SYNTHESIS METHOD APPLIED TO KRAS INHIBITOR DRUG HETEROCYCLIC INTERMEDIATE

Abstract

The present application provides a compound of formula II and a method for preparing a compound of formula I, i.e., 2-iso-propyl-4-methylpyridin-3-amine by using the same. The compound of formula I can be applied to synthesis of KRAS inhibitor drugs. The raw materials involved in the method of the present application are easy to obtain and low in price, operation is easy and convenient, economization and environmental protection are achieved, and industrial production is facilitated.

##STR00001##

Claims

1-20. (canceled)

21. A process of preparing a compound of formula I from a compound of formula II, comprising converting an amide group to amino group from the compound of formula II through a rearrangement reaction to make the compound of formula I: ##STR00018##

21. The process of claim 21 wherein the converting comprises reacting the compound of formula II under conditions of Hoffman rearrangement reaction to obtain the compound of formula I, wherein the conditions of Hoffman rearrangement reaction comprise a mixed system of NaOBr and water.

22. The process of claim 21 wherein the NaOBr is form of an aqueous solution of NaOBr;

23. The process of claim 21 wherein the NaOBr is prepared by the following step: adding Br2 to a mixture of NaOH and water to obtain the NaOBr aqueous solution; wherein the mass ratio of NaOH to Br2 is 0.9:1; in the mixture of NaOH and water, the mass ratio of NaOH to water is 0.3:1; and the mass ratio of the compound of formula II to Br2 is 1:1; the molar ratio of the compound of formula II to NaOBr is (0.8-1.2):1.

24. The process of claim 21 wherein the mixed system of NaOBr and water is obtained by the following step: adding NaOBr to a mixture of the compound of formula II and water; wherein the adding is dripping; the adding is carried out at a temperature of −10° C. to 10° C.; in the mixture of the compound of formula II and water, the mass ratio of the compound II to the water is 0.5:1.

25. The process of claim 21 wherein the mass ratio of the total amount of water in the mixed system to the compound of formula II is 7:1.

26. The process of claim 21 wherein a rearrangement reaction is carried out at 10° C. to 100° C.

27. The process of claim 21 further comprising a process of work-up, and the process of work-up comprises the following steps after the rearrangement reaction is completed and results in a reaction mixture, adding an organic solvent to the reaction mixture for extraction and obtaining an organic phase, washing, concentrating, separating, and purifying the organic phase; wherein the organic solvent is ethyl acetate; the washing is conducted with saturated brine as a washing solvent; the separating and purifying are conducted with silica gel column chromatography.

28. The process of claim 21 further comprising hydrolyzing a compound of formula III with an acid to obtain the compound of formula II: ##STR00019##

29. The process of claim 28 wherein the acid is sulfuric acid, a mass ratio of the acid to the compound of formula III is 2.25:1, and the hydrolyzing is conducted at 105° C.

30. The process of claim 28 further comprising the following steps after the hydrolyzing: adding water to adjust the pH of a hydrolyzing reaction mixture resulted from the hydrolyzing to 10-11; filtering and drying to obtain the compound of formula II; the pH is adjusted by adding 50% sodium hydroxide aqueous solution; and the compound of formula II is directly used in the rearrangement reaction.

31. The process of claim 28 further comprising: conducting a Kumada coupling reaction of a compound of formula IV with isopropyl Grignard reagent in an organic solvent in presence of N-methylpyrrolidone and iron catalyst to obtain the compound of formula III: ##STR00020##

32. The process of claim 31 wherein the organic solvent is an ether solvent, the mass-volume ratio of the compound of formula IV to the organic solvent is 0.03-0.04 g/mL, the volume-to-mass ratio of said N-methylpyrrolidone to said compound of formula IV is 9.5:1, the iron catalyst is iron triacetylacetonate, the isopropyl Grignard reagent is isopropyl magnesium chloride solution in an ether solvent, the volume-to-mass ratio of said isopropyl Grignard reagent to said compound IV is (2.6-4.4):1; and the Kumada coupling reaction is conducted at 0˜10° C.

33. The process of claim 28 further comprising: after the completion of the Kumada coupling reaction, adding citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and an organic solvent in sequence to a Kumada coupling reaction mixture resulting from the Kumada coupling reaction to obtain an organic phase; extracting, concentrating, separating and purifying the organic phase to obtain the compound of formula III; wherein the organic solvent for extraction is an ester solvent; the separating and purifying are conducted via silica gel column chromatography.

34. The process of claim 28 further comprising: subjecting a compound of formula V to a cyclization reaction to obtain the compound of formula III: ##STR00021##

35. The process of claim 34 wherein the cyclization reaction comprises reacting the compound of formula V and an ammonia source followed by an intra-molecular substitution reaction to form the compound of formula III.

36. The process of claim 35 wherein the ammonia source is selected from the group consisting of ammonia gas, ammonium acetate, and ammonium chloride.

37. The process of claim 34 further comprising subjecting a compound of formula VI to a condensation reaction to obtain the compound of formula V: ##STR00022##

38. The process of claim 37 wherein the condensation reaction is conducted in the presence of N,N-dimethylformamide dimethyl acetal (DMF-DMA) or N,N-Dimethylformamide dimethyl sulfate adduct (DMF-DMS as a reactant.

39. The process of claim 38 further comprising subjecting the condensation reaction of compound VII to a condensation reaction with acetone to obtain the compound of formula VI: ##STR00023##

40. The process of claim 34 further comprising: step (1): in an organic solvent and in presence of basic alumina, subjecting a compound of formula VII to a condensation reaction with acetone to obtain a compound of formula VI; step (2): in an organic solvent, in presence of acetic anhydride and triethylamine, subjecting the compound of formula VI to a condensation reaction with N,N-dimethylformamide dimethyl sulfate condensate to obtain the compound of formula V: ##STR00024##

41. The process of claim 36 wherein the organic solvent in step (1) is an aromatic solvent; and/or, in step (1), the mass-volume ratio of the compound of formula VII to the organic solvent is 0.10-0.20 g/mL; and/or, in step (1), the mass ratio of the basic alumina to the compound VII is (2-4):1; and/or, in step (1), the temperature of the condensation reaction is 0-50° C.; and/or, step (1) also comprises a work-up process, wherein the work-up process comprises the following steps: when the condensation reaction is completed, filtering, washing the filter cake with the organic solvent, and combining the resulting filtrate directly used in step (2); and/or, in step (2), the organic solvent is an aromatic solvent; and/or, in step (2), the mass ratio of the N,N-dimethylformamide dimethyl sulfate condensate to the compound VII is (2-4):1; and/or, in step (2), the mass ratio of the acetic anhydride to the compound of formula VII is (0.1-0.4):1; and/or, in step (2), the mass-to-volume ratio of the triethylamine to the compound VII is 1-2 mL/g; and/or, in step (2), the temperature of the condensation reaction is 0˜50° C.; and/or, step (2) is the following step: acetic anhydride and triethylamine are sequentially added to the compound VI obtained in step (1) to condense with N,N-dimethylformamide dimethyl sulfate in the mixture of substances, the condensation reaction is carried out; wherein the temperature of adding acetic anhydride is 0˜10° C.; the temperature of adding triethylamine is 20-30° C.; and/or, step (2) also includes a work-up process, wherein the work-up process comprises the following steps: when the condensation reaction is completed, water is added and stirred, the layers are separated, the aqueous phase is extracted with an organic solvent, and the organic phases are combined Concentrate, separate and purify to obtain the compound V; the organic solvent for extraction can be dichloromethane; the separation and purification can be silica gel column chromatography.

42. A compound having a formula II, V, or VI or a salt thereof: ##STR00025## wherein, in formula V, the double bond connected with the dimethylamino group is in a form of Z, E, or a mixture of Z and E.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0079] The following embodiments describe the implementation of the present application, and those skilled in the art should realize that these specific embodiments only show the implementation technical solutions selected to achieve the purpose of this application and are not limitations on the technical solutions. According to the teaching of this application, the improvement of the technical solution of this application in combination with the prior art is obvious, which all fall within the protection scope of this application.

[0080] The implementation conditions employed by the embodiments may be further adjusted according to particular requirements, and undefined implementation conditions usually are conditions in conventional experiments.

[0081] Among them, the known chemical reagents used in the following embodiments are all commercially available chemical reagents.

[0082] In the exemplary implementations of the present disclosure, those skilled in the art can also make changes to the synthetic route, for example, change specific reaction conditions or adjust a certain step or several steps of the synthetic route as needed. Any changes made without departing from the substance of this application are within the protection scope of this application.

Example 1

[0083] ##STR00013##

[0084] To a 500 mL three-necked flask were added compound IV (6.0 g), THF (150 mL), NMP (57 mL) and Fe(acac).sub.3 (2.77 g). The reaction mixture was refilled with nitrogen for three times, cooled to 0˜10° C. .sup.iPrMgCl in THF (39 mL) was added to the reaction mixture dropwise at 0˜10° C. After being stirred for 30 mins, the reaction was quenched with citric acid aqueous solution (60 mL, 0.5 mol/L), followed by addition of saturated NaHCO.sub.3 aqueous solution (60 mL) and EtOAc (60 mL). The layers were separated. The aqueous layer was extracted with EtOAc (60 mL). The organic phases were combined and concentrated under reduced pressure. Compound 3 (3.59 g) was obtained as an oily liquid with a yield of 57% via column chromatography purification (EtOAc:n-heptane=1:6).

[0085] .sup.11H NMR for compound III:

[0086] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (d, J=5.1 Hz, 1H), 7.35 (dd, J=5.0, 0.8 Hz, 1H), 3.41 (m, J=6.8 Hz, 1H), 2.50 (s, J=0.6 Hz, 3H), 1.27 (d, J=6.8 Hz, 6H).

[0087] MS for compound III: [M+H].sup.+=161.1.

Example 2

[0088] ##STR00014##

[0089] To compound III (3.0 g) in a 50 mL reaction flask, concentrated sulfuric acid (6.76 g) was added dropwise. The mixture was heated to 105° C. and stirred for 4 h. After the reaction was completed, the reaction was cooled to 70˜75° C. Water (6 g) was added to the reaction. After 30 minutes, the reaction was cooled down to 0˜10° C. Water (21 g) and 50% sodium hydroxide aqueous solution were added to adjust the reaction mixture pH=10˜11. After 30 min, the mixture was filtered. The cake was dried at 50° C. to obtain off-white solid (2.5 g, 75% yield).

[0090] .sup.1H NMR for compound II:

[0091] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.38 (d, J=4.9 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.08 (d, J=4.7 Hz, 1H), 3.14 (m, 1H), 2.26 (s, 3H), 1.20 (d, J=6.8 Hz, 6H).

[0092] MS for compound II: [M+H].sup.+=179.1.

Example 3

[0093] ##STR00015##

[0094] To a mixture of NaOH (0.45 g) and water (1.5 mL) in a 25 mL round-bottom flask A, Br.sub.2 (0.5 g) was added dropwise in an ice-water bath. After being stirred for 10 min at room temperature, the resulting NaOBr aqueous solution was added to a mixture of compound II (0.5 g) and water (1 mL) in a 25 mL round-bottom flask B in an ice-water bath. After being stirred for 1.5 h at room temperature, water (1 mL) was added. The reaction mixture was heated to 80° C. and stirred for 1.5 h. After the reaction completed, the reaction was cooled to 20˜30° C., EtOAc (10 mL) was added. The layers were separated. The aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were washed with saturated brine (10 mL) and concentrated. The crude product was purified by column chromatography (EtOAc:n-heptane=1:2) to afford compound I (140 mg, 33% yield) as a pale yellow oily liquid.

[0095] .sup.11H NMR for compound I:

[0096] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.67 (d, J=4.7 Hz, 1H), 6.78 (d, J=4.6, 0.8 Hz, 1H), 4.72 (s, 2H), 3.19 (m, 1H), 2.08 (s, 3H), 1.15 (d, J=6.7 Hz, 6H).

[0097] MS for compound I: [M+H].sup.+=151.2.

Example 4

[0098] ##STR00016##

[0099] To a mixture of compound VII (5.0 g) and acetone (6.7 mL) in a 100 mL round-bottom flask A, basic Al.sub.2O.sub.3 (11.5 g) and toluene (30 mL) were added. The reaction was stirred at 20-30° C. for 24 hours. After the reaction was completed, the mixture was filtered. The cake was rinsed with toluene (20 mL), the filtrate was transferred to 250 mL round-bottom flask B. N,N-dimethylformamide dimethyl sulfate adduct (DMF-DMS) (15.4 g), acetic anhydride (0.92 g) was added. The mixture was cooled to 0-10° C., followed by addition of triethylamine (7.5 mL) dropwise. The reaction was stirred at 20-30° C. for 15 h. Water (40 mL) was added. The mixture was stirred for another 5 h. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phases were concentrated. The crude material was purified by column chromatography (EtOAc:n-heptane=1:10) to afford compound V (3.0 g, 32%) as a light yellow solid.

[0100] .sup.1H NMR for compound V:

[0101] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (d, J=12.8 Hz, 1H), 7.55 (d, J=12.8 Hz, 1H), 3.31 (d, J=2.2 Hz, 1H), 3.25 (s, 3H), 3.13 (m, 1H), 2.97 (s, 3H), 2.24 (s, 3H), 1.01 (dd, J=6.8, 3.6 Hz, 7H).

[0102] MS for compound V: [M+H].sup.+=207.1.

Example 5

[0103] ##STR00017##

[0104] A mixture of compound V (60 mg), methanol (1.8 mL), and ammonium acetate (0.22 g) in a 10 mL round-bottom flask was stirred at 20-30° C. for 5 days. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc:N-heptane=1:6) to afford compound III (23 mg, 50% yield) as an oily liquid.

[0105] .sup.1H NMR for compound III:

[0106] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (d, J=5.1 Hz, 1H), 7.35 (dd, J=5.0, 0.8 Hz, 1H), 3.41 (m, 1H), 2.50 (s, J=0.6 Hz, 3H), 1.27 (d, J=6.8 Hz, 6H).

[0107] MS for compound III: [M+H].sup.+=161.1.

[0108] This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the principle of the spirit of this application will be deemed to be within the protection scope of this application.