METHOD FOR PREPARING PYRROLOAMINOPYRIDAZINONE COMPOUND AND INTERMEDIATES THEREOF

Abstract

The present invention relates to a method for preparing a pyrroloaminopyridazinone compound and intermediates thereof. Specifically relating to a method for preparing the compound of formula (I), the target product being prepared by means of changing the starting materials and intermediates; the present method has the advantages of reactants such as the starting materials being easy to purchase, the reaction conditions being simple and controllable, the post-reaction treatment method being simple, the yield being high, and being beneficial for industrial production.

##STR00001##

Claims

1-35. (canceled)

36. A compound of formula (E), a salt thereof, or a stereoisomer thereof, ##STR00108## wherein, R.sup.a is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, haloalkyl, haloalkoxy and alkoxy; R.sub.3 is selected from the group consisting of hydrogen, halogen, alkyl, —OR.sub.1, —NHR.sub.2, —NR.sub.2R.sub.2 and alkylsulfonamido; R.sub.1 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; G.sub.1 is selected from the group consisting of hydrogen and a hydroxy protecting group; L is an alkylene or absent; Y is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1, 2 or 3.

37. The compound of claim 36, wherein G is substituted by a substituent selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, alkoxy, alkylamino, hydroxyalkyl, dialkylamino, alkylcarbonyl, formylalkyl, alkoxycarbonyl, formylalkoxy, alkylcarbonylamino, alkylaminocarbonyl, alkylsulfonyl, alkenyl, alkenylcarbonyl, alkynyl and alkynylcarbonyl.

38. The compound of claim 36, wherein Y is substituted by a substituent selected from the group consisting of halogen, cyano, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonamido, alkyl, cycloalkyl, alkenyl, alkenylcarbonyl, alkynyl and alkynylcarbonyl.

39. The compound of claim 36, wherein Y is a 3 to 8 membered heterocyclyl.

40. The compound according to claim 36, wherein the compound has a formula: ##STR00109##

41. The compound according to claim 36, wherein the compound is selected from the group consisting of: ##STR00110## ##STR00111##

42. A method for preparing the compound of claim 36, wherein the method comprises a step of reacting a compound of formula (SM1) or a stereoisomer thereof, a compound of formula (SM2) or a stereoisomer thereof, and a compound of formula (SM3) or a stereoisomer thereof to obtain the compound of formula (E) or a stereoisomer thereof, ##STR00112##

43. The method according to claim 42, wherein R.sub.3 is not —OR.sub.1, and the method further comprises a step of: ##STR00113##

44. The method according to claim 43, wherein the method further comprises a step of: ##STR00114##

45. A method for preparing the compound of formula (E1) or a stereoisomer thereof, wherein the method comprises a step of: ##STR00115##

46. The method according to claim 45, wherein the method further comprises a step of: ##STR00116##

47. The method according to claim 46, wherein the method further comprises a step of: ##STR00117##

48. A compound of formula (B), a salt thereof, or a stereoisomer thereof, ##STR00118## wherein, R.sup.a is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, haloalkyl, haloalkoxy and alkoxy; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; L is an alkylene or absent; Y is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1, 2 or 3; and R.sub.4 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

49. The compound according to claim 48, wherein the compound is: ##STR00119##

50. A method for preparing the compound of formula (B) or a stereoisomer thereof, wherein the method comprises a step of: ##STR00120## wherein, R.sup.a is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, haloalkyl, haloalkoxy and alkoxy; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; L is an alkylene or absent; Y is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1, 2 or 3; and R.sub.4 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

51. The method according to claim 50, wherein the method further comprises a step of: ##STR00121##

52. The method according to claim 51, wherein the method further comprises steps of: ##STR00122## wherein, R.sub.3 is selected from the group consisting of hydrogen, halogen, alkyl, —OR.sub.1, —NR.sub.2R.sub.2 and alkylsulfonamido; and G.sub.1 is selected from the group consisting of hydrogen and a hydroxy protecting group.

53. A method for preparing the compound of formula (A) or a stereoisomer thereof, wherein the method comprises a step of: ##STR00123## wherein, R.sup.a is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, haloalkyl, haloalkoxy and alkoxy; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; L is an alkylene or absent; Y is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1, 2 or 3; and R.sub.4 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

54. A compound of formula (C), a salt thereof, or a stereoisomer thereof, ##STR00124## wherein, R.sup.a is selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, carboxy, amino, alkyl, haloalkyl, haloalkoxy and alkoxy; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkylcarbonyl, heterocyclyl, heterocyclylcarbonyl, aryl, arylcarbonyl, heteroaryl and heteroarylcarbonyl; G is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; L is an alkylene or absent; Y is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; and m is 0, 1, 2 or 3.

55. The compound according to claim 54, wherein the compound is: ##STR00125##

Description

DETAILED DESCRIPTION OF THE INVENTION

[0156] In order to understand the present invention more easily, certain technical and scientific terms are specifically defined below. Unless otherwise definitely and obviously defined, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present invention belongs.

[0157] The term “halogen” or “halogen atom” used in the present invention refers to fluorine, chlorine, bromine, iodine and the like.

[0158] The term “alkyl” used in the present invention refers to a linear or branched alkyl having 1 to 20 carbon atoms, including for example “C1-6 alkyl”, “C.sub.1-4 alkyl” and the like. The specific examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.

[0159] The term “alkylene” used in the present invention refers to a group formed by removing hydrogen atom(s) from an “alkyl”, including for example “C1-6 alkylene”, “C1-4 alkylene” and the like. The specific examples of alkylene include, but are not limited to methylene, ethylene, propylene, isobutylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neo-pentylene, n-hexylene, isohexylene and the like. The term “alkyl” is as defined above.

[0160] The term “alkenyl” used in the present invention refers to a linear or branched group having 2 to 20 carbon atoms and at least one carbon-carbon double bond, including for example “C.sub.2-6 alkenyl”, “C.sub.2-4 alkenyl” and the like. The examples of alkenyl include, but are not limited to vinyl, propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl and the like.

[0161] The term “alkynyl” used in the present invention refers to a linear or branched group having 2 to 20 carbon atoms and at least one carbon-carbon triple bond, including for example “C.sub.2-6 alkynyl”, “C.sub.2-4 alkynyl” and the like. The examples of alkynyl include, but are not limited to ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl and the like.

[0162] The term “haloalkyl” used in the present invention refers to a group derived from an “alkyl” in which one or more hydrogen atom(s) are substituted by one or more “halogen atom(s)”, and the terms “halogen atom” and “alkyl” are as defined above.

[0163] The term “hydroxyalkyl” used in the present invention refers to a group derived from an “alkyl” in which one or more hydrogen atom(s) are substituted by one or more “hydroxy(s)”, and the term “alkyl” is as defined above.

[0164] The term “alkoxy, haloalkoxy, alkylcarbonyl, formylalkyl, alkoxycarbonyl, formylalkoxy, alkylcarbonylamino, alkylaminocarbonyl, formylalkylamino, alkylamino, dialkylamino, alkylsulfonamido, alkylsulfonyl, alkenylcarbonyl or alkynylcarbonyl” used in the present invention refers to a group with a linkage form of alkyl-O—, haloalkyl-O—, alkyl-C(O)—, H—C(O)-alkyl-, alkyl-O—C(O)—, H—C(O)-alkyl-O—, alkyl-C(O)—NH—, alkyl-NH—C(O)—, H—C(O)-alkyl-NH—, alkyl-NH—, (alkyl).sub.2-N—, alkyl-S(O).sub.2—NH—, alkyl-S(O).sub.2—, alkenyl-C(O)- or alkynyl-C(O)—, wherein the terms “alkyl, haloalkyl, alkenyl, alkynyl” are as defined above.

[0165] The term “cycloalkyl” used in the present invention refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 14 carbon atoms, preferably 3 to 12 carbon atoms or 5 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, most preferably 5 to 6 carbon atoms, and the cycloalkyl is optimally cyclopropyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, and preferably cyclopropyl or cyclohexenyl. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.

[0166] The term “heterocyclyl” used in the present invention refers to a 3 to 14 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein at least one ring atoms are heteroatoms (for example nitrogen atoms, oxygen atoms or sulfur atoms), with the remaining ring atoms being carbon atoms. Optionally, the ring atoms (for example, carbon atoms, nitrogen atoms or sulfur atoms) of the cyclic structure can be oxidized. Preferably, the heterocyclyl has 3 to 12 ring atoms or 5 to 12 ring atoms wherein 1 to 4 heteroatoms, more preferably 3 to 8 ring atoms, and more preferably 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring.

[0167] The term “aryl” used in the present invention refers to a 6 to 14 membered all-carbon monocyclic ring or polycyclic fused ring (i.e. each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group having a conjugated 7r-electron system. The aryl is preferably a 6 to 8 membered aryl, more preferably phenyl, anthracenyl, phenanthryl, fluorenyl or indenyl, and most preferably phenyl.

[0168] The term “heteroaryl” used in the present invention refers to a 5 to 15 membered all-carbon monocyclic ring or fused polycyclic ring group having a conjugated 7r-electron system, and further having 1 to 4 heteroatoms selected from the group consisting of O, S and N. The heteroaryl is preferably a 5 to 8 membered heteroaryl, and more preferably a 5 or 6 membered heteroaryl. The specific examples of heteroaryl include, but are not limited to furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl and the like. The heteroaryl can also be fused to the ring of aryl, heterocyclyl or cycloalkyl.

[0169] The expression “carbon atoms, nitrogen atoms or sulfur atoms are oxidized” used in the present invention refers to the formation of a C=O, N=O, S=O or SO.sub.2 structure.

[0170] The term “amide solvent” used in the present invention refers to a liquid compound in which the hydroxy group of the carboxy group of a carboxylic acid molecule is substituted with an amino or a hydrocarbon amino group (—NHR or —NR.sub.2). It can also be regarded as a liquid compound in which the hydrogen on the nitrogen atom of an ammonia or amine molecule is substituted with an acyl. The specific examples of amide solvent include, but are not limited to N,N-dimethylformamide and N,N-dimethylacetamide.

[0171] The term “ester solvent” used in the present invention refers to a compound with less than 15 carbon atoms formed by a dehydration reaction between an organic acid and an alcohol or phenol, or a lower ester compound having a functional group —C(O)O— and less than 15 carbon atoms. The specific examples of ester solvent include, but are not limited to methyl acetate, ethyl acetate, dimethyl phthalate, butyl acetate or propyl acetate.

[0172] The term “ketone solvent” used in the present invention refers to a compound in which a carbonyl group (—C(O)—) is bonded to two hydrocarbon groups. Ketones can be classified into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones, depending on the hydrocarbon groups in the molecule. The specific examples of ketone solvent include, but are not limited to acetone, methyl ethyl ketone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone.

[0173] The term “ether solvent” used in the present invention refers to a chain compound or a cyclic compound having an ether bond —O— and 1 to 10 carbon atoms. The specific examples of ether solvent include, but are not limited to tetrahydrofuran, diethyl ether, propylene glycol methyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether or 1,4-dioxane.

[0174] The term “alcohol solvent” used in the present invention refers to a group derived from a “C.sub.1-6 alkyl” in which one or more hydrogen atom(s) are substituted by one or more “hydroxy(s)”, and the terms “hydroxy” and “C.sub.1-6 alkyl” are as defined above. The specific examples of alcohol solvent include, but are not limited to methanol, ethanol, isopropanol, n-propanol, isopentanol or trifluoroethanol.

[0175] The term “nitrile solvent” used in the present invention refers to a group derived from a “C.sub.1-6 alkyl” in which one or more hydrogen atom(s) are substituted by one or more “cyano(s)”, and the terms “cyano” and “C.sub.1-6 alkyl” are as defined above. The specific examples of nitrile solvent include, but are not limited to acetonitrile or propionitrile.

[0176] The term “halohydrocarbon solvent” used in the present invention refers to a group derived from a “C.sub.1-6 alkyl” in which one or more hydrogen atom(s) are substituted by one or more “halogen atom(s)”, and the terms “halogen atom” and “C.sub.1-6 alkyl” are as defined above. The specific examples of halohydrocarbon solvent include, but are not limited to chloromethane, dichloromethane, chloroform or carbon tetrachloride.

[0177] The term “arene solvent” used in the present invention refers to a general term for a carbon ring compound and a derivative thereof, wherein the molecule has a conjugated system of a closed ring, and the number of electrons conforms to the Huckel rule. The specific examples of arene solvent include, but are not limited to benzene, toluene, cumene or xylene.

[0178] The term “sulfoxide solvent” used in the present invention refers to a compound formed by the bond of a sulfinyl group (—SO—) to a hydrocarbon group. The specific examples of sulfoxide solvent include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide.

Advantageous Effects of the Present Invention

[0179] Compared with the prior art, the technical solution for preparing the compound of formula (I) of the present invention has the following advantages:

[0180] (1) The starting materials and intermediates of the present invention are different from the prior art. The present invention provides a synthesis method with a completely different idea, wherein the starting materials and reactants are simple and easy to purchase.

[0181] (2) The yield is improved.

[0182] (3) The work-up is simple. The crude product of each step can be used directly in the next step without purification. This method is conducive to industrial production.

Examples

[0183] The present invention will be further described with reference to the following examples, which should not be considered as limiting the scope of the present invention.

[0184] In the examples of the present invention, the experiment methods that do not specify the specific conditions are generally conducted in accordance with conventional conditions, or in accordance with conditions recommended by the material or product manufacturers. The reagents without a specific source are commercially available conventional reagents.

[0185] The structures of the compounds are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (6) are given in 10.sup.−6 (ppm).

[0186] NMR are determined by a Bruker AVANCE-400 machine. The solvent for determination is heavy water with sodium hydroxide (CDCl.sub.3), and the internal standard is tetramethylsilane (TMS).

[0187] High performance liquid chromatography (HPLC) is determined on a Waters Alliance 2695 high performance liquid chromatograph spectrometer and an Agilent 1200 series liquid chromatograph spectrometer, with octadecylsilane bonded silica gel as the column packing.

Example 1. Preparation of (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0188] ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##

Step 1. Synthesis of the Compound of Formula (SM1-1)

[0189] Compound SM1-b (20 g), tert-butylamine (9.91 g) and 4-dimethylaminopyridine (5.17 g) were added to toluene (400 mL) under a nitrogen atmosphere. The reaction solution was heated to reflux and stirred for 6 hours. The reaction was stopped after completion, and the reaction solution was concentrated. The resulting residues were purified by column chromatography (eluent:petroleum ether:ethyl acetate=5:1) to obtain the target compound (16.6 g, yield: 74.5%).

Step 2. Synthesis of the Compound of Formula (SM2-2)

[0190] Acetic acid (2600 mL) and ammonium acetate (411.42 g) were added to a reaction flask, and stirred to dissolve completely. A solution of compound SM2-c (500 g) in nitromethane (912.2 g) was added, and the reaction solution was heated to 90° C. with an oil bath and kept for 5 hours. The reaction was stopped, and the oil bath was removed. The reaction solution was added with water (5.2 L) to precipitate a solid. The system was stirred for crystallization for 2 hours, and then filtrated to give 662 g of crude product. The crude product was added to isopropanol (2.5 L), and heated to reflux to dissolve completely. The resulting solution was cooled to room temperature, stirred overnight, filtrated and dried to obtain the a product (443 g, yield: 74.9%).

Step 3. Synthesis of the Compound of Formula (E1)

[0191] Compound SM1-1(2.28 g), compound SM3-2 (1.88 g), compound SM2-2 (2 g), nitromethane (4.4 g) and ferric chloride (234 mg) were added to toluene (50 mL) under a nitrogen atmosphere. The reaction solution was heated to reflux and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and purified by column chromatography (eluent:petroleum ether:ethyl acetate=2:1) to obtain a product (3.4 g, yield: 69.9%).

Step 4. Synthesis of the Compound of Formula (D1)

[0192] Compound E1 (30 g) and methanol (300 mL) were added to a reaction flask and stirred, then palladium hydroxide (9.0 g) was added. The reaction system was purged with hydrogen three times, and the reaction solution was heated to 50° C. under hydrogen atmosphere and stirred. After completion of the reaction, the reaction solution was cooled to room temperature, and filtrated through celite. The filtrate was concentrated to obtain 27.0 g of crude product, which was used directly in the next oxidation reaction.

Step 5. Synthesis of the Compound of Formula (C1)

[0193] Compound D1 (27.0 g) and dimethyl sulfoxide (270 mL) were added to a reaction flask and stirred to dissolve, followed by an one-time addition of S-IBX (56.5 g, IBX content 47%). The reaction solution was stirred at 40° C. for 1 hour. After completion of the reaction, the reaction solution was cooled naturally, followed by the addition of methyl tert-butyl ether (200 mL). The reaction solution was stirred well, and then filtrated through celite to remove the solid. The filtrate was extracted with methyl tert-butyl ether (200 mL×3). The organic phases were combined, washed with water (150 mL×3) three times, dried over anhydrous sodium sulfate, filtrated and concentrated to obtain a product (26.0 g, yield: 96.6%).

Step 6. Synthesis of the Compound of Formula (B1)

[0194] Compound C1 (26.0 g), tert-butanol (500 mL) and isopentene (57.6 mL) were added to a reaction flask and stirred to dissolve. Sodium chlorite (20.7 g) and sodium dihydrogen phosphate (12.4 g) were dissolved in water (100 mL), and the resulting solution was added dropwise to the above reaction solution. After completion of the addition, the reaction solution was stirred at 20° C. After completion of the reaction, the reaction solution was concentrated to remove most of the tert-butanol. The residues were added with water (300 mL), and then extracted with methyl tert-butyl ether (300 mL×3). The organic phases were combined, washed with water (200 mL), dried over anhydrous sodium sulfate, filtrated and concentrated to obtain a product (28.3 g, yield: 105.8%).

Step 7. Synthesis of the Compound of Formula (A1-1)

[0195] Compound B1 (28.3 g) and dichloromethane (400 mL) were added to a reaction flask. Trifluoroacetic anhydride (20.4 g) was dissolved in dichloromethane (160 mL), and the resulting solution was added dropwise to the above reaction system. After completion of the addition, the reaction solution was reacted at room temperature. After completion of the reaction, 200 mL of water was added, and the solution was stirred well and separated into layers. The aqueous phase was extracted with dichloromethane (200 mL×2). The organic phases were combined, washed with water until neutral, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain a product (25.0 g, yield: 100%).

[0196] 25.0 g of the resulting crude product was dissolved in methyl tert-butyl ether (200 mL). Tert-butylamine (6.2 mL) was diluted in methyl tert-butyl ether (50 mL), and the resulting solution was slowly added dropwise to the above system. The solution was stirred at room temperature for 5 hours to slowly precipitate solid, and then filtrated. The filter cake was washed with methyl tert-butyl ether, and dried under vacuum to obtain a product (21.5 g, yield: 75%, purity: 94.1%).

Step 8. Synthesis of the Compound of Formula (A1)

[0197] The tert-butylamine salt of compound A1-1(21.5 g), potassium carbonate (15.3 g) and N,N-dimethylformamide (200 mL) were added to a reaction flask. Iodoethane (8.8 mL) was added under an ice bath. After completion of the addition, the ice bath was removed, and the reaction solution was reacted at 30° C. until the raw materials were consumed completely. The reaction mixture was added with water (200 mL), and then extracted with methyl tert-butyl ether (200 mL×3). The organic phases were combined, washed with water (100 mL×3), dried over anhydrous sodium sulfate, filtrated and concentrated to obtain a product (18.5 g, yield: 91%).

Step 9. Synthesis of the Compound of Formula (III)

[0198] Compound A1 (6.0 g), hydrazine hydrate (35 mL) and ethanol (60 mL) were added to a reaction flask. The system was purged with nitrogen, and the reaction solution was heated to reflux. After completion of the reaction, the reaction solution was naturally cooled to room temperature, and concentrated under reduced pressure to remove most of the ethanol solvent. The residues were added with saturated sodium chloride aqueous solution (100 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with water (100 mL), dried over anhydrous sodium sulfate, filtrated and concentrated to remove the solvent. The residues were purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=2:1) to obtain a product (4.5 g, yield: 78.7%).

Step 10. Synthesis of the Compound of Formula (II)

[0199] Compound III (4.5 g) and methanol (50 mL) were added to a reaction flask and stirred to dissolve. 6 N hydrochloric acid (40 mL) was added under an ice bath. The ice bath was removed, and the reaction solution was reacted at 25° C. until the raw materials were consumed completely. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and the pH was adjusted with NaOH to about 10. The solution was extracted with dichloromethane (150 mL×3). The organic phases were combined, washed with water (100 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated to remove the solvent and obtain a product (3.2 g, purity >99%, yield: 88.0%), which was used directly in the next condensation reaction.

Step 11. Synthesis of the Compound of Formula (Ia)

[0200] Compound II (3.2 g) and dichloromethane (33 mL) were added to a reaction flask, and then butynoic acid (0.95 g), EDCI (2.9 g) and triethylamine (3.2 mL) were added under an ice bath. The reaction solution was stirred at 20° C. until the raw materials were consumed completely. The reaction was quenched by adding water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to remove the solvent. The residues were purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=2:1) to obtain a product (3.2 g, yield: 86.0%, purity: 98.3%).

[0201] 2.5 g of the above product was dissolved in acetonitrile (25 mL) at room temperature, and heated to 70° C. to dissolve. The solution was naturally cooled to room temperature to precipitate a large amount of solid. The mixture was stirred for 2 hours and then filtrated, and the filter cake was washed with acetonitrile to give the target product (1.9 g, yield: 76%).

[0202] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 11.5 (br, 1H), 7.38-7.40 (d, 2H), 7.16-7.24 (m, 1H), 7.02-7.08 (m, 5H), 6.34-6.38 (m, 1H), 5.30-5.32 (br, 2H), 4.19-4.24 (m, 0.5H), 3.69-3.98 (m, 3.5H), 2.53-2.58 (m, 1H), 2.31-2.37 (m, 1H), 1.96-2.02 (d, 3H).

Example 2. Preparation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0203] ##STR00104## ##STR00105## ##STR00106## ##STR00107##

[0204] The target compound IA was obtained in accordance with the same preparation method of Example 1 except for replacing the reactant SM3-2 with compound SM3-3.