Synthesis method of 6-chloro-2, 8-dimethylimidazo [1, 2-B] pyridazine

Abstract

The invention discloses a synthesis method of 6-chloro-2, 8-dimethylimidazo [1, 2-B] pyridazine, which comprises the following steps: carrying out cyclization reaction on a compound shown as a formula I and a compound shown as a formula II or a formula III to generate a compound shown as a formula IV, and carrying out coupling reaction such as Negishi or Suzuki on the compound shown as the formula IV and a compound shown as a formula V to generate a compound shown as a formula VI. The synthesis method is high in yield, safe, environmentally friendly, low in material cost and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of pharmaceutical intermediates, and specifically relates to a method for synthesizing 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine. Background Art

[0002] In recent years, the 2,8-dimethylimidazo[1,2-b]pyridazine group, as a most critical structural fragment, has often been introduced into the drug skeleton structures for targeting the regulation of splicing genes. For example, Risdiplam (English name: Risdiplam, see the following structural formula) developed by Roche is a splicing modifier of the survival motor neuron 2 (SMN2) gene, and was approved by the US FDA on August 7, 2020 for the treatment of spinal muscular atrophy (SMA) in children and adult patients; on June 16, 2021, it was approved by the NMPA for marketing in China, and the trade name is Compound 1 (see the following structural formula, disclosed in CN115551593A) is a representative compound of a class of nucleic acid splicing modifiers being developed by Remix Therapeutics. It changes nucleic acids by increasing or decreasing splicing sites, thereby preventing or treating neurological diseases or disorders, autoimmune diseases or disorders, immunodeficiency diseases or disorders, etc. Compound 2 (see the following structural formula, disclosed in CN112805280A) and Compound 3 (see the following structural formula, disclosed in CN114245794A) are two representative active compounds with different parent nucleus structures being developed by PTC Therapeutics for the treatment of Huntington's disease (HD). This disease is caused by the uninterrupted expansion of the trinucleotide CAG repeat in the "mutant" Huntington (Htt) gene, which leads to the production of HTT (Htt protein) with an expanded polyglutamine (polyQ) fragment (also known as the "CAG repeat" sequence). Compound 4 (see the following structural formula, disclosed in WO2023092149A) is a representative compound being developed by Rgenta Therapeutics for regulating spliced mRNA. Compound 5 (see the following structural formula, disclosed in WO2023084011A) is a representative compound being developed by Remix Therapeutics for treating related diseases by regulating the expression of mRNA.

[0003]

[0004]

[0005] The 2,8-dimethylimidazo[1,2-b]pyridazine group is usually introduced into the backbone structure by coupling reactions such as Miyaura, Suzuki or Sonogashira using 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine. The prior art WO2017081111 reported a synthesis method for 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine, and the reaction formula is shown in Route 1 as follows:

[0006]

[0007] The synthesis method of Route 1 uses 3,6-dichloro-4-methylpyridazine as the starting material, and obtains Cpd 2 through an amination reaction. Cpd 2 undergoes a cyclization reaction with 1-bromo-2,2-dimethoxypropane to obtain Cpd 3. Although this scheme only has two steps, it has the following defects: (1) In the first amination reaction, when 3,6-dichloro-4-methylpyridazine reacts with ammonia water at 110 °C, a high-pressure reactor (about 100 psi) is required, which is dangerous. Moreover, the product obtained in this step is a mixture of Cpd 2 and its isomer Cpd 2-isomer, and the ratio of the two is about 1:1. Their properties are similar and difficult to separate, so they can only be directly fed into the next step. (2) In the second ring-closing reaction, it is carried out at a temperature as high as 105 °C. Under this condition, 1-bromo-2,2-dimethoxypropane is prone to produce black tar, and the product Cpd 3 and its isomer Cpd 3-isomer have similar properties and are difficult to separate. The literature reports that the yield is only 21% after purification by silica gel column chromatography.

[0008] The prior art WO2019057740 also reported a synthesis method for 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine, and the reaction formula is shown in Route 2 as follows:

[0009]

[0010] The synthetic method of Route 2 uses 3-amino-4-bromo-6-chloropyridazine (Cpd1) as the starting material. Through the Negishi coupling reaction, the methylation product Cpd 2 is obtained. Cpd 2 undergoes a cyclization reaction with chloroacetone to obtain Cpd 3. This synthetic scheme has the following defects: (1) In the first-step coupling reaction, methylmagnesium chloride preferentially reacts with the amino group of Cpd1 to produce 1 equivalent of methane. Methane is flammable, explosive and difficult to collect and process, which is very dangerous. Directly discharging it into the atmosphere seriously pollutes the environment. The primary amine proton of the reactant Cpd1 consumes the Grignard reagent, so the amount of methylmagnesium chloride used is as high as 2.73 equivalents. The obtained product intermediate Cpd 2 has a certain water solubility and is extremely hygroscopic. Moreover, the post-treatment of the reaction to obtain Cpd 2 requires complex operations such as extracting with acidic water and adjusting the acidic aqueous phase to alkaline to precipitate the product. The obtained product contains 5-10% salt and 5-10% water, and both the salt content and water content are relatively high, resulting in difficulty in storing the product. (2) In the second step of forming imidazole, Cpd2 and chloroacetone need to be refluxed at high temperature. Under such conditions, chloroacetone is prone to produce black tar, which is difficult to handle and affects the yield.

[0011] In summary, the synthetic methods of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine disclosed in the prior art have defects such as high danger, complex operation, low yield, and high cost. There is an urgent need in the art to develop a method for synthesizing 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine with low cost, simple operation, high yield and suitable for industrial production. Summary of the Invention

[0012] In view of the problems existing in the synthetic methods of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine in the prior art, the present invention provides a new synthetic method of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine. This synthetic method has low cost, simple operation, high yield and is suitable for industrial production. To achieve the purpose of the present invention, the following technical solutions are adopted in the present invention:

[0013] A synthetic method of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine, which comprises the following steps:

[0014] (1) React the compound of formula I with the compound of formula II or formula III to carry out a cyclization reaction to generate the compound of formula IV,

[0015] (2) React the compound of formula IV with the compound of formula V to carry out a coupling reaction to generate the compound of formula VI,

[0016] The reaction formulas are as follows:

[0017]

[0018] Wherein, in formula I, R 1is Cl, Br or I,

[0019] In Formulas II and III, R 2 is Cl, Br or I,

[0020] In Formula V, R 3 is a metal group, a methyl metal group or a halogen metal group, -B(OH) 2 or * is the connection position to the methyl carbon.

[0021] In another preferred example, in Formula I, R 1 is Br,

[0022] In another preferred example, in Formulas II and III, R 2 is Br,

[0023] In another preferred example, in step (1), the cyclization reaction is carried out in the presence of an inorganic base and an inorganic salt.

[0024] In another preferred example, in step (1), the inorganic base is selected from Cs 2 CO 3 、K 2 CO 3 、Na 2 CO 3 、Li 2 CO 3 、K 3 PO 4 、Na 3 PO 4 、K 2 HPO 4 、Na 2 HPO 4 、KHCO 3 、NaHCO 3 、KOH, NaOH, LiOH or a combination thereof.

[0025] In another preferred example, in step (1), the inorganic salt is selected from alkali metal halides.

[0026] In another preferred example, the alkali metal halides are selected from KCl, NaCl, LiCl, KBr, NaBr, LiBr, KI, NaI, LiI or a combination thereof.

[0027] In another preferred example, in step (1), the solvent used in the reaction is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, 3-methylfuran, 1,3-dioxolane, acetone, tetrahydropyran, 2-butanone, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, methanol, ethanol, isopropanol or a combination thereof.

[0028] In another preferred example, in step (1), when the raw material reacting with the compound of formula I is the compound of formula II, the reaction temperature is 30 - 65 °C, and when the raw material reacting with the compound of formula I is the compound of formula III, the reaction temperature is 60 - 95 °C.

[0029] In another preferred example, in formula V, R 3 is -Li, -MgBr, -MgCl, -BKF 3 , -ZnCl, -ZnBr, -MgCH 3 , -ZnCH 3 , -Al(CH 3 ) 2 , -Sn(CH 3 ) 3 , -B(OH) 2 or * is the connection position with the methyl carbon, more preferably, -ZnCH 3 or -MgCl.

[0030] In another preferred example, in step (2), the coupling reaction is carried out in the presence of a base, a transition metal catalyst and optionally a ligand. The transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, iron salts or iron organic complexes, nickel-containing salts or nickel organic complexes, or a combination thereof. The ligand is selected from phosphorus-containing ligands, amino acid-containing ligands, pyridine ring-containing ligands, or a combination thereof. The base is selected from organic bases or inorganic bases.

[0031] In another preferred example, in step (2), the transition metal catalyst is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ·CH 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dba) 2 , Pd 2 (dba) 3 , PdCl 2 , Ni(PPh 3) 2 Cl 2 、Pd(OAc) 2 、Ni(PPh 3 ) 4 、NiCl 2 、Ni(acac) 2 、Fe(acac) 3 or a combination thereof.

[0032] In another preferred example, in step (2), the ligand is selected from PPh 3 、XPhos、RuPhos、SPhos、XantPhos、BrettPhos、Me 4 t-BuXPhos、Mor-DalPhos、P(o-tolyl) 3 、PCy 3 、Dppp、Dppf or a combination thereof, more preferably PPh 3 .

[0033] In another preferred example, in step (2), the base is selected from Cs 2 CO 3 、Na 2 CO 3 、K 2 CO 3 、K 3 PO 4 、K 2 HPO 4 、Na 3 PO 4 、Na 2 HPO 4 、AcONa、AcOK、LiOH、KOH、NaOH、DMAP、Pyridine、TEA、DIPEA、DBU or a combination thereof, more preferably Cs 2 CO 3 .

[0034] In another preferred example, in step (2), the solvent used in the reaction is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydropyran, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene or a combination thereof.

[0035] In step (2), when the compound of formula V reacting with the compound of formula IV is a methyl metal, the reaction temperature is 0 - 45 °C; when the compound of formula V reacting with the compound of formula IV is a methyl halide metal, the reaction temperature is 20 - 60 °C; when the compound of formula V reacting with the compound of formula IV is methylboronic acid or methylboronic anhydride, the reaction temperature is 60 - 95 °C.

[0036] The present invention also provides a method for synthesizing an IV compound, and the synthesis method includes the steps:

[0037] (1) Subjecting a compound of formula I to a cyclization reaction with a compound of formula II or formula III in the presence of an inorganic base and an inorganic salt to form a compound of formula IV, and the reaction formula is as follows:

[0038]

[0039] Wherein, in formula I, R 1 is Cl, Br or I,

[0040] In formula II and formula III, R 2 is Cl, Br or I,

[0041] In another preferred embodiment, the inorganic base is selected from Cs 2 CO 3 、K 2 CO 3 、Na 2 CO 3 、Li 2 CO 3 、K 3 PO 4 、Na 3 PO 4 、K 2 HPO 4 、Na 2 HPO 4 、KHCO 3 、NaHCO 3 、KOH, NaOH, LiOH or a combination thereof,

[0042] In another preferred embodiment, the inorganic salt is selected from alkali metal halides.

[0043] In another preferred embodiment, the alkali metal halide is selected from KCl, NaCl, LiCl, KBr, NaBr, LiBr, KI, NaI, LiI or a combination thereof.

[0044] The present invention also provides a method for preparing risdiplam, compound 1, compound 2, compound 3, compound 4 or compound 5, and the preparation method includes the following steps:

[0045] (1) Subjecting a compound of formula I to a cyclization reaction with a compound of formula II or formula III to form a compound of formula IV,

[0046] (2) Subjecting a compound of formula IV to a coupling reaction with a compound of formula V to form a compound of formula VI,

[0047] The reaction formula is as follows:

[0048]

[0049] Among them, in formula I, R 1 is Cl, Br or I,

[0050] In formulas II and III, R 2 is Cl, Br or I,

[0051] In formula V, R 3 is a metal group, a methyl metal group, a halogen metal group, -B(OH) 2 or * is the connection position with the methyl carbon,

[0052] Among them, the structures of risdiplam, compound 1, compound 2, compound 3, compound 4 or compound 5 are shown as follows:

[0053]

[0054] In another preferred example, in step (1), the amination and dehydration condensation reaction is carried out in the presence of an inorganic base and an inorganic salt, and the inorganic salt is selected from alkali metal halides,

[0055] In step (2), the coupling reaction is carried out in the presence of a base, a transition metal catalyst and optionally a ligand. The transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, iron salts or iron organic complexes, nickel-containing salts or nickel organic complexes, or combinations thereof. The ligand is selected from phosphorus-containing ligands, amino acid-containing ligands, pyridine ring-containing ligands, or combinations thereof. The base is selected from organic bases and inorganic bases. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the HPLC chromatogram of the compound of formula IV-1 synthesized in Example 1;

[0057] Figure 2 is the 1 1H-NMR spectrum of the compound of formula IV-1 synthesized in Example 1;

[0058] Figure 3 is the HPLC chromatogram of the compound of formula IV-2 synthesized in Example 3;

[0059] Figure 4 is the 1 1H-NMR spectrum of the compound of formula IV-2 synthesized in Example 3;

[0060] Figure 5 is the HPLC chromatogram of the compound of formula VI synthesized in Example 6;

[0061] Figure 6 1H-NMR spectrum of the compound of Formula VI synthesized in Example 6 1 1H-NMR spectrum Detailed implementation mode

[0062] In view of the defects existing in the synthesis method of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine in the above-mentioned prior art, the inventors of the present application have found through in-depth research that the synthesis method of "ring closure first and then methylation" is more reasonable, and this synthesis method uses inexpensive and easily available compounds of Formula II or Formula III and commercially available compounds of Formula I as raw materials, undergoes a cyclization (ring closure) reaction to obtain Compound IV, and Compound IV undergoes a coupling reaction with a methylation reagent to obtain the target product. This synthesis method can obtain the target compound only through 2 steps, with low cost, safety and environmental protection, and simple operation. On this basis, the present invention has been completed.

[0063] Synthesis of Compound of Formula IV

[0064] In the present invention, Compound IV is synthesized through the following steps:

[0065] (1) React the compound of Formula I with the compound of Formula II or Formula III through a cyclization reaction to generate Compound IV,

[0066]

[0067] Among them, in Formula I, R 1 is Cl, Br or I,

[0068] In Formula II and Formula III, R 2 is Cl, Br or I.

[0069] In this step, the compound of Formula I and the compound of Formula II or III preferably undergo ring closure to form Compound IV in the presence of an inorganic salt and an inorganic base. The molar ratio of the compound of Formula I to the compound of Formula II or III is preferably 1:1.0 to 2.0, more preferably 1:1.5. The main function of the inorganic base is to extract protons and promote the occurrence of nucleophilic substitution and ring closure reactions. The inorganic base includes but is not limited to Cs 2 CO 3 、K 2 CO 3 、Na 2 CO 3 、Li 2 CO 3 、K 3 PO 4 、Na 3 PO 4 、K 2 HPO 4 、Na 2 HPO 4, KHCO 3 , NaHCO 3 , KOH, NaOH, LiOH. The amount of the inorganic base is the conventional amount for such reactions in the art. For example, the molar ratio of the inorganic base to the compound of formula I is 1 to 5:1, more preferably 1.5 to 2.5:1. The inorganic salt is preferably an alkali metal halide, and its main function is to inhibit the occurrence of the halogen exchange reaction. The alkali metal halides include but are not limited to KCl, NaCl, LiCl, KBr, NaBr, LiBr, KI, NaI, LiI. The amount of the inorganic salt is such that its molar ratio to the compound of formula I is 1 to 5:1, more preferably 1 to 1.5:1.

[0070] The solvents used in the reaction include but are not limited to N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, 3-methylfuran, 1,3-dioxolane, acetone, tetrahydropyran, 2-butanone, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, methanol, ethanol, isopropanol. The amount of the solvent is the conventional amount in the art, as long as the raw materials can be completely dissolved. Preferably, the weight-volume ratio of the compound of formula IV to the solvent is 50 to 90 g / L.

[0071] The reaction temperature of this step is related to the specific compounds of formula II and formula III used. When the raw material reacting with the compound of formula I is the haloacetone shown in formula II, the reaction temperature is about 30 to 65 °C, and the reaction time is about 2 to 6 h. When the raw material reacting with the compound of formula I is the dimethyl ketal shown in formula III, the reaction temperature is about 60 to 95 °C, and the reaction time is about 10 to 24 h. In this step, when using the compound of formula II to react with the compound of formula I, the reaction can be basically completed within 30 to 65 °C and 2 to 6 h. Under these reaction conditions (low temperature, short reaction time), basically no tar is produced from the haloacetone, and there are also few other impurities. In this step, when using the compound of formula III to react with the compound of formula I, the reaction can be basically completed below 90 °C. Under these reaction conditions, basically no tar is produced from the compound of formula III, and there are also few other impurities.

[0072] Synthesis of Compound of Formula VI

[0073] In the present invention, the compound of formula IV is synthesized through the following steps:

[0074] (2) React the compound of formula IV with the compound of formula V to undergo a coupling reaction to form the compound of formula VI,

[0075] The reaction formula is as follows:

[0076]

[0077] In formula V, R3 may be selected from a metal group, a methyl metal group or a halogen metal group, -B(OH) 2 or * is the connection position to the methyl carbon.

[0078] In this step, the compound of formula IV reacts with the compound of formula V in the presence of a base, a transition metal catalyst and optionally a ligand to form the compound of formula VI. The molar ratio of the compound of formula IV to the compound of formula V is preferably 1:1.0 - 5.0, more preferably 1:1 - 1.5.

[0079] The catalysts include but are not limited to Pd (palladium metal), palladium salts or palladium organic complexes, Cu (copper metal), copper salts or copper organic complexes, nickel-containing salts or nickel organic complexes. The molar ratio of the compound of formula IV to the catalyst is 1:0.0005 - 0.2, more preferably 1:0.001 - 0.01. The ligands include but are not limited to PPh 3 , XPhos, RuPhos, SPhos, XantPhos, BrettPhos, Me 4 t-BuXPhos, Mor-DalPhos, P(o-tolyl) 3 , PCy 3 , Dppp, Dppf, or a combination thereof.

[0080] "Optionally" means that it may or may not be present. For the ligand mentioned in this reaction step, when the catalyst itself contains a ligand or the ligand is not required to participate in the catalytic process of the catalyst, no ligand needs to be added to the reaction system in this step. For example, when using Pd(dppf)Cl 2 as the catalyst, no ligand needs to be added to the reaction system. When the catalyst itself does not contain a ligand and the ligand is required to participate in the catalytic process, a ligand needs to be added. When a ligand is added to the reaction system, the molar ratio of the amount of the ligand to the amount of the catalyst is 1 - 3:1. The organic solvents used in this step include but are not limited to N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydropyran, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene. The amount of the solvent used is the conventional amount in the art, as long as the raw materials can be completely dissolved. Preferably, the weight-volume ratio of the compound of formula VI to the solvent is 40 - 70 g / L.

[0081] The reaction temperature of this step is related to the specific compound of Formula V used. When the raw material reacting with the compound of Formula IV is methylzinc shown in Formula V, the reaction temperature is about 0 to 45 °C, such as 30 to 40 °C, and the reaction time is about 6 to 10 h. When the raw material reacting with the compound of Formula IV is methylmagnesium halide shown in Formula V, the reaction temperature is about 20 to 60 °C, such as 30 to 40 °C, and the reaction time is about 6 to 10 h. When the raw material reacting with the compound of Formula IV is methylboric anhydride shown in Formula V, the reaction temperature is about 60 to 95 °C, such as 80 to 90 °C, and the reaction time is about 15 to 20 h.

[0082] Compared with the prior art, the synthesis method of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine of the present invention has the following advantageous effects:

[0083] (a) The yield is greatly improved: The yields of steps (1) and (2) of the process reported in the prior art WO2019057740 are 66% and 76% respectively, and the total yield of the two steps is 50.8%; while the yields of steps (1) and (2) of the synthesis method of the present invention can reach 95% and 93% respectively, and the total yield of the two steps can reach 88.4%. Compared with this prior art, the yield is greatly improved. The main reason is that in the ring-closing step of step (1) of the synthesis method of the present invention, the compound of Formula I reacts with the halogenated ketone shown in Formula II or the dimethyl ketal shown in Formula III, and the reaction temperature is low. Under the reaction conditions of the present invention, almost no tar is produced during the reaction of the halogenated ketone or dimethyl ketal. In the coupling methylation step, the reactant Cpd2 in the prior art WO2019057740 contains a primary amine, and the primary amine is a strong electron-donating group, which is not conducive to the coupling reaction at the halogen position on the pyridazine ring, and dehalogenation impurities and dimethylation impurities are easily generated during the reaction at high temperature (50 to 60 °C); while in step (2) of the synthesis method of the present invention, the compound of Formula IV used contains a protected tertiary amine, and its electron-donating effect is significantly reduced, which is conducive to the coupling reaction at the halogen position on the pyridazine ring, and can smoothly carry out the coupling reaction with the metal methyl compound or methylmagnesium reagent at room temperature (for example, 30 to 40 °C), or can smoothly carry out the coupling reaction with methylboronic acid or methylboric anhydride at 80 to 90 °C, effectively inhibiting the generation of impurities and significantly improving the yield.

[0084] (b) Safe and environmentally friendly: In step (1) of the process reported in the prior art WO2019057740, methylmagnesium chloride reacts with the primary amine preferentially to generate 1 equivalent of methane, which is flammable, explosive and difficult to collect and treat, very dangerous, and directly discharged into the atmosphere, seriously polluting the environment. While in the synthesis method of the present invention, ring-closing is carried out first and then methylation. After ring-closing, the primary amine is protected and converted into a tertiary amine. During the methylation process, the tertiary amine does not react with the Grignard reagent and no methane is generated.

[0085] (c) Reduction in the amount of excipients: In step (1) of the process reported in the prior art WO2019057740, due to the proton consumption of the amino group by the Grignard reagent, the amount of methylmagnesium chloride used is as high as 2.73 equivalents. However, in the synthesis method of the present invention, only 1.3 equivalents of the Grignard reagent is required to complete the reaction.

[0086] (d) Simple post-treatment: The product in step (1) of the process reported in the prior art WO2019057740 (i.e., 3-amino-4-methyl-6-chloropyridazine) has a certain water solubility and is extremely hygroscopic. The post-treatment of the reaction solution in this step requires complex operations such as extraction with acidic water and adjusting the acidic aqueous phase to alkaline to precipitate the product. The resulting product has a salt content of 5 - 10% and a water content of 5 - 10%, both of which are relatively high, making it difficult to store the product. In the synthesis method of the present invention, the product in step (1) (e.g., 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine) is not hygroscopic, and a qualified product can be obtained by simple water washing.

[0087] (e) Reduction in the amount of catalyst: Palladium catalysts are relatively expensive. Placing them in the subsequent steps with a smaller amount is more reasonable.

[0088] (f) Control of halogen exchange impurities: Although relevant literature reports methods for synthesizing compounds of formula IV or their analogs from compounds of formula I or their analogs (see, WO2011051342, WO2016097347), that is, using inexpensive chloroacetone as a raw material and cyclizing it with 3-amino-4-bromo-6-chloropyridazine to obtain 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine, the proportion of halogen exchange impurities in the resulting product is about 30% and it is difficult to purify. The inventors of the present application, through process optimization, added the corresponding metal halide (halide salt) of the compound of formula II in the reaction, inhibited the halogen exchange reaction, and could control the halogen exchange impurity content to <0.1%.

[0089] As used herein, the term "room temperature" or "ambient temperature" refers to a temperature of 4 - 40 °C, preferably, 25 ± 5 °C.

[0090] "Metal group" refers to a metal connected to a methyl group, such as Li, which is directly connected to the methyl group of formula V in formula V.

[0091] "Methylmetal group" refers to a group formed by a methyl group and a metal connected to the methyl group, such as -MgCH 3 , -ZnCH 3 , -Al(CH 3 ) 2 or -Sn(CH 3 ) 3 , which is connected to the methyl group of formula V through the metal in formula V.

[0092] "Halogen metal group" refers to a group formed by a halogen element and a metal, such as -MgBr, -MgCl-, -ZnCl, -ZnBr, which is connected to the methyl group of Formula V through the metal in Formula V.

[0093] The present invention will be explained in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the essence and scope of the present invention are not limited thereto. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0094] In the following embodiments, the raw materials used are commercially available unless otherwise specified.

[0095] Example 1 Synthesis of Compound of Formula IV-1

[0096]

[0097] Under nitrogen protection, at 20-30 °C, add tetrahydrofuran (312 mL), isopropanol (31.2 mL), Compound of Formula I-1 (104.22 g, 0.5 mol), Compound of Formula II-1 (92.52 g, 1.0 mol) and lithium bromide (86.85 g) into the reaction kettle, heat up to 60-65 °C, after TLC detection shows that the conversion of the Compound of Formula I-1 is complete, cool down, concentrate to remove the solvent, add ethyl acetate (1042 mL) and saturated sodium chloride solution (521 mL) to the residue, separate the organic phase, and concentrate to obtain the residue. Add the residue to n-hexane for crystallization, and filter to obtain 114.62 g of light yellow solid, with a yield of 92.6% and a purity of 99.4%. 1 1H NMR (300 MHz, CDCl3): δ ppm: 7.77 (s, 1H), 7.11 (s, 1H), 2.52 (s, 3H). See Figure 2 。

[0098] Example 2 Synthesis of Compound of Formula IV-1

[0099]

[0100] Under nitrogen protection, at 20 - 30 °C, isopropyl acetate (416 mL), compound I-1 (104.22 g, 0.5 mol), and compound II-2 (102.6 g, 0.75 mol) were added to the reaction kettle. The temperature was raised to 60 - 65 °C. After the conversion of compound I-1 was detected to be complete by TLC, the temperature was lowered, and the solvent was concentrated to remove to obtain a residue. Ethyl acetate (1042 mL) and saturated sodium chloride solution (521 mL) were added to the residue, and the organic phase was separated and concentrated to obtain a residue. The residue was added to n-hexane for crystallization, and suction filtration was performed to obtain 117.08 g of a light yellow solid, with a yield of 94.4% and a purity of 99.2%.

[0101] Synthesis of Compound IV-2 in Example 3

[0102]

[0103] Under nitrogen protection, at 20 - 30 °C, absolute ethanol (815 mL), compound I-2 (163.99 g, 1.0 mol), compound II-1 (138.78 g, 1.5 mol), potassium chloride (82.0 g), and DIPEA (86.85 g) were added to the reaction kettle. The temperature was raised to 50 - 60 °C. After the conversion of compound I-2 was detected to be complete by TLC, the temperature was lowered, and the solvent was concentrated to remove to obtain a residue. Ethyl acetate (1640 mL) and saturated sodium chloride solution (656 mL) were added to the residue, and the organic phase was separated and concentrated to obtain a residue. The residue was added to n-hexane for crystallization, and suction filtration was performed to obtain 181.81 g of a light yellow solid, with a yield of 87.1% and a purity of 97.1%. 1 HNMR(300MHz,CDCl 3 )δppm:7.77(s,1H),7.13(s,1H),2.52(s,3H). See Figure 4 .

[0104] Synthesis of Compound IV-3 in Example 4

[0105]

[0106] Under nitrogen protection, at 20 - 30 °C, add dioxane (766 mL), compound I-3 (127.72 g, 0.5 mol), compound II-2 (102.74 g, 0.75 mol) and potassium iodide (51.37 g) into the reaction kettle. Heat up to 50 - 60 °C. After the conversion of compound I-3 is detected to be complete by TLC, cool down and concentrate to remove the solvent to obtain a residue. Add ethyl acetate (1277 mL) and saturated sodium chloride solution (512 mL) to the residue, separate the organic phase, and concentrate to obtain a residue. Add the residue into n-hexane for crystallization, filter by suction to obtain 130.6 g of light yellow solid, with a yield of 87.4% and a purity of 98.1%.

[0107] Synthesis of Compound IV-1 in Example 5

[0108]

[0109] Under nitrogen protection, at 20 - 30 °C, add isopropanol (500 mL), compound I-1 (104.22 g, 0.5 mol), compound III-1 (109.83 g, 1.0 mol) and pyridine p-toluenesulfonate (2.0 g) into the reaction kettle. Heat up to 80 - 90 °C. After the conversion of compound I-1 is detected to be complete by TLC, cool down and concentrate to remove the solvent to obtain a residue. Add ethyl acetate (1042 mL) and saturated sodium chloride solution (417 mL) to the residue, separate the organic phase, and concentrate to obtain a residue. Add the residue into n-hexane for crystallization, filter by suction to obtain 113.16 g of light yellow solid, with a yield of 90.6% and a purity of 98.6%.

[0110] Synthesis of Compound VI in Example 6

[0111]

[0112] Under nitrogen protection, at 20 - 30 °C, add tetrahydrofuran (1232 mL), compound IV-1 (123.25 g, 0.5 mol), tetrakis(triphenylphosphine)palladium (1.0 g) into the reaction kettle, and dropwise add a tetrahydrofuran solution (260 mL, 2 mol / L) of dimethylzinc (compound V-1). Heat up to 30 - 40 °C. After the conversion of compound IV-1 is detected to be complete by TLC, cool down and concentrate to remove the solvent to obtain a residue. Add ethyl acetate (1233 mL) and saturated sodium chloride solution (500 mL) to the residue, separate the organic phase, and concentrate to obtain a residue. Add the residue into n-hexane, stir well to dissolve, then cool down for crystallization, and filter by suction to obtain 84.5 g of light yellow solid, with a yield of 92.6% and a purity of 99.4%. 11H NMR (300 MHz, CDCl3) δ ppm: 7.66 (s, 1H), 6.84 (s, 1H), 2.67 (s, 3H), 2.49 (s, 3H). See Figure 6 。

[0113] Synthesis of Compound VI in Example 7

[0114]

[0115] Under nitrogen protection, at 20 - 30 °C, add tetrahydrofuran (1232 mL), Compound IV-1 (123.25 g, 0.5 mol), and diphenylphosphine dichloride palladium (1.0 g) to the reaction kettle. Dropwise add the tetrahydrofuran solution (180 mL, 3 mol / L) of methylmagnesium reagent (Compound V-2). Heat up to 30 - 40 °C. After TLC detection shows that the conversion of Compound IV-1 is complete, cool down and concentrate to remove the solvent. Add ethyl acetate (1233 mL) and saturated sodium chloride solution (500 mL) to the residue. Separate the organic phase and concentrate to obtain a residue. Add the residue to n-hexane, fully stir and dissolve it, then cool down to crystallize. Filter by suction to obtain 81.7 g of light yellow solid, with a yield of 89.0% and a purity of 98.9%.

[0116] Synthesis of Compound VI in Example 8

[0117]

[0118] Under nitrogen protection, at 20 - 30 °C, add dioxane (738 mL), Compound IV-1 (123.25 g, 0.5 mol), Pd(dppf)Cl 2 (1.0 g), cesium carbonate (360 g), trimethylcyclotriboroxane (Compound V-3, 100.0 g, 0.8 mol), and water (123 mL) to the reaction kettle. Heat up to 80 - 90 °C. After TLC detection shows that the conversion of Compound IV-1 is complete, cool down and concentrate to remove the solvent. Add ethyl acetate (1233 mL) and saturated sodium chloride solution (500 mL) to the residue. Separate the organic phase and concentrate to obtain a residue. Add the residue to n-hexane, fully stir and dissolve it, then cool down to crystallize. Filter by suction to obtain 68.1 g of light yellow solid, with a yield of 72.2% and a purity of 96.3%.

[0119] Synthesis of Compound VI in Example 9

[0120]

[0121] Under nitrogen protection, at 20 - 30 °C, add tetrahydrofuran (978 mL), compound of formula IV-3 (97.83 g, 0.33 mol), palladium acetate (1.0 g), tricyclohexylphosphine (2.0 g), and zinc chloride (15.0 g) to the reaction kettle. Dropwise add a tetrahydrofuran solution (120 mL, 3 mol / L) of methylmagnesium reagent (compound of formula V-2). Heat up to 30 - 40 °C. After TLC detection shows that the compound of formula IV-3 is completely converted, cool down, concentrate to remove the solvent. Add ethyl acetate (1000 mL) and saturated sodium chloride solution (500 mL) to the residue, separate the organic phase, and concentrate to obtain a residue. Add the residue to n-hexane, fully stir to dissolve, then cool down to crystallize, and filter by suction to obtain 52.1 g of a light yellow solid, with a yield of 85.5% and a purity of 98.2%.

[0122] Example 10 Synthesis of Compound of Formula VI

[0123]

[0124] Under nitrogen protection, at 0 - 10 °C, add tetrahydrofuran (616 mL), compound of formula IV-1 (61.6 g, 0.25 mol), Pd(dppf)Cl 2 (1.0 g) to the reaction kettle. Dropwise add a tetrahydrofuran solution (130 mL, 2 mol / L) of methyllithium (compound of formula V-4). Heat up to 30 - 40 °C. After TLC detection shows that the compound of formula IV-1 is completely converted, cool down, concentrate to remove the solvent. Add ethyl acetate (600 mL) and saturated sodium chloride solution (300 mL) to the residue, separate the organic phase, and concentrate to obtain a residue. Add the residue to n-hexane, fully stir to dissolve, then cool down to crystallize, and filter by suction to obtain 38.4 g of a light yellow solid, with a yield of 83.6% and a purity of 98.5%.

[0125] Example 11 Synthesis of Compound of Formula VI

[0126]

[0127] Under nitrogen protection, at 20 - 30 °C, add tetrahydrofuran (1232 mL), compound of formula IV-2 (101.12 g, 0.5 mol), diphenylphosphine dichloropalladium (1.0 g) to the reaction kettle. Dropwise add a tetrahydrofuran solution (180 mL, 3 mol / L) of methylmagnesium reagent (compound of formula V-2). Heat up to 30 - 40 °C. After TLC detection shows that the compound of formula IV-2 is completely converted, cool down, concentrate to remove the solvent. Add ethyl acetate (1000 mL) and saturated sodium chloride solution (400 mL) to the residue, separate the organic phase, concentrate, add n-hexane, cool down to crystallize, and filter by suction to obtain 78.1 g of a light yellow solid, with a yield of 85.2% and a purity of 99.0%.

[0128] All documents mentioned in this invention are cited herein by reference as if each individual document was cited by reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A method for synthesizing 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine, characterized in that, the preparation method comprises the following steps: (1) Subjecting a compound of formula I to a cyclization reaction with a compound of formula II or formula III to form a compound of formula IV, (2) Subjecting the compound of formula IV to a coupling reaction with a compound of formula V to form a compound of formula VI, The reaction formulas are as follows: Among them, in formula I, R 1 is Cl, Br or I, In Formulas II and III, R 2 is Cl, Br or I, In formula V, R 3 is a metal group, a methylmetal group or a halometal group, -B(OH) 2 or * is the connection position to the methyl carbon.

2. The synthesis method according to claim 1, characterized in that, in step (1), the cyclization reaction is carried out in the presence of an inorganic base and an inorganic salt.

3. The synthesis method according to claim 2, characterized in that, The inorganic base is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 , K 3 PO 4 , Na 3 PO 4 , K 2 HPO 4 , Na 2 HPO 4 , KHCO 3 , NaHCO 3 , KOH, NaOH, LiOH or a combination thereof, and / or the inorganic salt is selected from alkali metal halides, preferably, the alkali metal halide is selected from KCl, NaCl, LiCl, KBr, NaBr, LiBr, KI, NaI, LiI or a combination thereof.

4. The method according to claim 1, characterized in that, In formula V, R 3 is -Li, -MgBr, -MgCl, -BKF 3 , -ZnCl, -ZnBr, -MgCH 3 , -ZnCH 3 , -Al(CH 3 ) 2 , -Sn(CH 3 ) 3 , -B(OH) 2 or * is the connection position with the methyl carbon, more preferably, -ZnCH 3 or -MgCl.

5. The method according to claim 1, characterized in that, in step (2), the coupling reaction is carried out in the presence of a base, a transition metal catalyst and optionally a ligand, the transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, iron salts or iron organic complexes, nickel-containing salts or nickel organic complexes, or a combination thereof, the ligand is selected from phosphorus-containing ligands, amino acid-containing ligands, pyridine ring-containing ligands, or a combination thereof, the base is selected from organic bases or inorganic bases.

6. The synthesis method according to claim 5, characterized in that, The transition metal catalyst is selected from Pd(PPh 3 ) 4 、Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 、Pd(dba) 2 、Pd 2 (dba) 3 、PdCl 2 、Ni(PPh 3 ) 2 Cl 2 、Pd(OAc) 2 、Ni(PPh 3 ) 4 、NiCl 2 、Ni(acac) 2 、Fe(acac) 3 or a combination thereof, and / or The ligand is selected from PPh 3 , XPhos, RuPhos, SPhos, XantPhos, BrettPhos, Me 4 t-BuXPhos, Mor-DalPhos, P(o-tolyl) 3 , PCy 3 , Dppp, Dppf or a combination thereof, more preferably PPh 3 , and / or The base is selected from Cs 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 , K 2 HPO 4 , AcONa, AcOK, LiOH, KOH, NaOH, DMAP, pyridine, TEA, DIPEA, DBU or a combination thereof, more preferably Cs 2 CO 3 .

7. The synthesis method according to claim 1, characterized in that, in step (1), when the raw material reacting with the compound of formula I is the compound of formula II, the reaction temperature is 30-65 °C, and when the raw material reacting with the compound of formula I is the compound of formula III, the reaction temperature is 60-95 °C, and / or in step (2), when the compound of formula V reacting with the compound of formula IV is a methyl metal, the reaction temperature is 0-45 °C, and when the compound of formula V reacting with the compound of formula IV is a methyl halide metal, the reaction temperature is 20-60 °C; when the compound of formula V reacting with the compound of formula IV is methylboronic acid or methylboric anhydride, the reaction temperature is 60-95 °C.

8. A method for synthesizing a compound of formula IV, characterized in that, the synthesis method comprises the steps of: (1) Subjecting a compound of formula I to a cyclization reaction with a compound of formula II or formula III in the presence of an inorganic base and an inorganic salt to form a compound of formula IV, and the reaction formula is as follows: Among them, in formula I, R 1 is Cl, Br or I, In Formulas II and III, R 2 is Cl, Br or I, Preferably, the inorganic base is selected from Cs 2 CO 3 、K 2 CO 3 、Na 2 CO 3 、Li 2 CO 3 、K 3 PO 4 、Na 3 PO 4 、Na 2 HPO 4 、K 2 HPO 4 、NaHCO 3 、KHCO 3 、KOH, NaOH, LiOH or a combination thereof, Preferably, the inorganic salt is selected from alkali metal halides.

9. A method for preparing risdiplam, compound 1, compound 2, compound 3, compound 4 or compound 5, characterized in that, the preparation method comprises the following steps: (1) Subjecting a compound of formula I to a cyclization reaction with a compound of formula II or formula III to form a compound of formula IV, (2) Subjecting the compound of formula IV to a coupling reaction with a compound of formula V to form a compound of formula VI, The reaction formulas are as follows: Among them, in Formula I, R 1 is Cl, Br or I, In Formulas II and III, R 2 is Cl, Br or I, In formula V, R 3 is a metal group, a methyl metal group, a halogen metal group, -B(OH) 2 or * is the connection position to the methyl carbon, wherein the structures of risdiplam, compound 1, compound 2, compound 3, compound 4 or compound 5 are shown as follows:

10. The synthesis method according to claim 9, It is characterized in that in step (1), the cyclization reaction is carried out in the presence of an inorganic base and an inorganic salt, and the inorganic salt is selected from alkali metal halides. in step (2), the coupling reaction is carried out in the presence of a base, a transition metal catalyst and optionally a ligand. The transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, iron salts or iron organic complexes, nickel-containing salts or nickel organic complexes, or combinations thereof. The ligand is selected from phosphorus-containing ligands, amino acid-containing ligands, pyridine ring-containing ligands, or combinations thereof. The base is selected from organic bases or inorganic bases.

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