented by the following formula, so as to obtain compound V; step S2, performing a reaction of methylsufonyl chloride and compound V in an organic solvent as represented by the following formula, so as to obtain compound VI; and S3, performing a coupled reaction of compound VII and compound VI in a solvent as represented by the following formula, so as to obtain compound YY-20394. The preparation method has the advantages of higher yield, better selectivity, simple operation and mild reaction condition, and is applicable to industrial production. ##STR00001##

Claims

1. A method for preparing a compound of formula V, comprising: in the presence of a palladium catalyst and an alkaline reagent, performing a Suzuki reaction of compound S and compound IV as represented by the following formula in a solvent to obtain compound V; ##STR00074## wherein R.sup.1 and R.sup.2 are independently H or ##STR00075## M is ##STR00076## or —BF.sub.3K; X.sup.1 is Cl or Br; X.sup.2 is halogen, ##STR00077## R.sup.3 is C.sub.1-4 alkyl; R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e are independently H, C.sub.1-6 alkyl, nitro or halogen.

2. The method according to claim 1, wherein in X.sup.2, the halogen is Cl, Br or I; and/or, in R.sup.3, the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, ##STR00078## or tert-butyl; and/or, in R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e, the halogen is independently Cl, Br or I; and/or, in R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e, the C.sub.1-6 alkyl is independently C.sub.1-3 alkyl.

3. The method according to claim 1, wherein in X.sup.2, the halogen is Cl; and/or, in R.sup.3, the C.sub.1-4 alkyl is methyl; and/or, in R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e, the C.sub.1-6 alkyl is independently methyl, ethyl, n-propyl or isopropyl.

4. The method according to claim 1, wherein M is ##STR00079## and/or, X.sup.1 is Cl; and/or, X.sup.2 is halogen, ##STR00080## and/or, R.sup.4a, R.sup.4b, R.sup.4d and R.sup.4e are independently H.

5. The method according to claim 1, where M is ##STR00081## and/or, X.sup.2 is ##STR00082##

6. The method according to claim 1, wherein in the Suzuki reaction, the palladium catalyst is one or more of tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride, dichlorobis (tri-o-tolylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium, bis (tri-tert-butylphosphine)palladium (Pd[P(t-Bu).sub.3].sub.2), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; and/or, in the Suzuki reaction, the palladium catalyst reacts in the presence of a ligand; the ligand is one or more of triphenylphosphine, tris(o-tolyl)phosphine, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl and 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl; and/or, in the Suzuki reaction, the molar ratio of the palladium catalyst to compound IV is 0.01-0.5; and/or, in the Suzuki reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is one or more of aromatic hydrocarbon solvent, alcohol solvent, chlorinated hydrocarbon solvent and ether solvent; the volume ratio of the organic solvent to the water is 1:1-10:1; and/or, in the Suzuki reaction, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide; and/or, in the Suzuki reaction, the molar ratio of the alkaline reagent to compound IV is 1-10; and/or, in the Suzuki reaction, the molar ratio of compound S to compound IV is 0.9-3; and/or, in the Suzuki reaction, the temperature of the Suzuki reaction is 0-130° C.; and/or, the Suzuki reaction is performed in a protective gas atmosphere; and/or, in the Suzuki reaction, compound S is ##STR00083## and/or, in the Suzuki reaction, compound IV is ##STR00084##

7. The method according to claim 1, wherein in the Suzuki reaction, the palladium catalyst is tetrakis(triphenylphosphine)palladium; and/or, in the Suzuki reaction, the molar ratio of the palladium catalyst to compound IV is 0.02-0.2; and/or, in the Suzuki reaction, the solvent is a mixed solvent of aromatic hydrocarbon solvent and water solvent; the organic solvent is a mixed solvent of aromatic hydrocarbon solvent and alcohol solvent; and/or, the solvent is a mixed solvent of aromatic hydrocarbon solvent and water solvent; the volume ratio of the organic solvent to the water is 5:1-10:1; and/or, in the Suzuki reaction, the molar ratio of the alkaline reagent to compound IV is 2-10; and/or, in the Suzuki reaction, the molar ratio of compound S to compound IV is 0.9-1.5; and/or, in the Suzuki reaction, the temperature of the Suzuki reaction is 20-70° C.

8. The method according to claim 1, further comprising a method for preparing compound IV, wherein the method is method 1 or method 2: method 1 comprising: performing a halogenation reaction of compound III and phosphorus oxyhalide and/or phosphorus halide as represented by the following formula to obtain compound IV; method 2 comprising: in the presence of an alkaline reagent, performing a nucleophilic substitution reaction of compound III and a sulfonation reagent as represented by the following formula in an organic solvent to obtain compound IV; the sulfonation reagent is ##STR00085## ##STR00086## when X.sup.2 is halogen, then the method for preparing compound IV is method 1; when X.sup.2 is ##STR00087## then the method for preparing compound IV is method 2.

9. The method according to claim 8, wherein in method 1, the halogenation reaction is a neat reaction; and/or, in method 1, the halogen in the phosphorus oxyhalide and/or phosphorus halide is Cl, Br or I; and/or, in method 1, the molar ratio of the phosphorus oxyhalide and/or phosphorus halide to compound III is greater than or equal to 1; and/or, in method 1, the temperature of the halogenation reaction is 20-130° C.; and/or, in method 2, the alkaline reagent is a weak organic alkali and/or a weak inorganic alkali salt; and/or, in method 2, when the sulfonation reagent is ##STR00088## the ##STR00089## and/or, in method 2, when the sulfonation reagent is ##STR00090## the ##STR00091## and/or, in method 2, the molar ratio of the sulfonation reagent to compound III is 1-1.5; and/or, in method 2, the organic solvent is one or more of a nitrile solvent, a chlorinated hydrocarbon solvent and an ether solvent; and/or, in method 2, the volume-to-mass ratio of the organic solvent to compound III is 5-15 mL/g.

10. The method according to claim 8, wherein in method 1, the halogen in the phosphorus oxyhalide and/or phosphorus halide is Cl; and/or, in method 1, the molar ratio of the phosphorus oxyhalide and/or phosphorus halide to compound III is 1-30; and/or, in method 1, the temperature of the halogenation reaction is 60-110° C.; and/or, in method 2, the alkaline reagent is a weak organic alkali and/or a weak inorganic alkali salt, and the organic weak alkali is a tertiary amine weak organic alkali and/or a pyridine weak organic alkali; the weak inorganic alkaline salt is an alkali metal carbonate.

11. The method according to claim 8, further comprising: performing a nucleophilic substitution reaction of compound II and compound A as represented by the following formula in an organic solvent to obtain compound III; ##STR00092##

12. The method according to claim 11, further comprising: in the presence of an alkaline reagent, performing a reaction of compound I as represented by the following formula to obtain compound II; ##STR00093##

13. A method for preparing a compound of formula YY-20394, comprising: step S1: in the presence of a palladium catalyst and an alkaline reagent, performing a Suzuki reaction of compound S and compound IV as represented by the following formula in a solvent to obtain compound V; step S2: in the presence of an alkaline reagent, performing a reaction of methylsulfonyl chloride and compound V as represented by the following formula in an organic solvent to obtain compound VI; step S3: in the presence of an alkaline reagent and in the presence of a palladium catalyst and a ligand, performing a conjugation reaction of compound VII and compound VI as represented by the following formula in a solvent to obtain compound YY-20394; ##STR00094## wherein, when R.sup.1 and R.sup.2 in compound V are both ##STR00095## compound V is directly subjected to the conjugation reaction in step S3 without step S2; in step S1, the conditions and procedures of the method for preparing compound V are as defined in claim 1.

14. The method according to claim 13, wherein in the method for preparing the compound of formula YY-20394, when R.sup.1 and R.sup.2 in compound V are not both H or ##STR00096## compound V is directly subjected to the conjugation reaction in step S3 without step S2; and/or, in step S2, the alkaline reagent is a weak organic alkali; and/or, in step S2, the molar ratio of methylsulfonyl chloride to compound V is 1-5; and/or, in step S2, the molar ratio of the alkaline reagent to compound V is 3-25; and/or, in step S2, the organic solvent is a chlorinated hydrocarbon solvent; and/or, in step S2, the reaction temperature is 10-50° C.; and/or, in step S2, compound V is ##STR00097## and/or, in step S3, the palladium catalyst is one or more of tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride, dichlorobis(tri-o-tolylphosphine)palladium(II), tris(dibenzylideneacetone) dipalladium, bis(tri-tert-butylphosphine)palladium (Pd[P(t-Bu).sub.3].sub.2), [1,1′-bis(diphenylphosphino) ferrocene]palladium dichloride, and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex; and/or, in step S3, the molar ratio of the palladium catalyst to compound VI is 0.01-0.2; and/or, in step S3, the ligand is one or more of triphenylphosphine, tris (o-tolyl)phosphine, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphino-2′, 4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl and 2-dicyclohexylphosphino-2′,6′-diisopropoxy -1,1′-biphenyl; and/or, in step S3, the molar ratio of the ligand to compound VI is 0.02-0.4; and/or, in step S3, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide; and/or, in step S3, the molar ratio of the alkaline reagent to compound VI is 1-20; and/or, in step S3, the molar ratio of compound VII to compound VI is 0.8-6; and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the volume ratio of the water-soluble organic solvent to water is 1:1-15:1; and/or, in step S3, compound VI is ##STR00098## and/or, in step S3, the conjugation reaction is performed in a protective gas atmosphere, wherein the protective gas is nitrogen or argon.

15. The method according to claim 13, wherein in step S2, the alkaline reagent is a weak organic alkali; the weak organic alkali is a pyridine weak organic alkali and/or a tertiary amine weak organic alkali; and/or, in step S2, the organic solvent is dichloromethane; and/or, in step S3, the palladium catalyst is palladium acetate; and/or, in step S3, the ligand is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; and/or, in step S3, the molar ratio of compound VII to compound VI is 1-3; and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is an ether solvent and/or an alcohol solvent; and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the volume ratio of the water-soluble organic solvent to water is 3:1-15:1.

16. The method according to claim 13, wherein in step S2, the alkaline reagent is a weak organic alkali; the weak organic alkali is a pyridine weak organic alkali; and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is an ether solvent.

17. The method according to claim 13, wherein in step S2, the alkaline reagent is a weak organic alkali; the weak organic alkali is pyridine; and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is one or more of tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.

18. The method according to claim 13, wherein in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is tetrahydrofuran.

19. A compound of formula IV: ##STR00099## wherein X.sup.1 and X.sup.2 are as defined in claim 1; or, a compound of formula III: ##STR00100## wherein X.sup.1 is Cl or Br; or, a compound of formula II: ##STR00101##

20. Compound IV according to claim 19, wherein compound IV is ##STR00102## ##STR00103##

Description

DETAILED DESCRIPTION

(1) The present invention is further illustrated by the following examples, which are not intended to limit the present invention. Experimental procedures without specified conditions in the following examples were performed in accordance with conventional procedures and conditions, or in accordance with instructions.

Example 1. Synthesis of Compound I-11

(2) ##STR00049##

(3) 2-Amino-5-fluorobenzoic acid (100.2 g, 0.65 mol) was dissolved in DMF (600 mL), and the mixture was added with NCS (104.5 g, 0.78 mol) in portions while stirring at room temperature. After the addition was completed, the mixture was stirred at room temperature overnight. Water (1200 mL) was added to the reaction solution to precipitate solids. The mixture was filtered, and the filter cake was washed with water, dried, and resuspended in dichloromethane. The mixture was filtered, and the residues were dried to obtain compound I-11-1 (85.1 g, 70% yield) as an off-white solid. LC-MS (ESI): m/z=190.0 [M+H].sup.+.

(4) Compound I-11-1 (25.0 g, 0.13 mol) and urea (119.1 g, 1.98 mol) were added to a flask and the mixture was incubated at 180° C. for 8 h. The reaction solution was cooled to about 100° C. and water was added for 2 h of resuspension. The mixture was filtered, and the filter cake was resuspended in water, filtered and dried twice to obtain compound 1-11-2 (26.7 g, 94% yield) as a brown solid. LC-MS (ESI): m/z=215.0 [M+H].sup.+.

(5) Compound 1-11-2 (20.0 g, 0.093 mol) and phosphorus oxychloride (160 g, 1.04 mol) were added to a flask before DIPEA (24.0 g, 0.19 mol) was added dropwise below 50° C. After the addition was completed, the mixture was incubated at 110° C. for 2 h. The reaction solution was concentrated and washed with toluene twice. A small amount of toluene was then slowly & dropwise added to aqueous phase, with the temperature controlled at 40° C. or less. After the addition was completed, the mixture was continuously stirred for 0.5 h and separated. The aqueous phase was extracted with toluene. The toluene phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residues were resuspended in n-heptane, filtered, and dried to obtain compound I-11 (19.9 g, 85% yield) as an off-white solid. LC-MS (ESI): m/z=251.1 [M+H].sup.+.

Example 2. Synthesis of Compound II-11

(6) ##STR00050##

(7) To a solution of compound I-11 (5 g, 0.020 mol) in acetonitrile (70 mL), an aqueous sodium hydroxide solution (2 N, 40 mL) was added at room temperature. After the addition was completed, the reaction solution was stirred at 45° C. overnight. The reaction solution was cooled to room temperature, and then transferred to an ice-water bath before an aqueous hydrochloric acid solution (2 N, 42 mL) was slowly added to adjust the pH to 5-6. A solid was precipitated. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound II-11 (4.1 g, 89% yield) as an off-white solid. LC-MS (ESI): m/z=232.9 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.63 (brs, 1H), 8.06 (dd, 1H, J=2.8, 8.4 Hz), 7.78 (dd, 1H, J=2.8, 8.0 Hz).

Example 3. Synthesis of Compound III-11

(8) ##STR00051##

(9) To a solution of compound II-11 (3 g, 0.013 mol) in DMAC (30 mL), morpholine (2.7 g, 0.031 mol) was added at room temperature. After the addition was completed, the reaction solution was stirred at 85° C. for 2 h. The reaction solution was cooled to room temperature, and then transferred to an ice-water bath before water (70 mL) was slowly added. A solid was precipitated. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound III-11 (3.2 g, 88% yield) as a pale yellow solid. LC-MS (ESI): m/z=284.1[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.69 (brs, 1H), 7.81 (dd, J=8.4 Hz, 2.8 Hz 1H), 7.59 (dd, J=8.0 Hz, 2.8 Hz 1H), 3.55-3.80 (m, 8H).

Example 4. Synthesis of Compound IV-11

(10) ##STR00052##

(11) To a solution of compound III-11(36.0 g, 0.13 mol) in acetonitrile (360 mL), potassium carbonate (24 g, 0.17 mol) andp-toluenesulfonyl chloride (24.0 g, 0.13 mol) were added at room temperature. After the addition was completed, the reaction solution was stirred at 80° C. for 2 h. The reaction solution was cooled to room temperature, transferred to an ice-water bath, and dropwise added with water with the temperature controlled at 25° C. or less. After the addition was completed, the mixture was continuously stirred for 1 h. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound IV-11 (48 g, 86% yield) as a yellow solid. LC-MS (ESI): m/z=438.0 [M+H].sup.+.

Example 5. Synthesis of Compound V-11

(12) ##STR00053##

(13) To a flask, the compounds IV-11 (157.0 g, 0.36 mol) and 5-11 (81.5 g, 0.33 mol), sodium carbonate (345.5 g, 3.26 mol), toluene (3.5 L), isopropanol (1.2 L) and water (1.6 L) were added. The reaction system was purged with nitrogen three times, and tetrakis(triphenylphosphine)palladium (18.8 g, 0.016 mol) was added in nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 35-40° C. for 1 h. The reaction solution was cooled to room temperature and separated. The aqueous phase was extracted with toluene. The toluene phases were combined, concentrated to some extent, added with n-heptane, filtered and purified by silica gel column chromatography to obtain compound V-11 (115 g, 91% yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.94 (d, J=2.8 Hz, 1H), 7.63 (dd, J=8.0 Hz, 2.8 Hz, 1H), 7.55 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.24-7.27 (m, 1H), 4.11 (s, 3H), 3.90-4.06 (m, 6H), 3.84(t, J=5.2 Hz, 4H).

Example 6. Synthesis of Compound VI-11

(14) ##STR00054##

(15) To a solution of compound V-11 (110 g, 0.28 mol) in pyridine (550 g, 6.59 mol) in an ice-salt bath, methanesulfonyl chloride (63.8 g, 0.56 mol) was added dropwise. After the addition was completed, the reaction solution was stirred at room temperature until the reaction was completed. The reaction solution was carefully added with water (1100 mL) and filtered, and the filter cake was washed with water, dried, resuspended in dichloromethane, filtered, and dried to obtain compound VI-11 (105.0 g, 80% yield) as a yellow solid. LC-MS (ESI): m/z=468.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.53 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.07 (dd, J=11.2 Hz, 2.4 Hz; 1H), 8.03 (d, J=2.4 Hz, 1H), 7.57(dd, J=9.2 Hz, 2.4 Hz; 1H), 4.04 (s, 3H), 3.92-3.86 (m, 4H), 3.74-3.72 (m, 4H),.3.12(s, 3H).

Example 7. Synthesis of Compound VI-11

(16) ##STR00055##

(17) To a solution of compound S-11 (2.0 g, 8 mmol) in pyridine (20 mL) at 0-10° C., methanesulfonyl chloride (1.24 mL, 16.0 mmol) was slowly & dropwise added, and after the addition was completed, the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to remove pyridine, and saturated aqueous sodium bicarbonate (20 mL) and dichloromethane (40 mL) were added to the residues. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound T-11 (4.29 g, 100% yield) as a yellow oil. LC-MS (ESI): m/z=329.2 [M+H].sup.+.

(18) To a flask, the compounds T-11 [352 mg, 0.65 mmol (61% purity)] and IV-11 (281 mg, 0.64 mmol), sodium carbonate (0.102 g, 0.96 mmol), tetrakis(triphenylphosphine) palladium(0) (74 mg, 0.064 mmol) and a mixture of toluene/isopropanol/water (volume ratio=4/1/1, 8 mL) were added. After the addition was completed, the reaction system was purged with nitrogen and stirred at 60° C. for 4 h. The reaction solution was concentrated and the residues were extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residues were resuspended in dichloromethane and filtered to obtain compound VI-11 (170 mg, 53% yield) as a yellow solid. LC-MS (ESI): m/z=468.1 [M+H].sup.+.

Example 8. Synthesis of Compound VII-11

(19) ##STR00056##

(20) To a flask, the compounds P-11 (100 g, 0.70 mol) and Q-21 (127.5 g, 0.63 mol), acetonitrile (100 g) and potassium iodide (6 g, 0.036 mol) were added. After the addition was completed, the reaction solution was stirred at 80° C. overnight. The reaction solution was concentrated, and the residues were resuspended in hot acetonitrile, filtered and dried to obtain compound VII-11 (140.0 g, 98%) as an off-white solid. .sup.1H NMR (400 MHz, D20): δ 3.51 (d, J=12.8 Hz, 2H), 2.80 (t, J=12.8 Hz, 2H), 2.05-2.22 (m, 2H), 1.90 (d, J=13.2 Hz, 2H), 1.40-1.62 (m, 3H), 1.12 (s, 6H).

Example 9. Synthesis of Compound YY-20394

(21) ##STR00057##

(22) To a flask, the compounds VI-11 (35 g, 0.075 mol) and VII-11 (34 g, 0.15 mol), cesium carbonate (244 g, 0.75), x-Phos (3.55 g, 0.0074 mol), and a mixture of THF and water (10/1 v/v, 385 mL) and palladium acetate (0.84 g, 0.0037 mol) were added at room temperature. The mixture was purged with nitrogen three times and stirred at 80° C. overnight. The reaction solution was cooled to room temperature and concentrated to remove THF, and the residues were extracted with DCM. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography. The crude product was resuspended in ethanol, filtered and dried to obtain compound YY-20394 (26 g, 59% yield) as a yellow solid. LC-MS (ESI): m/z=589.3 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ .53(brs, 1H), 8.35(d, J=2.0 Hz, 1H), 8.01(d, J=2.4 Hz, 1H), 7.61(dd, J=9.6 Hz, 2.4 Hz, 1H), 7.39(dd, J=9.6 Hz, 2.4 Hz, 1H), 4.05(s, 4H), 3.87(s, 2H), 3.82-3.81(m, 4H), 3.73-3.72(m, 4H), 3.13(s, 3H), 2.94(d, J=10.8 Hz, 1H), 2.04-1.98(m, 2H), 1.66(d, J=11.6 Hz, 2H), 1.36-1.64(m, 2H), 1.21-1.18(m, 1H), 1.21-1.18(m, 1H), 1.04(s, 6H).

Example 10. Synthesis of Compound V-11

(23) ##STR00058##

(24) To a solution of compound III-11 (1.0 g, 3.52 mmol) in acetonitrile (10 mL) in an ice-water bath, methanesulfonyl chloride (0.55 mL, 7.06 mmol) and DIPEA (1.33 mL, 7.76 mmol) were added dropwise in sequence. After the addition was completed, the mixture was stirred at room temperature for 2 h. The reaction solution was added with ice-water (15 mL), stirred for 10 min, and filtered. The filter cake was washed with water and dried to obtain compound IV-12 (3.01 g, 100% yield).

(25) To a flask, the compounds IV-12 (3.01 g, 3.52 mmol) and 5-11 (0.88 g, 3.52 mmol), sodium carbonate (0.56 g, 5.30 mmol), tetrakis(triphenylphosphine)palladium (408 mg, 0.353 mmol) and a mixture of toluene/isopropanol/water (volume ratio=4/1/1, 15 mL) were added at room temperature. After the addition was completed, the reaction system was purged with nitrogen, and stirred at 30° C. for 2 h and then at 45° C. overnight. The reaction solution was concentrated, and dichloromethane (40 mL) and water (20 mL) were added to the residues. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound V-11 (1.02 g, 74% yield) as a yellow solid. LC-MS (ESI): m/z=390.2 [M+H].sup.+.

Example 11. Synthesis of Compound V-11

(26) ##STR00059##

(27) To a solution of compound III-11 (0.28 g, 0.99 mmol) in dichloromethane (10 mL) in an ice-water bath, DIPEA (0.26 g, 2.0 mmol) was added before trifluoromethanesulfonic anhydride (0.56 g, 2.0 mmol) was added dropwise. After the addition was completed, the mixture was stirred for 2 h in an ice-water bath. The reaction solution was added with ice water (20 mL), and extracted with dichloromethane (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound IV-13 (0.18 g, 44% yield) as a brown solid. LC-MS (ESI): m/z=416.1 [M+H].sup.+.

(28) To a flask, the compounds IV-13 (0.18 g, 0.43 mmol) and S11 (0.2 g, 0.8 mmol), sodium carbonate (0.1 g, 1.0 mmol), tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) and a mixture of toluene/isopropanol/water (volume ratio=4/1/1, 6 mL) were added at room temperature. After the addition was completed, the reaction system was purged with nitrogen, and stirred at 70° C. for 6 h. The reaction solution was concentrated, added with ethyl acetate (8 mL) and filtered. The filtrate was concentrated and purified by preparative TLC (petroleum ether/ethyl acetate=1/1) to obtain compound V-11 (0.09 g, 53% yield). LC-MS (ESI): m/z=390.1 [M+H].sup.+.

Example 12. Synthesis of Compound V-11

(29) ##STR00060##

(30) A mixture of compound III-11 (1.0 g, 3.52 mmol) in phosphorus oxychloride (10 mL) was stirred at 105° C. for 3 h. The reaction solution was concentrated, and washed twice with toluene. The residues were added with ice water (15 mL), and the mixture was stirred for 10 min and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride and concentrated to obtain compound IV-14 (1.13 g, 100% yield) as a yellow solid.

(31) To a flask, the compounds IV-14 (1.13 g, 3.52 mmol) and S-11 (0.97 g, 3.88 mmol), sodium carbonate (0.66 g, 6.23 mmol), tetrakis(triphenylphosphine)palladium (408 mg, 0.353 mmol) and a mixture of toluene/isopropanol/water (volume ratio=4/1/1, 60 mL) were added at room temperature. After the addition was completed, the reaction system was purged with nitrogen, and stirred at 80° C. overnight. The reaction solution was concentrated, and dichloromethane (50 mL) and water (20 mL) were added to the residues. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound V-11 (1.21 g, 88% yield) as a yellow solid. LC-MS (ESI): m/z=390.2 [M+H].sup.+.

Example 13. Synthesis of Compound VI-11

(32) ##STR00061##

(33) To a flask, compound T-11 [520 mg, 0.97 mmol (61% purity, the same as in Example 7)], potassium bifluoride (494 mg, 6.34 mmol) and a mixture of 1,4-dioxane/water (10/1, 4 mL) were added at room temperature. After the addition was completed, the mixture was stirred at room temperature for 1 h. The reaction solution was filtered, and the filter cake was washed with 1,4-dioxane. The filtrates were combined, concentrated, and dried to obtain compound T-31 (480 mg, 100% yield) as a pale yellow oil.

(34) To a flask, the compounds T-31 (480 mg, 0.97 mmol) and IV-11 (395 mg, 0.90 mmol), cesium carbonate (340 mg, 1.35 mmol), palladium acetate (10 mg, 0.045 mmol), x-Phos (43 mg, 0.09 mmol) and a mixture of THF/H.sub.2O (volume ratio=1/1, 8 mL) were added. The mixture was purged with nitrogen and stirred at 60° C. for 2 h. The reaction solution was concentrated and the residues were extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residues were resuspended in dichloromethane, filtered and dried to obtain compound VI-11 (280 mg, 62% yield). LC-MS (ESI): m/z=468.1 [M+H].sup.+.

Example 14. Synthesis of Compound V-11

(35) ##STR00062##

(36) To a flask, compound S-11 (1.25 g, 5.00 mmol), sodium periodate (3.2 g, 15.00 mmol), ammonium acetate (1.1 g, 15.00 mmol), acetone (40 mL) and water (10 mL) were added. The reaction solution was stirred at 80° C. for 12 h. After the reaction was completed, the reaction solution was concentrated, added with water (30 mL), and extracted with EA (50 mL×3). The organic phase was concentrated to obtain compound S-21 (0.66 g, 78% yield). LC-MS (ESI): m/z=169.3 [M+H].sup.+.

(37) To a flask, the compounds IV-11 (1.2 g, 2.74 mmol) and S-21 (0.51 g, 3.04 mmol), sodium carbonate (0.4 g, 3.77 mmol), toluene (16 mL), isopropanol (4 mL) and water (4 mL) were added. After stirring and purging with nitrogen, tetrakis(triphenylphosphine) palladium(0) (0.1 g, 0.09 mmol) was added to the flask, the reaction system was purged with nitrogen again, and the mixture was incubated at 60° C. for 12 h. The reaction solution was concentrated, added with water (60 mL), filtered and dried to obtain a crude product (0.76 g). The crude product was resuspended in a mixture of petroleum ether/ethyl acetate (volume ratio=1/1; 40 mL), and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound V-11 (0.46 g, 43%). LC-MS (ESI): m/z=390.1 [M+H].sup.+.

Example 15. Synthesis of Compound VI-11

(38) ##STR00063##

(39) To a solution of compound T-11 (0.74 g, 2.26 mmol) in acetone (15 mL) was added a solution of sodium periodate (1.45 g, 6.78 mmol) and ammonium acetate (0.87 g, 11.3 mmol) in water (5 mL). The reaction solution was incubated at 80° C. for 12 h. After the reaction was completed, the reaction solution was concentrated to remove the solvent, added with diluted hydrochloric acid (2 N) and water, and extracted with ethyl acetate. The organic phase was concentrated to obtain compound T-21 (0.54 g, 96% yield).

(40) To a flask, the compounds IV-11 (0.5 g, 1.14 mmol) and T-21 (423 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium (132 mg, 0.114 mmol), sodium carbonate (363 mg, 3.42 mmol), toluene (16 mL), isopropanol (4 mL) and water (4 mL) were added. The reaction system was purged with nitrogen, and incubated at 60° C. overnight. The reaction solution was concentrated by rotary evaporation, added with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM:MeOH=50:1-20:1) to obtain compound VI-11 (290 mg, 54% yield). LC-MS (ESI): m/z=468.1 [M+H].sup.+.

Example 16. Synthesis of Compound YY-20394

(41) ##STR00064##

(42) To a solution of compound 5-11 (1 g, 4.00 mmol) in dichloromethane (10 mL), triethylamine (1.2 g, 11.85 mmol) was added. MsCl (0.92 g, 8.03 mmol) was then slowly added to the reaction system in an ice-water bath. After the addition was completed, the reaction system was stirred at room temperature overnight. The reaction solution was concentrated, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound T-12 (1.6 g, 98% yield).

(43) To a flask, the compounds IV-11 (500 mg, 1.14 mmol) and T-12 (697 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium (132 mg, 0.114 mmol), sodium carbonate (363 mg, 3.42 mmol), toluene (16 mL), isopropanol (4 mL) and water (4 mL) were added. The reaction system was purged with nitrogen, and incubated at 60° C. overnight. The reaction solution was concentrated, added with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound VI-12 (350 mg, 56% yield). LC-MS (ESI): m/z=546.1 [M+H].sup.+.

(44) To a 10-mL microwave tube, the compounds VI-12 (93 mg, 0.17 mmol) and VII-11 (192 mg, 0.85 mmol), palladium acetate (4 mg, 0.017 mmol), x-Phos (16 mg, 0.034 mmol), cesium carbonate (166 mg, 0.51 mmol), THF (1.4 mL) and water (0.35 mL) were added. The microwave tube was purged with nitrogen, and incubated at 80° C. overnight. The reaction solution was concentrated, added with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=30:1) to obtain compound YY-20394 (80 mg, 80% yield) as a yellow solid. LC-MS (ESI): m/z=589.3 [M+H].sup.+.

Example 17. Synthesis of Compound 1-21

(45) ##STR00065##

(46) 2-Amino-5-fluorobenzoic acid (10 g, 64.5 mmol) was dissolved in DMF (50 mL), and the mixture was added with NBS (12.6 g, 70.9 mmol) in portions while stirring at room temperature. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was added with water (120 mL) and a solid was precipitated. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound I-21-1 (15 g, 100% yield) as a yellow solid. LC-MS (ESI): m/z=234.1 [M+H]+.

(47) To a flask, compound I-21-1 (15 g, 64.1 mmol) and urea (38.5 g, 641 mmol) were added and the mixture was incubated 180° C. for 5 h. The reaction solution was cooled to about 100° C. and water was added for 2 h of resuspension. The mixture was filtered, and the filter cake was resuspended in water, filtered and dried twice to obtain compound I-21-2 (16 g, 96% yield) as a yellow solid. LC-MS (ESI): m/z=259.0 [M+H].sup.+.

(48) Compound I-21-2 (16 g, 61.8 mmol) and phosphorus oxychloride (95 g, 618 mmol) were added to a flask before DIPEA (16 g, 123.6 mmol) was added dropwise at room temperature. After the addition was completed, the reaction solution was incubated at 110° C. for 2 h. The reaction solution was concentrated and the concentrate was slowly added to ice-water. The mixture was stirred for 10 min and filtered. The filter cake was dried to obtain compound I-21 (19 g, 100% yield).

Example 18. Synthesis of Compound II-21

(49) ##STR00066##

(50) To a solution of compound I-21 (19 g, 64.2 mmol) in acetonitrile (240 mL), an aqueous sodium hydroxide solution (2 N, 128 mL) was added at room temperature. After the addition was completed, the reaction solution was stirred at 45° C. overnight, cooled to room temperature, and then, in an ice-water bath, slowly added with an aqueous hydrochloric acid solution (2 N) to adjust the pH to 5-6. A solid was precipitated. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound II-21 (10.3 g, 58%). LC-MS (ESI): m/z=277.0 [M+H].sup.+.

Example 19. Synthesis of Compound II-21

(51) ##STR00067##

(52) To a solution of compound II-21 (10.3 g, 37.1 mmol) in DMAC (60 mL), morpholine (8.1 g, 92.8 mmol) was added at room temperature. After the addition was completed, the reaction solution was stirred at 85° C. for 2 h. The reaction solution was cooled to room temperature, and then transferred to an ice-water bath before water (70 mL) was slowly added. A solid was precipitated. The mixture was filtered, and the filter cake was dried to obtain compound III-21 (8 g, 66% yield). LC-MS (ESI): m/z=328.1[M+H].sup.+.

Example 20. Synthesis of Compound IV-21

(53) ##STR00068##

(54) To a solution of compound III-21 (0.5 g, 1.52 mol) in acetonitrile (10 mL), potassium carbonate (274 mg, 1.98 mmol) and p-toluenesulfonyl chloride (290 mg, 1.52 mol) were added at room temperature. After the addition was completed, the reaction solution was stirred at 80° C. for 2 h. The reaction solution was cooled to room temperature, transferred to an ice-water bath, and dropwise added with water with the temperature controlled at 25° C. or less.

(55) After the addition was completed, the mixture was continuously stirred for 1 h. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound IV-21 (650 mg, 88% yield) as a yellow solid. LC-MS (ESI): m/z=482.1[M+H]t

Example 21. Synthesis of Compound V-21

(56) ##STR00069##

(57) To a flask, the compounds IV-21 (200 mg, 0.41 mmol) and S-11 (104 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (47 mg, 0.041 mmol), sodium carbonate (130 mg, 1.23 mmol), toluene (7.5 mL), isopropanol (2.5 mL) and water (3 mL) were added. The reaction solution was purged with nitrogen, and incubated 40° C. for 4 h. The reaction solution was concentrated by rotary evaporation, added with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (PE:EA=3:1) to obtain compound V-21 (140 mg, 78% yield) as a yellow solid. LC-MS (ESI): m/z=434.1[M+H].sup.+.

Example 22. Synthesis of Compound VI-21

(58) ##STR00070##

(59) To a solution of compound V-21 (140 mg, 0.32 mmol) in pyridine (5 mL) in an ice bath, MSCl (37 mg, 0.32 mmol) was added. The reaction solution was stirred at room temperature overnight, concentrated by rotary evaporation, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain compound VI-21 (160 mg, 97% yield). LC-MS (ESI): m/z=512.1 [M+H].sup.+.

Example 23. Synthesis of Compound YY-20394

(60) ##STR00071##

(61) To a 10-mL microwave tube, the compounds VI-21 (140 mg, 0.27 mmol) and VII-11 (308 mg, 1.37 mmol), palladium acetate (6 mg, 0.027 mmol), x-Phos (26 mg, 0.054 mmol), cesium carbonate (264 mg, 0.81 mmol), THF (2 mL) and water (0.5 mL) were added. The microwave tube was purged with nitrogen. The reaction solution was incubated at 80° C. overnight. The reaction solution was concentrated by rotary evaporation, added with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=30:1) to obtain compound YY-20394 (80 mg, 50% yield) as a yellow solid. LC-MS (ESI): m/z =589.4[M+H].sup.+.

Example 24: Synthesis of Compound V-11

(62) ##STR00072##

(63) To a flask, the compounds IV-11 (159 mg, 0.36 mmol, 1 eq.) and S-11 (100 mg, 0.40 mmol, 1.1 eq.), sodium carbonate (385 mg, 3.63 mmol, 10 eq.), toluene (4.3 mL), isopropanol (1.5 mL) and water (2 mL) were added. The reaction solution was purged with nitrogen three times, and tetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol, 0.05 eq.) was added in nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 35-40° C. for 1 h and subjected to LC-MS. When compound IV-11 in the reaction solution was completely converted, the content of compound V-11 was 72.59% (wavelength 214 nm) and 99.03% (wavelength 254 nm). After the reaction was completed, the reaction solution was concentrated by rotary evaporation, added with water, and extracted with ethyl acetate (25 mL). The organic phase was concentrated by rotary evaporation, and purified by silica gel column chromatography (PE:EA=2:1) to obtain compound V-11 (142 mg, 92% yield) as a yellow solid with purities of 85.41% (wavelength 214 nm) and 91.71% (wavelength 254 nm) (the yield was calculated as per the purity 91.71% at wavelength 254 nm in LC-MS).

Comparative Example 1

(64) ##STR00073##

(65) Compound IV-11 in Example 24 was replaced by compound I-11 (91 mg, 0.36 mmol, 1 eq.). According to the Suzuki reaction in the conditions of Example 24, the reaction solution was stirred at 35-40° C. for 1 h, and subjected to LC-MS. Through the assay, the content of compound V-12 was 28.64% (wavelength 214 nm) and 35.39% (wavelength 254 nm), with the presence of large amounts of reactants I-11 and S-11. The reaction solution was continuously stirred at 35-40° C. overnight, and subjected to LC-MS. Through the assay, some reactant I-11 and S-11 were still present in the reaction solution, and the content of compound V-12 was 35.28% (wavelength 214 nm) and 65.04% (wavelength 254 nm). After the reaction was completed, the reaction solution was concentrated by rotary evaporation, added with water, and extracted with ethyl acetate (25 mL). The organic phase was concentrated, and purified by column chromatography (PE:EA=4:1) to obtain compound V-12 (73 mg, 50% yield) as a yellow solid with purities of 84.62% (wavelength 214 nm) and 96.08% (wavelength 254 nm) (the yield was calculated as per the purity 96.08% at wavelength 254 nm in LC-MS).

(66) This comparative example compared the Suzuki reaction using the compounds I-11 and IV-11 in the same conditions, and the results are summarized in Table 1.

(67) TABLE-US-00001 TABLE 1 Content of product in reaction solution/% Mass of 1 h Overnight purified Yield of Wavelength Wavelength Wavelength Wavelength Purity after product/ purified No. 214 nm 254 nm 214 nm 254 nm purification/% mg product/% Example 24 72.59 99.03 / / 85.4 (wavelength 142 92 214 nm), 91.71 (wavelength 254 nm) Comparative 28.64 35.39 35.28 65.04 84.6 (wavelength 73 50 example 1 214 nm), 96.08 (wavelength 254 nm) Note: In Table 1, “/” indicates no detection.

(68) From the results in Table 1, it is understood that the substituent at position 2 in the quinoline ring will affect the rate, progress, effect and yield of the Suzuki reaction in the same conditions. Compared with the substrate I-11 (namely the compound with chlorine at position 2 in the quinoline ring disclosed in Patent No. WO2015055071A1), the reaction time with the substrate IV-11 can be reduced to 1 hour, and the yield is improved by 42%, thus giving an elevated production efficiency and improved cost-efficiency, which cannot be expected on the basis of the prior art. The inventors of the present application, through continuous attempt and screening, have creatively found that when using the substrate IV-11, the Suzuki reaction may provide a higher yield in a reduced period of time, and side reactions at position 2 in the quinoline ring may also be avoided, which is advantageous for post-treatment.

(69) Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of protection of the present invention is therefore defined by the appended claims.