PREPARATION METHOD OF PYRROLO-AMINO-PYRIDAZINONE COMPOUND AND INTERMEDIATE THEREOF

Abstract

Provided are a preparation method of pyrrolo-amino-pyridazinone compound and an intermediate thereof. The reaction conditions are easy to control, the processing following the reaction is simple, the production rate is high, and the method is advantageous for industrial production.

Claims

1. A compound of formula (b), a salt thereof or a stereoisomer thereof, ##STR00105## wherein, A is selected from CR.sup.0 or N; R.sup.0 is selected from hydrogen atom, cyano, carboxyl, hydroxyl, amino, halogen or alkyl; R.sup.a is selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, haloalkyl, haloalkoxyl or alkoxyl; each of R.sub.3, R.sub.4 is independently selected from hydrogen atom, alkyl, alkylcarbonyl, alkoxylcarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; G is selected from optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclyl, the substituent is selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, alkoxyl, alkylamino, hydroxylalkyl, dialkylamino, alkylcarbonyl, aldehyde alkyl, alkoxycarbonyl, aldehyde alkoxyl, alkylcarbonylamino, alkylaminocarbonyl, alkylsulfonyl, alkenyl, alkenylcarbonyl, alkynyl or alkynylcarbonyl; L is selected from alkylene or absent; Y is selected from optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl, the substituent is selected from halogen, cyano, alkylcarbonyl, alkoxylcarbonyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkyl, cycloalkyl, alkenyl, alkenylcarbonyl, alkynyl or alkynylcarbonyl; Y is preferably optionally substituted 3-8 membered heterocyclyl, more preferably optionally substituted pyrrolidinyl or optionally substituted piperidinyl; m=0, 1, 2 or 3.

2. The compound as defined in claim 1, wherein the compound is selected from ##STR00106##

3. A method for preparing a compound of formula (b) or a stereoisomer thereof, wherein the method comprises ##STR00107## wherein, R.sup.a, R.sub.3, R.sub.4, A, G, L, Y and m are as defined in claim 1; each of R.sub.1, R.sub.2 is independently selected from hydrogen atom, alkyl, haloalkyl, benzyl, allyl, trimethylsilyl, triethylsilyl, tetrahydropyranyl or fluorene methyl, or R.sub.1 and R.sub.2 combine with the groups they are attached to form a 5-membered cyclic anhydride.

4. The method as defined in claim 3, wherein the method further comprises ##STR00108##

5. The method as defined in claim 4, wherein the method further comprises ##STR00109## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

6. The method as defined in claim 5, wherein the method further comprises ##STR00110##

7. The method as defined in claim 6 wherein the method further comprises ##STR00111## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

8. A method for preparing the compound of formula (a) or a stereoisomer thereof, wherein the method comprises ##STR00112## optionally, the method further comprises the method for preparing the compound of formula (b) as defined in claim 3; wherein, R.sup.a, R.sub.3, R.sub.4, A, G, L, Y and m are as defined in claim 1.

9. A method for preparing the compound of formula (I) or a stereoisomer thereof, wherein the method comprises ##STR00113## optionally, the method further comprises the method for preparing the compound of formula (b) as defined in claim 3; wherein, R.sup.a, R.sub.3, R.sub.4, A, G, L, Y and m are as defined in claim 1.

10. A compound of formula (c), a salt thereof or a stereoisomer thereof, ##STR00114## wherein, R.sup.a, R.sub.1, R.sub.2, A, G, L, Y and m are as defined in claim 3.

11. The compound as defined in claim 10, wherein the compound is selected from ##STR00115## ##STR00116## ##STR00117##

12. A method for preparing a compound of formula (c) or a stereoisomer, wherein the method comprising ##STR00118## wherein, R.sup.a, R.sub.1, R.sub.2, A, G, L, Y and m are as defined in claim 10.

13. The method as defined in claim 12, wherein the method further comprises ##STR00119## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

14. The method as defined in claim 13, wherein the method further comprises ##STR00120##

15. The method as defined in claim 14, wherein the method further comprises ##STR00121## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

16. A compound of formula (e), a salt thereof or a stereoisomer thereof ##STR00122## wherein, R.sup.a, A, G, L, Y and m are as defined in claim 4.

17. The compound as defined in claim 16, wherein the compound is selected from ##STR00123##

18. A method for preparing a compound of formula (e) or a stereoisomer thereof, wherein the method comprises ##STR00124## wherein, R.sup.a, A, G, L, Y and m are as defined in claim 16; X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

19. The method as defined in claim 18, wherein the method further comprises ##STR00125##

20. The method as defined in claim 19, wherein the method further comprises ##STR00126## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

21. A compound of formula (g), a salt thereof or a stereoisomer thereof ##STR00127## wherein, R.sup.a, A, G, X, m are as defined in claim 5.

22. The compound as defined in claim 21, wherein the compound is selected from ##STR00128##

23. A method for preparing a compound of formula (g) or a stereoisomer thereof, wherein the method comprises ##STR00129## wherein, R.sup.a, A, G, X, m are as defined in claim 21.

24. The method as defined in claim 23, wherein the method further comprises ##STR00130## wherein, X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.

25. A method for preparing a compound of formula (Ia) or a stereoisomer thereof, wherein the method comprises ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##

26. A method for preparing a compound of formula (a1) or a stereoisomer thereof, wherein the method comprises ##STR00136## ##STR00137## ##STR00138## ##STR00139##

27. A method for preparing a compound of formula (c1) or a stereoisomer thereof, wherein the method comprises ##STR00140## ##STR00141##

28. A method for preparing a compound of formula (IA) or a stereoisomer thereof, wherein the method comprises ##STR00142## ##STR00143## ##STR00144##

29. A method for preparing a compound of formula (A1) or a stereoisomer thereof, wherein the method comprises ##STR00145## ##STR00146##

30. A method for preparing a compound of formula (C) or a stereoisomer thereof, wherein the method comprises ##STR00147##

Description

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

[0365] ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100##

[0366] Step 1, the Synthesis of the Compound of Formula (h1)

[0367] The compound of formula (i1) (550 g), the compound of formula (j1), p-fluoroacetophenone (700.8 g), potassium carbonate (1.75 kg) and dimethylacetamide (6.4 L) was added into a reaction flask, the temperature was raised to 150° C., and the reaction was stirred for 24 hours. The reaction mixture was poured into ice water (12.5 L), stirred, a solid precipitated, filtered under reduced pressure, and dried to obtain the compound of formula (h1) (960 g) with a yield of 91.5%.

[0368] Step 2, the Synthesis of the Compound of Formula (g1)

[0369] The compound of formula (h1) (2 kg) was dissolved in acetonitrile (20 L), sulfuric acid (80 mL) was added, N-bromosuccinimide (1.68 kg) was added, after the addition, the reaction was carried out at room temperature for 20 hours overnight, the reaction mixture was poured into ice water (80 L), a solid precipitated out, stirred for 30 minutes and filtered to obtain the crude title product (2.6 kg). The crude product (2.6 kg) was dissolved in methyl tertiary butyl ether (2.6 L), heated to reflux until it was dissolved and clarified, then n-hexane (3.4 L) was slowly added, a large number of solids was precipitated when the temperature was cooled down naturally to 40° C., the temperature was kept at 40° C. for 30 minutes and then cooled to room temperature. The reaction flask was placed in an ice bath, kept for 2 hours, filtered, and dried to obtain the compound of formula (g1) (2.025 kg) with a yield of 76.8%.

[0370] Step 3, the Synthesis of the Compound of Formula (e1)

[0371] The compound of formula (f1) (250.5 g) and N,N-diisopropylethylamine (197.6 g) were dissolved in N,N-dimethylformanmide (2700 mL), the mixture was ventilated with argon gas three times, and cooled with an ice-salt bath to −5 to 0° C., the N,N-dimethylformanmide solution (1300 mL) of the compound of formula (g1) (400 g) was added dropwise, after dripping, the reaction was carried out at −5° C. for 3 hours for the next step.

[0372] Step 4, the Synthesis of the Compound of Formula (c1)

[0373] The compound of formula (d1) dimethyl butynedioate (521.3 g) was added to the above reaction mixture, the solution was brown and clear after heated to 90° C.; the reaction mixture was stirred for 2.5 hours, then the reaction was stopped and used in the next step.

[0374] Step 5, the Synthesis of the Compound of Formula (c1-1)

[0375] The system was firstly cooled, then an aqueous solution (2.7 L) of potassium hydroxide (1095 g) was added to the reaction mixture, the reaction was carried out for 5 hours after heated to 95° C., then stopped and cooled down. Ice water (24.0 L) was poured into the above reaction mixture, and concentrated hydrochloric acid was slowly added dropwise under stirring to adjust the pH of the reaction mixture to 4-5, and a large number of solids were precipitated, after stirring for 30 minutes, the mixture was filtered and washed and then dried to obtain the solid for the next step.

[0376] Step 6, the Synthesis of the Compound of Formula (c1-2)

[0377] The solid was dissolved in methanol (2.3 L), then an aqueous solution (2.2 L) of potassium hydroxide (617.7 g) was added, the mixture was heated to reflux and the reaction was carried out for 6 hours and then stopped; the mixture was concentrated to remove methanol, and the residue was washed into ice water (6.9 L), the pH of the mixture was adjusted to 3-4 using the concentrated hydrochloric acid, then a large number of solids were precipitated, filtered, washed with water until neutral, then the filter cake was collected, and dried to obtain the product (586 g) with a yield of 90.7%.

[0378] MS m/z (LC-MS): 526.56 [M-2].

[0379] Step 7, the Synthesis of the Compound of Formula (c1-3)

[0380] The compound of formula (c1-2) (250.0 g) was dissolved in tetrahydrofuran (2.5 L), and acetic anhydride (966 g) was added. After the addition, the reaction was carried out while stirring at room temperature for 10 minutes and refluxed for 4 hours, and then the reaction was stopped, the reaction mixture was concentrated under reduced pressure to obtain the residue, which was used in the next step.

[0381] MS m/z (LC-MS): 533.2 [M+23].

[0382] Step 8, the Synthesis of the Compound of Formula (b1-1)

[0383] The residue was dissolved in dichloromethane (2.4 L), tert-butylamine (103.8 g) was added dropwise under an ice water bath. After the addition, the reaction was carried out while stirring for 2 hours, and then the reaction was stopped. The reaction mixture was washed with water, separated, and dried over anhydrous sodium sulfate, then filtered, and the organic phase was concentrated to dryness, which was used in the next step.

[0384] MS m/z (LC-MS): 606.2 [M+23].

[0385] Step 9, the Synthesis of the Compound of Formula (b1)

[0386] The compound of formula (b1-1) obtained in the previous step was dissolved in tetrahydrofuran (2.76 L), potassium carbonate (130.8 g), diethyl sulfate (109.3 g) were added. The reaction was carried out while stirring and heated to reflux for 10 hours, then the reaction was stopped, the reaction mixture was reduced to room temperature, concentrated to dryness, and purified by column chromatography (ethyl acetate:petroleum ether=1:5) to obtain the product of the compound of formula (b1), with a yield of 78% and a purity of 97.96%.

[0387] MS m/z (LC-MS): 612.47 [M+1]

[0388] Step 10, the Synthesis of the Compound of Formula (a1)

[0389] The compound of formula (b1) obtained in the previous step was added to dichloromethane (1.7 L), trifluoroacetic anhydride (165.7 g) was slowly added in dichloromethane solution (500 mL) at 0° C. After addition, the mixture was slowly raised to room temperature and stirred for 5 hours, and then the reaction was stopped. The reaction was quenched by adding methanol (200 mL), then the reaction mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was the compound of formula (a1), with a yield of 92% and a purity of 96.2%.

[0390] Step 11, the Synthesis of the Compound of Formula (III)

[0391] Anhydrous ethanol (12.0 kg) was added into the reaction kettle, and the compound of formula (a1) ethyl (R)-1-(1-(t-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylate (3.0 kg) was added while stirring, the mixture was heated to 60-65° C. to dissolve and clarify, then 85% hydrazine hydrate (9.86 kg) was added. The mixture was heated and refluxed for 9-10 hours, then cooled to below 30° C., concentrated to remove ethanol, and then cooled to below 30° C. again, purified water (10 kg) and dichloromethane (15 kg) were added thereto and the phases of the mixture were separated after stirring, the aqueous phase was extracted with dichloromethane (15 kg), the organic phases were combined, dried over anhydrous sodium sulfate (1 kg), filtered, the filter cake was washed with dichloromethane (1 kg), the filtrate was concentrated under reduced pressure to dryness, and purified by silica gel column (dichloromethane:methanol=200:1-80:1) to obtain the product (1.87 kg) with a yield of 64.0%.

[0392] Step 12, the Synthesis of the Compound of Formula (II)

[0393] Anhydrous ethanol (12.0 kg) was added to a reaction kettle and the temperature was reduced to 0 to 5° C., hydrogen chloride gas (2.78 kg) was introduced to the reaction kettle, the compound of formula (III) (1.5 kg) was added while stirring, and the temperature of the reaction mixture was controlled between 15 to 25° C., the reaction was carried out for 3-4 hours while stirring. Then the mixture was concentrated to dryness under reduced pressure, and the residue was dried to obtain the product (1.35 kg) with a yield of 100%.

[0394] Step 13, the Synthesis of the Compound of Formula (Ia)

[0395] Dichloromethane (39.75 kg) was added into the reaction kettle, the temperature was reduced until the temperature of the reaction mixture was lower than 10° C., then N,N-diisopropylethylamine (1.35 kg), the compound of formula (II) (1.5 kg), 2-butynoic acid (438.7 g) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloide (1.25 kg) was added successively, after the addition, the reaction was carried out for 3 to 4 hours at 15 to 25° C. while stirring. Purified water (20 kg) was then added to the reaction mixture, stirred, the phases were separated and the organic phase was washed with purified water (20 kg), dried over anhydrous sodium sulfate (750 g), filtered, and the filter cake was washed with dichloromethane (1 kg), the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel column (dichloromethane:methanol=150:1-60:1) to obtain the product (1.26 kg) with a yield of 78.9%.

[0396] .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-acryloylpiperidine-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one

[0397] ##STR00101## ##STR00102## ##STR00103## ##STR00104##

[0398] Step 1, the Synthesis of the Compound of Formula (E)

[0399] 1-Boc-3-amino piperidine (9.91 g), N,N-diisopropylethylamine (7.25 g) were dissolved in N,N-dimethylformanmide (100 mL), the mixture was ventilated with argon gas for three times, and cooled to −40 to −45° C. with dry ice-acetonitrile, the raw material of a solution of the compound of formula (g1) (14.7 g) in N,N-dimethylformanmide (50 mL) was added dropwise, after the addition, the reaction was carried out at −45° C. for 27.5 hours, then the reaction was stopped, and the reaction mixture was poured into ice water, extracted with dichloromethane (20 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, then oxalic acid (4.45 g) was added to the filtrate, the reaction was stirred at room temperature, and a solid was precipitated, the mixture was concentrated under reduced pressure after 1 hour, then isopropanol (50 mL) was added to the residue, and the reaction was stirred at room temperature for 2 hours, filtered, and the filter cake was collected and dried to obtain the title product (18.9 g) with a yield of 78.4%.

[0400] Step 2, the Synthesis of the Compound of Formula (C)

[0401] Methanol (187 mL) was added to the raw material of the compound of formula (E) (18.7 g), the mixture was stirred for 10 minutes, then dimethyl butynedioate (14.9 g) was added, the reaction was refluxed and the solution gradually become clear, which was a brown clear liquid, the reaction mixture was refluxed and stirred for 1.5 hours, the methanol was removed by distillation, then tert-butanol was added, and the reaction was carried out for 6.5 hours then stopped, which was used in the next step.

[0402] Step 3, the Synthesis of the Compound of Formula (C-1)

[0403] An aqueous solution (200 mL) of potassium hydroxide (34.5 g) was added slowly to the reaction mixture of the compound of formula (C) obtained in the previous step, the reaction was carried out while stirring and under reflux for 28 hours, then stopped, and the reaction mixture was poured into ice water (2 L), acetic acid was slowly added dropwise while stirring, and the pH of the reaction mixture was adjusted to 4 to 5 with acetic acid (60 mL), solids precipitated, after stirring for 30 minutes, the mixture was filtered, and the filter cake was collected, the title product (17.9 g) was obtained after vacuum drying with a yield 94.7%.

[0404] Step 4, the Synthesis of the Compound of Formula (C-2)

[0405] The raw material of the compound of formula (C-1) (5.4 g) was dissolved in tetrahydrofuran (54 mL), acetic anhydride (2.04 g) was added thereto, after the addition, the reaction was carried out while stirring at room temperature for 10 minutes and refluxed for an hour, then the reaction was stopped, the reaction mixture was concentrated under reduced pressure to remove the acetic anhydride to obtain the title product, which was used in the next reaction.

[0406] Step 5, the Synthesis of the Compound of Formula (B)

[0407] The raw material of the compound of formula (C-2) (5.22 g) was dissolved in dichloromethane (50 mL), tert-butylamine (876 mg) was added dropwise, after the addition, the reaction was carried out at room temperature for 2 hours then stopped, and the reaction mixture was washed sequentially with water and saturated sodium chloride solution, the organic phases were combined and dried over anhydrous sodium sulfate, and filtered to obtain the title product, which was used in the next reaction.

[0408] Step 6, the Synthesis of the Compound of Formula (A1)

[0409] Under ice bath, a solution of trifluoroacetic anhydride (2.52 g) in dichloromethane solution (5 mL) was slowly added to the dichloromethane solution of the raw material of the compound of formula (B). After the dropwise addition, the reaction was carried out for 5 hours after slowly warmed to room temperature, then stopped, a small amount of methanol was added to the reaction mixture to quench the reaction, and the mixture was washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (4.9 g) with a yield of 94.0%.

[0410] Step 7, the Synthesis of the Compound of Formula (IIIA)

[0411] Under ice bath, the raw material of the compound of formula (A1) (1.04 g) was dissolved in 1,4-dioxane (15 mL), the mixture was stirred for 10 minutes and then N,N-carbonyldiimidazole (356.4 mg) was added, after the addition, the reaction was carried out while stirring for 21 hours after the temperature was warmed to room temperature slowly, then stopped; under ice bath, hydrazine hydrate (10 g) was added to the reaction mixture, the reaction was carried out under reflux for 9 hours then stopped, the reaction mixture was extracted with dichloromethane, the organic phase was collected and dried over anhydrous sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent is dichloromethane:methanol=500:1-100:1) to obtain the title product (825 mg) with a yield of 76.8%.

[0412] Step 8, the Synthesis of the Compound of Formula (IIA)

[0413] The raw material of the compound of formula (IIIA) (15 g) was added to dichloromethane (300 mL), and trifluoroacetic acid (75 mL) was added thereto, the reaction was carried out for 3 hours then stopped; the reaction mixture was concentrated under reduced pressure and dissolved with dichloromethane (300 mL), saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8 to 9, then the phases were separated, the aqueous phase was extracted with dichloromethane (150 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the title product (10.5 g) with a yield of 86.3%.

[0414] Step 9, the Synthesis of the Compound of Formula (IA)

[0415] The compound of formula (IIA) (10.5 g) was dissolved in dichloromethane (250 mL) at 0° C., N,N-diisopropylethylamine (10.8 mL) was added thereto, a solution of acrylic chloride (3.1 g) in dichloromethane (50 mL) was added dropwise at 0 to 5° C., the reaction was carried out at 0 to 5° C. for 2 hours while stirring then stopped; methanol (5 mL) was added to quench the reaction, and then saturated ammonium chloride solution (100 mL) was added, the phases were separated, and the aqueous phase was extracted with dichloromethane (100 mL×3), the organic phases were combined and distilled under reduced pressure, the residue was purified by column chromatography (eluent: methanol:dichloromethane=1:200-1:100-1:50) to obtain title product (9.55 g) with a yield of 80.9%.

[0416] MS m/z (LC-MS): 492.2 [M+1].

[0417] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 11.43 (d, 1H), 7.71 (d, 1H), 7.47 (d, 2H), 7.40-7.33 (m, 2H), 7.05 (d, 2H), 6.99-6.84 (m, 1H), 6.12 (d, 1H), 6.64-5.73 (dd, 1H), 5.40 (d, 1H), 4.75 (s, 2H), 4.60-4.35 (m, 1.5H), 4.08 (d, 0.5H), 3.21-3.13 (m, 1H), 2.67 (t, 1H), 2.25-2.13 (m, 2H), 1.86 (m, 1H), 1.52 (m, 1H).

[0418] Although the specific embodiments of the present disclosure are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims.