A method for synthesizing a lysopram intermediate and the lysopram intermediate

Abstract

The present invention discloses a method for synthesizing a key intermediate of risdiplam, which includes subjecting a compound of formula I to a coupling reaction with a compound of formula II to generate a novel compound of formula III, and after adding a compound of formula IV to the compound of formula III, cyclizing to form a compound of formula V. The synthesis method of the risdiplam intermediate of the present invention, i.e., the compound of formula V, is simple. Starting from the starting material, the compound of formula I, it can be obtained in only two steps. Moreover, the intermediate obtained by the method of the present invention is stable, facilitating impurity research and quality control, with low material costs and being suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a synthesis method of a risdiplam intermediate and a risdiplam intermediate. Background Art

[0002] Risdiplam (English name: Risdiplam) is a splicing modifier of survival motor neuron 2 (SMN2), which 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, NMPA approved its listing in China, and the trade name is Its structure is shown in the following formula:

[0003]

[0004] The prior art WO2015173181 reported a synthesis method of risdiplam, and the reaction formula is as follows:

[0005]

[0006] For the intermediate Cpd6 of this synthesis method, four steps of reaction are required using Cpd1 as the starting material. The first step of the reaction is carried out at a high temperature of 220 - 230 °C, which is relatively dangerous during scale-up production. Secondly, during scale-up synthesis, the yield of the chlorination reaction is relatively low, and the overall yield of the two steps is only 50%.

[0007] The prior art WO2019057740 reported a synthesis method of risdiplam, and the reaction formula is as follows:

[0008]

[0009] For the intermediate Cpd 9 of this synthesis method, five steps of reaction are required using Cpd3 and 4 as the starting materials, and precious metal catalysts are used in multiple steps, resulting in high costs.

[0010] The prior art WO2022194909 reported a synthesis method of risdiplam, and the reaction formula is as follows:

[0011]

[0012] For the intermediate compound Cpd11 of this synthesis method, six steps of reaction are required using Cpd1 as the starting material. The first step of the carbonylation reaction requires high-pressure equipment, and the intermediates Cpd3, Cpd4, Cpd5, etc. are unstable, making it difficult to establish an effective impurity control strategy, which poses a challenge to product quality control.

[0013] In summary, the existing synthesis techniques for lysopram intermediates generally have defects such as long synthesis routes, complex operations, and low yields. There is an urgent need in this field to develop a method for synthesizing lysopram intermediates that is low-cost, easy to operate, has a high yield, and is suitable for industrial production. Summary of the Invention

[0014] Aiming at the defects in the synthesis method of lysopram intermediates in the above-mentioned existing technologies, the present invention provides a new synthesis method for lysopram and its intermediates. The synthesis method of the present invention uses inexpensive and readily available raw materials, has short reaction steps, and the intermediates are stable, which is convenient for impurity research and quality control.

[0015] On the one hand, the present invention provides a compound having the following structural formula III:

[0016]

[0017] wherein R 3 is -COR 6 , -C(OR 7 ) 3 or N,N-dialkylaminocarbonyl, wherein R 6 is C 1 -C 8 alkoxy or benzyloxy, wherein R 7 is C 1 -C 6 alkyl, more preferably R 7 is C 1 -C 3 alkyl.

[0018] In another preferred embodiment, R 6 is C 1 -C 6 alkyl. In another preferred embodiment, R 7 is C 1 -C 3 alkyl.

[0019] In another more preferred embodiment, R 3 is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, n-butoxycarbonyl, -C(MeO) 3 , -C(EtO) 3 , N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl. In another more preferred embodiment, R 3 is methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, N,N-dimethylaminocarbonyl.

[0020] On the other hand, the present invention provides a method for synthesizing a compound of formula III:

[0021] Wherein, R 3 is as defined above,

[0022] The method includes the steps of: reacting a compound of formula I:

[0023] Wherein, R 1 is halogen, -S(O 2 )R 8 , -B(OR 9 ) 2 or a halogenated metal group, wherein R 8 is C 1 -C 6 alkyl or phenyl, wherein R 9 is H, C 1 -C 8 alkyl or a functional group containing an ether bond,

[0024] with a compound of formula II in a coupling reaction,

[0025] Wherein, R 2 is hydrogen, halogen, -Si(R 10 ) 3 , Li, -B(OR 11 ) 2 or a halogenated metal group, wherein R 10 is C 1 -C 6 alkyl or phenyl, wherein R 11 is H, C 1 -C 8 alkyl or a functional group containing an ether bond, wherein, R 3 is as defined above,

[0026] to obtain a compound of formula III.

[0027] In another more preferred example, R 9 is H or C 1 -C 6 alkyl. In another more preferred example, R 11 is H or C 1 -C 6 alkyl.

[0028] In another preferred example, R 1 is Cl, Br, I, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl, p-nitrophenylsulfonyl, -PdBr, -CuCl, a borate group or a borate ester group.

[0029] In another preferred example, R 2is H, Cl, Br, I, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, -Li, -ZnBr, -ZnCl, -ZnI, -PdBr, -PdCl, -PdI, boronic acid group or borate group.

[0030] In another preferred embodiment, the coupling reaction is carried out in the presence of a transition metal catalyst, a ligand and a base.

[0031] In another preferred embodiment, the transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, nickel salts or nickel organic complexes, or combinations thereof. In another more preferred embodiment, the catalyst is selected from Pd(PPh 3 ) 2 Cl 2 、Pd(PPh 3 ) 4 、Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 、Pd(OAc) 2 、Pd(dba) 2 、Pd 2 (dba) 3 、PdCl 2 、Pd(CN) 2 Cl 2 、Pd(PhCN) 2 Cl 2 、bis(triphenylphosphine)nickel chloride, tetrakis(triphenylphosphine)nickel, bis(triphenylphosphine)nickel dibromide, NiCl 2 、CuI, CuBr, CuCl, CuCN, CuOAc, or combinations thereof. In another more preferred embodiment, the catalyst is selected from Pd(PPh 3 ) 2 Cl 2 、Pd(PPh 3 ) 4 、Pd(dppf)Cl 2 、Pd(OAc) 2 、Pd(dba) 2 、PdCl 2 、bis(triphenylphosphine)nickel chloride, tetrakis(triphenylphosphine)nickel, CuI, CuBr, or combinations thereof.

[0032] In another preferred embodiment, the ligand is selected from phosphorus-containing ligands, amino acid-containing ligands, pyridine ring-containing ligands, or combinations thereof. In another more preferred embodiment, 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.

[0033] In another preferred example, the base is selected from inorganic bases. In another more preferred example, the base is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 or a combination thereof.

[0034] In another preferred example, the molar ratio of the transition metal catalyst to the compound of formula I is 0.01 - 0.5:1.

[0035] In another preferred example, the molar ratio of the compound of formula I to the compound of formula II is 1:1 - 3, more preferably 1:1.5 - 2.5.

[0036] In another preferred example, the molar ratio of the base to the compound of formula I is 2 - 6:1, more preferably 3 - 5:1.

[0037] In another preferred example, the solvent used in the above reaction is selected from tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, acetonitrile, toluene, dichloroethane, acetone, ether, methyl tert-butyl ether.

[0038] In another preferred example, the above reaction temperature is 40 - 70 °C, more preferably 40 - 50 °C.

[0039] On the other hand, the present invention provides a method for synthesizing a compound of formula V,

[0040] wherein, R 4 is a halogen, -S(O 2 )R 12 or wherein P 1 is hydrogen or a nitrogen protecting group and * represents the connection site,

[0041] The method includes the step of: reacting a compound of formula III:

[0042] wherein, R 3 is as defined above,

[0043] React with the compound of formula IV

[0044] wherein, R 4 As defined above, R 5 is hydrogen or -C(O)R 13 where R 13 is hydrogen, C 1 -C 8 alkyl, phenyl, C 1 -C 8 alkoxy or benzyloxy,

[0045] to obtain the compound of formula V.

[0046] In another more preferred example, R 12 is C 1 -C 6 alkyl or phenyl. In another more preferred example, R 13 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or benzyloxy.

[0047] In another preferred example, R 4 is -H, -Cl, -Br, -I, formyl, acetyl, propionyl, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrophenylsulfonyl, o-nitrophenylsulfonyl,

[0048] In another preferred example, R 5 is hydrogen, formyl, acetyl, propionyl, trifluoroacetyl, pivaloyl, p-methylbenzoyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl.

[0049] In another preferred example, the nitrogen protecting group is selected from tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, isopropyl, benzyl, p-methylbenzyl, p-bromobenzyl, 2,4-dimethoxybenzyl, etc., acetyl, trifluoroacetyl, benzoyl, p-methylbenzoyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, p-nitrophenylsulfonyl, trimethylsilyl, triethylsilyl.

[0050] In another preferred example, the reaction of the compound of formula IV with the compound of formula III is carried out in the presence of a base.

[0051] In another preferred example, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, calcium hydroxide, barium hydroxide, 4-dimethylaminopyridine, pyridine, imidazole, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0052] In another preferred example, in the reaction of the compound of formula IV with the compound of formula III, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8 to 1.5, more preferably 1:1.

[0053] In another preferred example, in the reaction of the compound of formula IV with the compound of formula III, the molar ratio of the compound of formula III to the base is 1:2 to 5, more preferably 1:2.5 to 3.5.

[0054] In another preferred example, the solvent used in the reaction of the compound of formula IV with the compound of formula III is a water-containing organic solvent, and the organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, or a combination thereof.

[0055] In another preferred example, the volume content of water in the water-containing organic solvent is 1 / 5 to 1 / 15, more preferably 1 / 8 to 1 / 12.

[0056] In another preferred example, the reaction temperature of the compound of formula IV with the compound of formula III is 40 to 100 °C, more preferably 50 to 60 °C.

[0057] On the other hand, the present invention provides a method for synthesizing risdiplam, which includes the steps of:

[0058] Reacting a compound of formula III,

[0059] wherein R 3 is as defined above,

[0060] with a compound of formula IV,

[0061] wherein R 4 is wherein P 1 is hydrogen or a nitrogen protecting group, and wherein R 5 is as defined above,

[0062] to obtain a compound of formula VII,

[0063]

[0064] When P 1 is hydrogen, the compound of formula VII is risdiplam,

[0065] When P 1 is a nitrogen protecting group, the synthesis process further includes removing the nitrogen protecting group to obtain risdiplam. Description of the Drawings

[0066] Figure 1 is the HPLC chromatogram of the compound of formula III-1 synthesized in Example 1;

[0067] Figure 2 is the 1 1H-NMR spectrum of the compound of formula III-1 synthesized in Example 1;

[0068] Figure 3 is the HPLC chromatogram of the compound of formula III-1 synthesized in Example 2;

[0069] Figure 4 is the HPLC chromatogram of the compound of formula V-1 synthesized in Example 9;

[0070] Figure 5 is the 1 1H-NMR spectrum of the compound of formula V-1 synthesized in Example 9; Detailed Description of the Invention

[0071] In view of the defects existing in the synthesis method of risdiplam in the prior art, the inventors of the present application have conducted in-depth research and found that using inexpensive and readily available substrate II and commercial substrate I as raw materials, an intermediate with a risdiplam skeleton fragment can be obtained through only two steps of reaction, greatly reducing the raw material cost of synthesizing risdiplam, and the intermediate is stable, which is convenient for impurity research.

[0072] Unless otherwise specified, the following terms used in the specification and claims have the meanings given below.

[0073] “C 1 -C 8 alkyl” refers to a branched or straight-chain hydrocarbon chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl or octyl. “C 1 -C 6 alkyl” refers to a branched or straight-chain hydrocarbon chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl. “C 1 -C 3 alkyl” refers to methyl, ethyl, n-propyl or isopropyl. “C 1 -C 8 alkoxy” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy. “C1 -C 6 "Alkoxy" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, pentyloxy, hexyloxy. "C 1 -C 3 -alkyl" such as methoxy, ethoxy, n-propoxy or isopropoxy.

[0074] In the description of the present invention, the alkyl group, phenyl group, benzyl group may be substituted or unsubstituted. "Substituted" means being substituted by halogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, phenoxy, nitro, cyano, amide group, etc.

[0075] "C 1 -C 6 -alkyl substituted amino group" means that the amino group can be substituted by one, two or three C 1 -C 6 -alkyl.

[0076] The term "halogen" refers to the substituents fluorine, chlorine, bromine or iodine.

[0077] The term "room temperature" refers to 4 to 40 °C, for example, 15 to 35 °C, 15 to 35 °C, 25 to 28 °C.

[0078] In the compound of formula III of the present invention, R 3 is a carbonyl-containing substituent -COR 6 , an orthoester-forming substituent -C(OR 7 ) 3 or an amide substituent N,N-dialkylaminocarbonyl.

[0079] In the compound of formula I of the present invention, R 1 is halogen, a sulfonyl-containing substituent -S(O 2 )R 8 , a boron-containing substituent -B(OR 9 ) 2 or a metal-halogen formed halo-metal group obtained by a Grignard reaction.

[0080] In the compound of formula II of the present invention, R 2 is hydrogen, halogen, a silicon-containing substituent -Si(R 10 ) 3 , Li, a boron-containing substituent -B(OR 9 ) 2 or a metal-halogen formed halo-metal group obtained by a Grignard reaction.

[0081] In the compound of formula V of the present invention, R 4 is a halogen, an acyl-containing substituent -C(O)R 12 a sulfonyl-containing substituent -S(O)R 12 or a substituent

[0082] In the compound of formula IV of the present invention, R 5 is hydrogen or a carbonyl-containing substituent -C(O)R 12 .

[0083] In the description of the present invention, the structure of "boronic acid group" is * represents the connection site.

[0084] In the description of the present invention, "boronic ester group" refers to an ester formed by the condensation of two hydroxyl groups on the boronic acid group with other hydroxyl groups, for example * represents the connection site.

[0085] Synthesis of the compound of formula III

[0086]

[0087] In this synthesis reaction process, the compound of formula I and the compound of formula II are first coupled in the presence of a catalyst, a ligand and a base, and then cyclized to form the compound of formula III. 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 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. The bases include but are not limited to Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 .

[0088] Although both R 1 and R 2 are optionally selected from halogens, their selection enables the coupling reaction of the compound of formula I and the compound of formula II.

[0089] The solvents used in the reaction include but are not limited to tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, isopropyl acetate, acetonitrile, toluene, dichloroethane, acetone, ether, methyl tert-butyl ether. 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-to-volume ratio of the compound of formula III to the solvent is 50-90 g / L.

[0090] Synthesis of the compound of formula V

[0091]

[0092] In the process of this synthesis reaction, the compound of formula III reacts with the compound of formula IV in the presence of a base to form the compound of formula IV. The role of the base is to abstract a proton to promote the Michael addition and the ring-closing reaction. The bases include but are not limited to potassium carbonate, sodium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, sodium hydroxide. The solvent used in the reaction is selected from water-containing organic solvents. The role of water is to increase the solubility of the base and promote the forward progress of the reaction. The volume content of water in the water-containing organic solvent enables the base to be fully dissolved in the reaction system. The volume content of water is preferably 1 / 5-1 / 15, more preferably 1 / 8-1 / 12. The organic solvents include but are not limited to N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-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-to-volume ratio of the compound of formula III to the solvent is 40-70 g / L.

[0093] The present invention will be explained in more detail below with reference to the examples. The examples 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. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0094] In the following examples, the raw materials used are commercially available unless otherwise specified. The synthesis of the compound of formula I refers to pages 54-57 of WO2019057740 and page 27 of WO2007033080.

[0095] Example 1 Synthesis of the compound of formula III-1

[0096]

[0097] Under nitrogen protection, at 20 - 30°C, add tetrahydrofuran (5.8 L), Compound I-1 (289.0 g), Compound II-2 (207.4 g), potassium carbonate (585.0 g), bis(triphenylphosphine)palladium(II) dichloride (4.34 g) and copper(I) iodide (20.16 g) into the reaction kettle. Heat up to 40 - 50°C. After the conversion of Compound I-1 is complete as detected by TLC, cool down the temperature, add ethyl acetate and saturated sodium chloride solution, separate the organic phase, concentrate it, and obtain 201.1 g of off-white solid by column chromatography with a yield of 78.2% and a purity of 98.26%. The HPLC spectrum is shown in Figure 1 ; 1 H NMR (300 MHz, CDCl 3 ) spectrum is shown in Figure 2 .

[0098] Synthesis of Compound III-1 in Example 2

[0099]

[0100] Under nitrogen protection, at 20 - 30°C, add methyltetrahydrofuran (5.9 L), Compound I-2 (295.0 g), Compound II-1 (196.1 g), potassium carbonate (552.8 g), bis(triphenylphosphine)palladium(II) dichloride (4.43 g) and copper(I) iodide (19.0 g) into the reaction kettle. Heat up to 40 - 50°C. Monitor the complete conversion of Compound I-1 by TLC, cool down to room temperature, add ethyl acetate and saturated sodium chloride solution, separate the organic phase, concentrate it, and obtain 184.9 g of off-white solid by column chromatography with a yield of 76.1% and a purity of 98.20%. The HPLC spectrum is shown in Figure 3 .

[0101] Synthesis of Compound III-1 in Example 3

[0102]

[0103] Under nitrogen protection, at 20 - 30°C, add tetrahydrofuran (382.0 mL), Compound I-3 (19.1 g), Compound II-2 (44.8 g), cesium carbonate (130.3 g) and palladium(II) acetate (0.29 g) into the reaction kettle. Heat up to 45 - 55°C. Monitor the complete conversion of Compound I-3 by TLC, cool down to room temperature, add ethyl acetate and saturated sodium chloride solution, separate the organic phase and concentrate it, and obtain 16.4 g of off-white solid by column chromatography with a yield of 67.4%.

[0104] Synthesis of Compound III-1 in Example 4

[0105]

[0106] Under nitrogen protection, DMF (2.9 L), Compound I-1 (144.5 g), Compound II-2 (103.7 g), potassium carbonate (292.5 g), nickel tetrakis(triphenylphosphine) (14.5 g), and CuCl (30.26 g) were added to the reaction kettle. The temperature was slowly raised to 40 - 50 °C. After the conversion of Compound I-1 was detected to be complete by TLC, the temperature was lowered to room temperature. Ethyl acetate and saturated sodium chloride solution were added. The organic phase was separated, concentrated, and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain 83.2 g of a off-white solid with a yield of 65.1% and a purity of 98.44%.

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

[0108]

[0109] Under nitrogen protection, at 20 - 30 °C, Dioxane (1.9 L), Compound I-1 (91.0 g), Compound II-2 (69.1 g), potassium carbonate (195.0 g), NiCl 2 (11.2 g), and CuBr (25.16 g) were added to the reaction kettle. The temperature was raised to 50 - 60 °C. After the conversion of Compound I-1 was detected to be complete by TLC, the temperature was lowered. Isopropyl acetate and saturated sodium chloride solution were added. The organic phase was separated, concentrated, and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain 55.8 g of a off-white solid with a yield of 69.1%.

[0110] Synthesis of Compound III-2 in Example 6

[0111]

[0112] Under nitrogen protection, at 20 - 30 °C, DMAc (5.46 L), Compound I-1 (273.0 g), Compound II-3 (258.32 g), potassium carbonate (585.0 g), bis(triphenylphosphine)palladium dichloride (5.46 g), and copper(I) iodide (20.16 g) were added to the reaction kettle. The temperature was slowly raised to 40 - 50 °C. After the conversion of Compound I-1 was detected to be complete by TLC, the temperature was lowered to room temperature. Ethyl acetate and saturated sodium chloride solution were added. The organic phase was separated, concentrated, and purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain 279.3 g of a off-white solid with a yield of 88.2% and a purity of 98.61%.

[0113] Synthesis of Compound III-1 in Example 7

[0114]

[0115] Under nitrogen protection, at 20 - 30 °C, add DMF (273 mL), Compound I-1 (27.3 g), Compound II-4 (20.0 g), potassium carbonate (20.7 g), Pd(CN) 2 Cl 2 (0.54 g) and cuprous iodide (1.06 g) into the reaction kettle. Slowly heat up to 40 - 50 °C. After TLC detection shows that the conversion of Compound I-1 is complete, cool down to room temperature, add ethyl acetate and saturated sodium chloride solution, separate the organic phase, concentrate, and obtain 18.7 g of off-white solid by column chromatography with a yield of 76.8%.

[0116] Synthesis of Compound III-3 in Example 8

[0117]

[0118] Under nitrogen protection, at 20 - 30 °C, add tetrahydrofuran (546.0 mL), Compound I-1 (27.3 g), Compound II-5 (19.4 g), potassium carbonate (55.3 g), bis(triphenylphosphine)palladium dichloride (0.41 g) and cuprous iodide (1.90 g) into the reaction kettle. Slowly heat up to 50 - 60 °C. Monitor the complete conversion of Compound I-4 by TLC, cool down to room temperature, concentrate, and obtain 19.7 g of off-white solid by column chromatography (eluent: PE / EA = 3 / 1) with a yield of 81.3%.

[0119] Synthesis of Compound V-1 in Example 9

[0120]

[0121] Under nitrogen protection, at 20 - 30 °C, add N,N-dimethylformamide (1728 mL), water (192 mL), potassium carbonate (81.8 g), Compound III-1 (96.0 g) and Compound IV-1 (68.2 g) into the reaction kettle. Heat up to 50 - 60 °C. Monitor the complete conversion of Compound III-1 by HPLC. Cool down the system, add pure water dropwise, filter by suction, and dry to obtain 120.0 g of yellow solid with a yield of 82.2% and a purity of 98.60%. The HPLC spectrum is shown in Figure 4 . The 1 HNMR (300 MHz, CDCl 3 ), see Figure 5 .

[0122] Synthesis of Compound V-1 in Example 10

[0123]

[0124] Under nitrogen protection, at 20 - 30 °C, add N,N-dimethylformamide (218 mL), pure water (24 mL), potassium phosphate (15.8 g), compound III-2 (12.1 g) and compound IV-1 (8.60 g) to the reaction kettle. Slowly heat the system to 50 - 60 °C. After the conversion of compound III-2 is complete as detected by TLC, cool the system to room temperature, add pure water dropwise, stir for 15 min, filter by suction. Wash the filter cake with water and isopropanol successively, and dry in vacuum to obtain 14.6 g of yellow solid, with a yield of 79.0% and a purity of 99.11%.

[0125] Synthesis of Compound V-2 in Example 11

[0126]

[0127] Under nitrogen protection, at 20 - 30 °C, add N,N-dimethylformamide (438 mL), pure water (48 mL), DBU (20.7 g), compound III-1 (24.3 g) and compound IV-2 (32.2 g) to the reaction kettle. Heat to 50 - 60 °C. After the conversion of compound III-1 is complete as detected by TLC, cool the system to room temperature, add pure water dropwise, filter by suction, and dry to obtain 28.9 g of solid, with a yield of 78.3%.

[0128] Synthesis of Compound V-3 in Example 12

[0129]

[0130] The synthesis of compound IV-3 refers to the methods disclosed in the prior art WO2019057740 or WO2022194909. Specifically as follows:

[0131] Under nitrogen protection, at 20 - 30 °C, add N,N-dimethylformamide (864.0 mL), pure water (70.0 mL), potassium carbonate (41.5 g), compound III-1 (48.6 g) and compound IV-3 (60.9 g) to the reaction kettle. Heat to 50 - 60 °C and react for 7 - 8 hours. Monitor the conversion of compound III-1 by TLC. After the conversion is complete, cool the system to room temperature, add pure water and dichloromethane, let it stand, separate the organic phase, concentrate to dryness, and perform column chromatography to obtain 70.0 g of yellow solid, with a yield of 70.2% and a purity of 99.11%.

[0132] Synthesis of Risdiplam in Example 13

[0133]

[0134] Under nitrogen protection, at 20 - 30 °C, add N,N-dimethylformamide (864.0 mL), water (70.0 mL), potassium carbonate (41.5 g), compound of formula III-1 (48.6 g) and compound of formula IV-4 (40.8 g) into the reaction kettle. Heat up to 50 - 60 °C. Monitor by TLC until the conversion of the compound of formula III-1 is complete. Cool the system to room temperature, add water and dichloromethane, let it stand, separate the organic phase, concentrate to dryness, and perform column chromatography (the eluent is DCM / MeOH) to obtain 58.8 g of solid, with a yield of 73.3% and a purity of 99.61%.

[0135] All documents mentioned in the present invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound having the following structural formula III: wherein R 3 is -COR 6 , -C(OR 7 ) 3 , N,N-dimethylaminocarbonyl or N,N-diethylaminocarbonyl, wherein R 6 is C 1 -C 8 alkoxy or benzyloxy, R 7 is C 1- C 6 alkyl.

2. The compound having the structural formula III as described in claim 1, wherein R 3 is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, n-butoxycarbonyl, -C(MeO) 3 or -C(EtO) 3 .

3. A method for synthesizing the compound of formula III, wherein, R 3 As defined in claim 1, characterized in that the method comprises the step of reacting a compound of formula I Among them, R 1 is halogen, -S(O 2 )R 8 , -B(OR 9 ) 2 or a halogenated metal group, where R 8 is C 1 -C 6 alkyl or phenyl, where R 9 is H or C 1 -C 8 alkyl, with a compound of formula II in a coupling reaction, Wherein, R 2 is hydrogen, a halogen, -Si(R 10 ) 3 , Li, -B(OR 11 ) 2 or a halogenated metal group, wherein R 10 is C 1 -C 6 alkyl or phenyl, wherein R 11 is H or C 1 -C 8 alkyl, wherein, R 3 is as defined above. to obtain the compound of formula III, Among them, the C 1 -C 6 alkyl group, the C 1 -C 8 alkyl group and the phenyl group are substituted or unsubstituted, and the substituents are selected from halogen, C 1 -C 3 alkyl group, C 1 -C 3 haloalkyl group, C 1 -C 3 alkoxy group, phenoxy group, nitro group, cyano group, amide group or a combination thereof.

4. The method according to claim 3, characterized in that, R 1 is Cl, Br, I, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl, p-nitrophenylsulfonyl, -PdBr, -CuCl, borate or C 1 -C 8 borate group, and / or R 2 is H, Cl, Br, I, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, -Li, -ZnBr, -ZnCl, -ZnI, -PdBr, -PdCl, -PdI, borate or C 1 -C 8 borate group.

5. The method according to claim 3, characterized in that, the coupling reaction is carried out in the presence of a transition metal catalyst, a ligand and a base, the transition metal catalyst is selected from Pd, palladium salts or palladium organic complexes, Cu, copper salts or copper organic complexes, nickel salts, 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 inorganic bases.

6. The synthesis method according to claim 5, characterized in that, The catalyst is selected from Pd(PPh 3 ) 2 Cl 2 、Pd(PPh 3 ) 4 、Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 、Pd(OAc) 2 、Pd(dba) 2 、Pd 2 (dba) 3 、PdCl 2 、Pd(CN) 2 Cl 2 、Pd(PhCN) 2 Cl 2 、bis(triphenylphosphine) nickel chloride, tetrakis(triphenylphosphine) nickel, bis(triphenylphosphine) nickel dibromide, NiCl 2 、CuI, CuBr, CuCl, CuCN, CuOAc, or a combination thereof, and / or The base is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , Li 2 CO 3 or a combination thereof.

7. A method for synthesizing the compound of formula V, wherein, R 4 is a halogen, -S(O 2 )R 12 or wherein R 12 is -H, C 1 -C 6 alkyl or phenyl, wherein, P 1 is hydrogen or a nitrogen protecting group and * represents a connection site, the method comprises the step of reacting a compound of formula III wherein, R 3 as defined in claim 1, with a compound of formula IV, wherein, R 4 as defined above, R 5 is hydrogen or -C(O)R 13 wherein R 13 is hydrogen, C 1 -C 8 alkyl, phenyl, C 1 -C 8 alkoxy or benzyloxy, to obtain the compound of formula V, Wherein the C 1 -C 6 alkyl group, the C 1 -C 8 alkyl group and the phenyl group are substituted or unsubstituted, and the substituents are selected from halogen, C 1 -C 3 alkyl group, C 1 -C 3 haloalkyl group, C 1 -C 3 alkoxy group, phenoxy group, nitro group, cyano group, amide group or a combination thereof.

8. The method according to claim 7, characterized in that, R 4 -H, -Cl, -Br, -I, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrophenylsulfonyl, o-nitrophenylsulfonyl or and / or R 5 is hydrogen, formyl, acetyl, propionyl, trifluoroacetyl, pivaloyl, p-toluoyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, and / or the nitrogen protecting group is selected from tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, isopropyl, benzyl, p-methylbenzyl, p-bromobenzyl, 2,4-dimethoxybenzyl, etc., acetyl, trifluoroacetyl, benzoyl, p-methylbenzoyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, trimethylsilyl or triethylsilyl.

9. The method according to claim 7, characterized in that, the reaction of the compound of formula IV with the compound of formula III is carried out in the presence of a base.

10. The method according to claim 9, characterized in that, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, calcium hydroxide, barium hydroxide, 4-dimethylaminopyridine, pyridine, imidazole, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or combinations thereof.

11. The method according to claim 7, characterized in that, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8 to 1.5, and / or the molar ratio of the compound of formula III to the base is 1:2 to 5, and / or the reaction solvent is a water-containing organic solvent, and the organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, or combinations thereof, the reaction temperature is 40 to 100 °C.

12. The method according to claim 11, characterized in that, the molar ratio of the compound of formula III to the compound of formula IV is 1:1, the molar ratio of the compound of formula III to the base is 1:2.5 to 3.5, and / or the reaction temperature is 50 to 60 °C.

13. A method for synthesizing risdiplam, which comprises: reacting a compound of formula III, wherein, R 3 as defined in claim 1, with a compound of formula IV, wherein R 4 is wherein P 1 is a hydrogen or nitrogen protecting group, wherein R 5 is as defined in claim 7, to give a compound of formula VII When P 1 is hydrogen, the compound of formula VII is risdiplam, When P 1 is a nitrogen protecting group, the synthesis method further includes removing the nitrogen protecting group to obtain risdiplam.

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