Method for synthesizing risdiplam intermediate and risdiplam intermediate

Abstract

Disclosed is a method for synthesizing a risdiplam intermediate compound of formula V. The method comprises: carrying out a coupling reaction on a compound of formula I and a compound of formula II to generate a novel compound of formula III; and after addition of the compound of formula III and a compound of formula IV, performing a ring-closing reaction to generate the compound of formula V. The method for synthesizing the risdiplam intermediate of the present application is simple, wherein starting from the starting raw material compound of formula I, only two steps are needed to obtain said intermediate; the intermediate obtained by the method is stable, facilitating impurity research and quality control; and the material cost is low. Therefore, the method is suitable for industrial production.

Description

A synthesis method of lisapram intermediate and lisapram intermediate

[0001] This application claims the priority of Chinese patent application No. 202311011783.9, filed on August 11, 2023, and cites the full text of the above-mentioned Chinese application. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a synthesis method of a lisapram intermediate and the lisapram intermediate. Background Art

[0003] Risdiplam is a survival motor neuron 2 (SMN2) splicing modifier. It was approved by the U.S. FDA on August 7, 2020, for the treatment of spinal muscular atrophy (SMA) in children and adults. On June 16, 2021, the NMPA approved its marketing in China under the trade name of Aimanxin. Its structure is shown below:

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

[0005] The intermediate Cpd6 in this synthesis method, using Cpd1 as the starting material, requires four steps to obtain. The first step is carried out at a high temperature of 220-230°C, which is relatively dangerous when scaled up. The second step, the chlorination reaction, has a relatively low yield when scaled up, with the yield of the two steps being only 50%.

[0006] The prior art WO2019057740 reports a method for synthesizing lisapram, and the reaction formula is as follows:

[0007] The intermediate Cpd 9 in this synthesis method requires five reaction steps to obtain using Cpd 3 and 4 as starting materials, and precious metal catalysts are used in multiple steps, resulting in high costs.

[0008] The prior art WO2022194909 reports a synthesis method of lisapram, and the reaction formula is as follows:

[0009] The intermediate compound Cpd11 in this synthesis method, obtained using Cpd1 as the starting material, requires six reaction steps. The first carbonylation reaction requires high-pressure equipment, and the intermediates Cpd3, Cpd4, and Cpd5 are unstable, making it difficult to establish an effective impurity control strategy and posing challenges to product quality control.

[0010] In summary, the existing synthesis technology of lisapram intermediates generally has defects such as long synthesis route, complex operation and low yield. There is an urgent need in the art to develop a method for the industrial production of lisapram intermediates with low cost, simple operation, high yield and suitability.

[0011] Summary of the Invention

[0012] In response to the defects of the above-mentioned prior art methods for synthesizing lisapram intermediates, the present invention provides a novel method for synthesizing lisapram and its intermediates. The synthesis method of the present invention utilizes cheap and readily available raw materials, has a short reaction process, and produces stable intermediates, which facilitates impurity research and quality control.

[0013] In one aspect, the present invention provides a compound having the following structural formula III:

[0014] Wherein R3 is -COR6, -C(OR7)3 or N,N-dialkylaminocarbonyl, wherein R6 is C1-C8 alkoxy or benzyloxy, wherein R7 is C1-C6 alkyl, more preferably R7 is C1-C3 alkyl.

[0015] In another preferred embodiment, R6 is a C1-C6 alkyl group. In another preferred embodiment, R7 is a C1-C3 alkyl group.

[0016] In another more preferred embodiment, R3 is methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, benzyloxycarbonyl, n-butyloxycarbonyl, -C(OMe)3, -C(OEt)3, N,N-dimethylaminocarbonyl or N,N-diethylaminocarbonyl. In another more preferred embodiment, R3 is methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or N,N-dimethylaminocarbonyl.

[0017] Another aspect of the present invention provides a method for synthesizing a compound of formula III:

[0018] Wherein, R3 is as defined above,

[0019] The method comprises the steps of: making a compound of formula I:

[0020] wherein R1 is a halogen, -OS(O2)R8, -B(OR9)2 or a halogenated metal group, wherein R8 is a C1-C6 alkyl group or a phenyl group, wherein R9 is H, a C1-C8 alkyl group or a functional group containing an ether bond,

[0021] Carry out coupling reaction with compound of formula II,

[0022] Wherein, R2 is hydrogen, halogen, -Si(R 10 )3、Li、-B(OR11 )2 or a halogenated metal group, wherein R 10 is a C1-C6 alkyl group or a phenyl group, wherein R 11 is H, C1-C8 alkyl or a functional group containing an ether bond, wherein R3 is as defined above,

[0023] The compound of formula III is obtained.

[0024] In another more preferred embodiment, R9 is H or C1-C6 alkyl. In another more preferred embodiment, R 11 is H or C1-C6 alkyl.

[0025] In another preferred embodiment, R1 is Cl, Br, I, methanesulfonyloxy, isopropylsulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, p-nitrophenylsulfonyloxy, -MgBr, -ZnCl, boronic acid or boric acid ester.

[0026] In another preferred embodiment, R2 is H, Cl, Br, I, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, -Li, -ZnBr, -ZnCl, -ZnI, -MgBr, -MgCl, -MgI, boronic acid or boronic ester.

[0027] In another preferred embodiment, the coupling reaction is carried out in the presence of a transition metal catalyst, a ligand and a base.

[0028] In another preferred embodiment, the transition metal catalyst is selected from Pd, a palladium salt or a palladium organic complex, Cu, a copper salt or a copper organic complex, a nickel salt or a nickel organic complex, or a combination thereof. In another more preferred embodiment, the catalyst is selected from Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2, Pd(CN)2Cl2, Pd(PhCN)2Cl2, bis(triphenylphosphine)nickel chloride, tetrakis(triphenylphosphine)nickel, bis(triphenylphosphine)nickel dibromide, NiCl2, CuI, CuBr, CuCl, CuCN, CuOAc, or a combination thereof. In another more preferred embodiment, the catalyst is selected from Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd(dba)2, PdCl2, bis(triphenylphosphine)nickel chloride, tetrakis(triphenylphosphine)nickel, CuI, CuBr, or a combination thereof.

[0029] In another preferred embodiment, the ligand is selected from a phosphorus-containing ligand, an amino acid-containing ligand, a pyridine ring-containing ligand, or a combination thereof. In another more preferred embodiment, the ligand is selected from PPh3, XPhos, RuPhos, SPhos, XantPhos, BrettPhos, Me4t-BuXPhos, Mor-DalPhos, P(o-tolyl)3, PCy3, Dppp, Dppf, or a combination thereof.

[0030] In another preferred embodiment, the base is selected from an inorganic base. In another more preferred embodiment, the base is selected from Cs2CO3, K2CO3, Na2CO3, Li2CO3 or a combination thereof.

[0031] In another preferred embodiment, the molar ratio of the transition metal catalyst to the compound of formula I is 0.01 to 0.5:1.

[0032] In another preferred embodiment, 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.

[0033] In another preferred embodiment, the molar ratio of the base to the compound of formula I is 2-6:1, more preferably 3-5:1.

[0034] In another preferred embodiment, 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, diethyl ether, and methyl tert-butyl ether.

[0035] In another preferred embodiment, the reaction temperature is 40-70°C, more preferably, 40-50°C.

[0036] Another aspect of the present invention provides a method for synthesizing a compound of formula V,

[0037] Wherein, R4 is halogen, -OS(O2)R 12 or Wherein P1 is a hydrogen or nitrogen protecting group and * indicates the attachment site,

[0038] The method comprises the steps of: making a compound of formula III:

[0039] Wherein, R3 is as defined above,

[0040] reacting with a compound of formula IV,

[0041] Wherein, R4 is as defined above, R5 is hydrogen or -C(O)R 13 , where R13 is hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkoxy or benzyloxy,

[0042] The compound of formula V is obtained.

[0043] In another more preferred embodiment, R 12 is C1-C6 alkyl or phenyl. In another more preferred embodiment, R 13 It is hydrogen, C1-C6 alkyl, C1-C6 alkoxy or benzyloxy.

[0044] In another preferred embodiment, R4 is -H, -Cl, -Br, -I, formyloxy, acetoxy, propionyloxy, methanesulfonyloxy, isopropylsulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrophenylsulfonyloxy, o-nitrobenzenesulfonyloxy,

[0045] In another preferred embodiment, R5 is hydrogen, formyl, acetyl, propionyl, trifluoroacetyl, pivaloyl, p-methylbenzoyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl.

[0046] In another preferred embodiment, the nitrogen protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, isopropyl, benzyl, p-methylbenzyl, p-bromobenzyl, 2,4-dimethoxybenzyl, acetyl, trifluoroacetyl, benzoyl, p-methylbenzoyl, methylsulfonyl, trifluoromethylsulfonyl, p-methylphenylsulfonyl, p-nitrobenzenesulfonyl, trimethylsilyl, and triethylsilyl.

[0047] In another preferred embodiment, the reaction of the compound of formula IV with the compound of formula III is carried out in the presence of a base.

[0048] In another preferred embodiment, 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.

[0049] In another preferred embodiment, in the reaction between the compound of formula IV and the compound of formula III, the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8-1.5, more preferably 1:1.

[0050] In another preferred embodiment, in the reaction of the compound of formula IV and the compound of formula III, the molar ratio of the compound of formula III to the base is 1:2-5, more preferably 1:2.5-3.5.

[0051] In another preferred embodiment, the solvent used in the reaction of the compound of formula IV and the compound of formula III is an aqueous 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.

[0052] In another preferred embodiment, the volume content of water in the aqueous organic solvent is 1 / 5 to 1 / 15, more preferably 1 / 8 to 1 / 12.

[0053] In another preferred embodiment, the reaction temperature of the compound of formula IV and the compound of formula III is 40-100°C, more preferably, 50-60°C.

[0054] In another aspect, the present invention provides a method for synthesizing lisapram, comprising the steps of:

[0055] The compound of formula III,

[0056] Wherein, R3 is as defined above,

[0057] reacting with a compound of formula IV,

[0058] Where R4 is wherein P1 is hydrogen or a nitrogen protecting group, and wherein R5 is as defined above, to obtain a compound of formula VII,

[0059] When P1 is hydrogen, the compound of formula VII is lisapram,

[0060] When P1 is a nitrogen protecting group, the synthesis process further comprises removing the nitrogen protecting group to obtain lisapram. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] FIG1 is an HPLC spectrum of the compound of formula III-1 synthesized in Example 1;

[0062] Figure 2 is a diagram of the compound of formula III-1 synthesized in Example 1 1 H-NMR spectrum;

[0063] FIG3 is an HPLC spectrum of the compound of formula III-1 synthesized in Example 2;

[0064] FIG4 is an HPLC spectrum of the compound of formula V-1 synthesized in Example 9;

[0065] Figure 5 is a diagram of the compound of formula V-1 synthesized in Example 9 1 H-NMR spectrum; DETAILED DESCRIPTION

[0066] In view of the defects in the synthesis methods of lisapram in the prior art, the inventors of the present application have discovered through in-depth research that an intermediate having a lisapram skeleton fragment can be obtained by using cheap and readily available substrate II and commercial substrate I as raw materials in just two steps of reaction, which greatly reduces the raw material cost of synthesizing lisapram. In addition, the intermediate is stable, which facilitates impurity research.

[0067] Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below.

[0068] "C1-C8 alkyl" refers to a branched or straight hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl or octyl. "C1-C6 alkyl" refers to a branched or straight hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl. "C1-C3 alkyl" refers to methyl, ethyl, n-propyl or isopropyl. "C1-C8 alkoxy" refers to methoxy, ethoxy, n-propoxy, isopropyl, n-butoxy, isobutyl, sec-butoxy and tert-butoxy, pentyl, hexyl, heptyl or octyl. "C1-C6 alkoxy" refers to methoxy, ethoxy, n-propoxy, isopropyl, n-butoxy, isobutyl, sec-butoxy and tert-butoxy, pentyl, hexyl. "C1-C3 alkyl" is, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

[0069] In the present invention, alkyl, phenyl, and benzyl groups may be substituted or unsubstituted. "Substituted" refers to substitution with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amide, or the like.

[0070] The "C1-C6 alkyl-substituted amino group" means that the amino group may be substituted by one, two or three C1-C6 alkyl groups.

[0071] The term "halogen" refers to the substituents fluorine, chlorine, bromine, or iodine.

[0072] The term "room temperature" refers to 4 to 40°C, for example, 15 to 35°C, 15 to 35°C, 25 to 28°C.

[0073] In the compound of formula III of the present invention, R3 is a carbonyl-containing substituent -COR6, an orthoester-formed substituent -C(OR7)3, or an amide substituent N,N-dialkylaminocarbonyl.

[0074] In the compound of formula I of the present invention, R1 is a halogen, a sulfonyloxy-containing substituent -OS(O2)R8, a boron-containing substituent -B(OR9)2, or a halogenated metal group formed by a metal obtained by a Grignard reaction and a halogen.

[0075] In the compound of formula II of the present invention, R2 is hydrogen, halogen, silicon-containing substituent -Si(R 10 )3, Li, a boron-containing substituent -B(OR9)2 or a halogenated metal group formed by a metal obtained by a Grignard reaction and a halogen.

[0076] In the compound of formula V of the present invention, R4 is halogen, the acyl-containing substituent -C(O)R 12 Sulfonyloxy-containing substituent -OS(O)R 12 or substituents

[0077] In the compound of formula IV of the present invention, R5 is hydrogen or a carbonyl-containing substituent -C(O)R 12 .

[0078] In the description of the present invention, the structure of "boronic acid group" is * indicates the attachment site.

[0079] In the description of the present invention, "boronic acid ester group" refers to an ester formed by condensation of two hydroxyl groups on the boric acid group with other hydroxyl groups, for example * indicates the attachment site.

[0080] Synthesis of compound of formula III

[0081] In this building-up reaction process, the compound of formula I and the compound of formula II are first coupled in the presence of a catalyst, a part and a base, and then the ring-closure forms the compound of formula III. The catalyst includes, but is not limited to, Pd (metal palladium), a palladium salt or a palladium organic complex, Cu (metal copper), a cuprate or a copper organic complex, a nickelous salt or a nickel organic complex. The part includes, but is not limited to, PPh , XPhos, RuPhos, SPhos, XantPhos, BrettPhos, Me t-BuXPhos, Mor-DalPhos, P(o-tolyl) , PCy , Dppp, Dppf, or a combination thereof. The base includes, but is not limited to, Cs CO , K CO , Na CO , Li CO .

[0082] Although both R1 and R2 may be selected from halogen, their selection enables the compound of formula I and the compound of formula II to undergo a coupling reaction.

[0083] The solvent used in the reaction includes, but is 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, diethyl ether, and methyl tert-butyl ether. The amount of solvent used is conventional in the art, sufficient to completely dissolve the raw materials. Preferably, the weight-to-volume ratio of the compound of Formula III to the solvent is 50-90 g / L.

[0084] Synthesis of compound of formula V

[0085] During this synthesis reaction, the compound of Formula III reacts with the compound of Formula IV in the presence of a base to produce the compound of Formula IV. The base acts to extract protons, promoting Michael addition and ring closure reactions. Such bases include, but are not limited to, potassium carbonate, sodium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, and sodium hydroxide. The solvent used in the reaction is selected from an aqueous organic solvent. The water increases the solubility of the base and promotes the forward reaction. The volume fraction of water in the aqueous organic solvent is sufficient to fully dissolve the base in the reaction system, and is preferably 1 / 5 to 1 / 15, more preferably 1 / 8 to 1 / 12. Such 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, and toluene. The amount of solvent used is conventional in the art, sufficient to completely dissolve the raw materials. Preferably, the weight-to-volume ratio of the compound of Formula III to the solvent is 40 to 70 g / L.

[0086] The present invention will be explained in more detail below in conjunction with embodiment. The embodiment of the present invention is only used to illustrate the technical solution of the present invention, and the spirit and scope of the present invention are not limited thereto. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

[0087] In the following examples, all raw materials used are commercially available unless otherwise specified. The synthesis of the compound of formula I is described in WO2019057740, pages 54-57 and WO2007033080, page 27.

[0088] Example 1 Synthesis of Compound of Formula III-1

[0089] Under nitrogen protection, tetrahydrofuran (5.8 L), the compound of formula I-1 (289.0 g), the compound of formula II-2 (207.4 g), potassium carbonate (585.0 g), bis(triphenylphosphine)palladium dichloride (4.34 g) and cuprous iodide (20.16 g) were added to the reaction kettle at 20-30° C., and the temperature was raised to 40-50° C. After TLC detection of complete conversion of the compound of formula I-1, the temperature was lowered, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and column chromatography was performed to obtain 201.1 g of an off-white solid with a yield of 78.2% and a purity of 98.26%. The HPLC spectrum is shown in Figure 1; 1 See Figure 2 for the H NMR (300 MHz, CDCl3) spectrum.

[0090] Example 2 Synthesis of Compound of Formula III-1

[0091] Under nitrogen protection, at 20-30°C, methyltetrahydrofuran (5.9 L), the compound of formula I-2 (295.0 g), the compound of formula II-1 (196.1 g), potassium carbonate (552.8 g), bis(triphenylphosphine)palladium dichloride (4.43 g) and cuprous iodide (19.0 g) were added to the reaction kettle, and the temperature was raised to 40-50°C. After monitoring the complete conversion of the compound of formula I-1 by TLC, the temperature was lowered to room temperature, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and column chromatography was performed to obtain 184.9 g of an off-white solid with a yield of 76.1% and a purity of 98.20%. See Figure 3 for the HPLC spectrum.

[0092] Example 3 Synthesis of Compound of Formula III-1

[0093] Under nitrogen protection, at 20-30°C, tetrahydrofuran (382.0 mL), a compound of formula I-3 (19.1 g), a compound of formula II-2 (44.8 g), cesium carbonate (130.3 g) and palladium acetate (0.29 g) were added to the reaction kettle, and the temperature was raised to 45-55°C. After monitoring the complete conversion of the compound of formula I-3 by TLC, the temperature was lowered to room temperature, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated and concentrated, and 16.4 g of an off-white solid was obtained by column chromatography with a yield of 67.4%.

[0094] Example 4 Synthesis of Compound of Formula III-1

[0095] Under nitrogen protection, DMF (2.9 L), the compound of formula I-1 (144.5 g), the compound of formula II-2 (103.7 g), potassium carbonate (292.5 g), tetrakistriphenylphosphine nickel (14.5 g) and CuCl (30.26 g) were added to the reactor, and the temperature was slowly raised to 40-50° C. After TLC detection of complete conversion of the compound of formula I-1, the temperature was lowered to room temperature, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and silica gel column chromatography (eluent: PE / EA=3 / 1) was used to obtain 83.2 g of an off-white solid with a yield of 65.1% and a purity of 98.44%.

[0096] Example 5 Synthesis of Compound of Formula III-1

[0097] Under nitrogen protection, at 20-30°C, Dioxane (1.9 L), the compound of formula I-1 (91.0 g, the compound of formula II-2 (69.1 g), potassium carbonate (195.0 g), NiCl2 (11.2 g) and CuBr (25.16 g) were added to the reaction kettle, and the temperature was raised to 50-60°C. After TLC detection of complete conversion of the compound of formula I-1, the temperature was lowered, isopropyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and subjected to silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain 55.8 g of an off-white solid with a yield of 69.1%.

[0098] Example 6 Synthesis of Compound of Formula III-2

[0099] Under nitrogen protection, DMAc (5.46 L), the compound of formula I-1 (273.0 g), the compound of formula II-3 (258.32 g), potassium carbonate (585.0 g), bis(triphenylphosphine)palladium dichloride (5.46 g) and cuprous iodide (20.16 g) were added to the reaction kettle at 20-30°C, and the temperature was slowly raised to 40-50°C. After TLC detection of complete conversion of the compound of formula I-1, the temperature was lowered to room temperature, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and subjected to silica gel column chromatography (eluent: PE / EA=3 / 1) to obtain 279.3 g of an off-white solid with a yield of 88.2% and a purity of 98.61%.

[0100] Example 7 Synthesis of Compound of Formula III-1

[0101] Under nitrogen protection, at 20-30°C, DMF (273 mL), the compound of formula I-1 (27.3 g), the compound of formula II-4 (20.0 g), potassium carbonate (20.7 g), Pd(CN)2Cl2 (0.54 g) and cuprous iodide (1.06 g) were added to the reactor, and the temperature was slowly raised to 40-50°C. After TLC detection of complete conversion of the compound of formula I-1, the temperature was lowered to room temperature, ethyl acetate and a saturated sodium chloride solution were added, the organic phase was separated, concentrated, and column chromatography was performed to obtain 18.7 g of an off-white solid with a yield of 76.8%.

[0102] Example 8 Synthesis of Compound of Formula III-3

[0103] Under nitrogen protection, at 20-30°C, tetrahydrofuran (546.0 mL), a compound of formula I-1 (27.3 g), a compound of formula II-5 (19.4 g), potassium carbonate (55.3 g), bis(triphenylphosphine)palladium dichloride (0.41 g) and cuprous iodide (1.90 g) were added to the reaction kettle, and the temperature was slowly raised to 50-60°C. After monitoring by TLC, the conversion of the compound of formula I-4 was complete. The reaction mixture was cooled to room temperature, concentrated, and subjected to column chromatography (eluent: PE / EA=3 / 1) to give 19.7 g of an off-white solid with a yield of 81.3%.

[0104] Example 9 Synthesis of Compound V-1

[0105] Under nitrogen protection, 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) were added to the reaction kettle at 20-30°C, and the temperature was raised to 50-60°C. HPLC monitoring showed that the conversion of the compound of formula III-1 was complete. The system was cooled, purified water was added dropwise, filtered, and dried to obtain 120.0 g of a yellow solid with a yield of 82.2% and a purity of 98.60%. The HPLC spectrum of the obtained product is shown in Figure 4. 1 H NMR (300 MHz, CDCl 3 ), see FIG5 .

[0106] Example 10 Synthesis of Compound V-1

[0107] Under nitrogen protection, N,N-dimethylformamide (218 mL), purified water (24 mL), potassium phosphate (15.8 g), compound III-2 (12.1 g) and compound IV-1 (8.60 g) were added to the reactor at 20-30°C, and the system was slowly heated to 50-60°C. After TLC detection showed that the compound of formula III-2 was completely converted, the system was cooled to room temperature, purified water was added dropwise, stirred for 15 minutes, and filtered. The filter cake was washed with water and isopropanol in turn, and vacuum dried to obtain 14.6 g of a yellow solid with a yield of 79.0% and a purity of 99.11%.

[0108] Example 11 Synthesis of Compound of Formula V-2

[0109] Under nitrogen protection, N,N-dimethylformamide (438 mL), purified water (48 mL), DBU (20.7 g), compound III-1 (24.3 g) and compound IV-2 (32.2 g) were added to the reactor at 20-30°C, and the temperature was raised to 50-60°C. After TLC detection, the conversion of the compound of formula III-1 was complete, the system was cooled to room temperature, purified water was added dropwise, filtered, and dried to obtain 28.9 g of solid with a yield of 78.3%.

[0110] Example 12 Synthesis of Compound of Formula V-3

[0111] The synthesis of compound IV-3 refers to the method disclosed in the prior art WO2019057740 or WO2022194909. The details are as follows:

[0112] Under nitrogen protection, at 20-30°C, N,N-dimethylformamide (864.0 mL), purified water (70.0 mL), potassium carbonate (41.5 g), a compound of formula III-1 (48.6 g) and a compound of formula IV-3 (60.9 g) were added to the reactor, and the temperature was raised to 50-60°C. The reaction was carried out for 7-8 hours. TLC monitored the complete conversion of the compound of formula III-1. The system was cooled to room temperature, purified water and dichloromethane were added, and the mixture was allowed to stand. The organic phase was separated, concentrated to dryness, and 70.0 g of a yellow solid was obtained by column chromatography with a yield of 70.2% and a purity of 99.11%.

[0113] Example 13 Synthesis of Risdiplam

[0114] Under nitrogen protection, 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) were added to the reactor at 20-30°C, and the temperature was raised to 50-60°C. TLC monitored the complete conversion of compound of formula III-1. The system was cooled to room temperature, water and dichloromethane were added, and the mixture was allowed to stand. The organic phase was separated, concentrated to dryness, and 58.8 solids were obtained by column chromatography (eluent: DCM / MeOH) with a yield of 73.3% and a purity of 99.61%.

[0115] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having the following structural formula III: wherein R3 is -COR6, -C(OR7)3 or N,N-dialkylaminocarbonyl, wherein R6 is C1-C8 alkoxy or benzyloxy, and R7 is C 1- C6 alkyl, 2. The compound according to claim 1, wherein R3 is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, n-butoxycarbonyl, -C(OMe)3, -C(OEt)3, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, more preferably, ethoxycarbonyl, -C(OMe)3 or N,N-dimethylaminocarbonyl.

3. A method for synthesizing a compound of formula III, in, R3 as defined in claim 1, The method comprises the steps of: making a compound of formula I Wherein, R1 is halogen, -OS(O2)R8, -B(OR9)2 or a halogenated metal group, wherein R8 is a C1-C6 alkyl group or a phenyl group, wherein R9 is H, a C1-C8 alkyl group or a functional group containing an ether bond, Carry out coupling reaction with the compound of formula II, Wherein R2 is hydrogen, halogen, -Si(R 10 )3、Li、-B(OR 11 )2 or a halogenated metal group, wherein R 10 is a C1-C6 alkyl group or a phenyl group, wherein R 11 is H, C1-C8 alkyl or a functional group containing an ether bond, wherein R3 is as defined above, The compound of formula III is obtained.

4. The method according to claim 3, wherein R1 is Cl, Br, I, methanesulfonyloxy, isopropylsulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, p-nitrophenylsulfonyloxy, -MgBr, -ZnCl, boric acid or borate, more preferably, I, boric acid or toluenesulfonyloxy.

5. The method according to claim 3, wherein R2 is H, Cl, Br, I, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, -Li, -ZnBr, -ZnCl, -ZnI, -MgBr, -MgCl, -MgI, boric acid or borate, more preferably, H, I, trimethylsilyl.

6. The synthesis method according to claim 3, wherein R1 is trifluoromethanesulfonyloxy, R2 is H, and R3 is ethoxycarbonyl, or R1 is I, R2 is H or trimethylsilyl, R3 is ethoxycarbonyl or -C(MeO)3 or N,N-dimethylaminocarbonyl, or R1 is a boronic acid group, R2 is I, and R3 is an ethoxycarbonyl group.

7. The method according to claim 3, wherein 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 salt or palladium organic complex, Cu, copper salt or copper organic complex, nickel salt or nickel organic complex, or a combination thereof. The ligand is selected from a phosphorus-containing ligand, an amino acid-containing ligand, a pyridine ring-containing ligand, or a combination thereof, and The base is selected from inorganic bases.

8. The synthesis method according to claim 7, wherein the catalyst is selected from Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2, Pd(CN)2Cl2, Pd(PhCN)2Cl2, bis(triphenylphosphine)nickel chloride, tetrakis(triphenylphosphine)nickel, bis(triphenylphosphine)nickel dibromide, NiCl2, CuI, CuBr, CuCl, CuCN, CuOAc, or a combination thereof, and / or The ligand is selected from PPh3, XPhos, RuPhos, SPhos, XantPhos, BrettPhos, Me4t-BuXPhos, Mor-DalPhos, P(o-tolyl)3, PCy3, Dppp, Dppf, or a combination thereof, and / or The base is selected from Cs2CO3, K2CO3, Na2CO3, Li2CO3 or a combination thereof.

9. A method for synthesizing a compound of formula V, in, R4 is halogen, -OS(O2)R 12 or Where R 12 is -H, C1-C6 alkyl or phenyl, wherein P1 is hydrogen or a nitrogen protecting group and * indicates a connection site, The method comprises the steps of: making a compound of formula III Wherein, R3 is as defined in claim 1, Reaction with a compound of formula IV, Wherein, R4 is as defined above, R5 is hydrogen or -C(O)R 13 , where R 13 is hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkoxy or benzyloxy, To obtain a compound of formula V, 10. The method according to claim 9, wherein R4 is H, Cl, Br, I, methanesulfonyloxy, isopropylsulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrophenylsulfonyloxy, o-nitrobenzenesulfonyloxy, More preferably, Br, p-toluenesulfonyloxy, 11. The method according to claim 9, wherein R5 is hydrogen, formyl, acetyl, propionyl, trifluoroacetyl, pivaloyl, p-methylbenzoyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, more preferably, hydrogen or methoxycarbonyl.

12. The method according to claim 9, wherein the nitrogen protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, isopropyl, benzyl, p-methylbenzyl, p-bromobenzyl, 2,4-dimethoxybenzyl, etc., acetyl, trifluoroacetyl, benzoyl, p-methylbenzoyl, methylsulfonyl, trifluoromethanesulfonyl, p-methylphenylsulfonyl, p-nitrobenzenesulfonyl, trimethylsilyl, triethylsilyl.

13. The method according to claim 9, wherein the reaction of the compound of formula IV with the compound of formula III is carried out in the presence of a base, more preferably 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.

14. The method according to claim 9, wherein the molar ratio of the compound of formula III to the compound of formula IV is 1:0.8-1.5, more preferably 1:1, and / or The molar ratio of the compound of formula III to the base is 1:2-5, preferably 1:2.5-3.5, and / or The solvent used in the reaction is an aqueous 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. The reaction temperature is 40-100°C, more preferably, 50-60°C.

15. A method for synthesizing lisapram, comprising: The compound of formula III, Wherein, R3 is as defined in claim 1, Reaction with a compound of formula IV, Where R4 is wherein P1 is hydrogen or a nitrogen protecting group, wherein R5 is as defined in claim 6, To obtain a compound of formula VII, When P1 is hydrogen, the compound of formula VII is lisapram, When P1 is a nitrogen protecting group, the synthesis process further comprises removing the nitrogen protecting group to obtain lisapram.

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