A synthetic method, intermediate and application of furoxidine

Abstract

The present invention discloses a synthesis method, intermediate and application of furoldesine, belonging to the field of organic drug synthesis. The raw materials for the synthesis method of furoldesine include the compounds shown in formula (I) and formula (Ra), wherein R<supgt;1< / supgt> is selected from substituted or unsubstituted alkyl, cycloalkyl; R<supgt;2< / supgt>, R<supgt;3< / supgt> are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R<supgt;4< / supgt> is selected from substituted or unsubstituted silyl; Ar<supgt;1< / supgt> is selected from substituted or unsubstituted aryl; X<supgt;1< / supgt> is selected from Cl, Br or I. This synthesis method can synthesize furoldesine through 5 steps of reactions, with convenient operation, high yield, no need for photocatalysis, and has broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of organic drug synthesis, and relates to a synthesis method, intermediate and application of forodesine, in particular to a synthesis method of forodesine or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and the application of the above synthesis method in pharmacy, the intermediate of forodesine, and the synthesis method and application of the intermediate. Background Art

[0002] Forodesine, also known as BCX-1777 and Immucillin-H, has the following chemical structural formula:

[0003] 。

[0004] Forodesine is a purine-nucleoside phosphorylase inhibitor (PNPI) and has potential value in the treatment of diseases such as leukemia, tumors, malaria, and gout. In 2017, forodesine was approved in Japan for the treatment of relapsed / refractory peripheral T-cell lymphoma.

[0005] Traditional forodesine synthesis methods use chiral five-membered ring imines as iminosugar precursors to form glycosidic bonds through C-nucleophilic reagent reactions. For example, Evans et al. proposed in the article "Improved Syntheses of 3H,5H-Pyrrolo[3,2-d]pyrimidines" (J. Org. Chem. 1999, 64, 22, 8411–8412) that the iminosugar precursor reacts with Li-based acetonitrile to form a glycosidic bond, and then the nitrile group is used as the starting point to construct a heterocycle.

[0006]

[0007] Furthermore, Evans et al. proposed an improved synthesis method of direct coupling of the iminosugar precursor with a Li-based heterocycle in the article "Addition of Lithiated 9-Deazapurine Derivatives to a Carbohydrate Cyclic Imine: Convergent Synthesis of the Aza-C-nucleoside Immucillins" (J. Org. Chem. 2001, 66, 17, 5723–5730).

[0008]

[0009] Both of the above methods involve chiral iminosugar precursors, and the structure of this precursor is unstable.

[0010] Ou Jingdan et al. disclosed a synthetic route of furapidil in the article "Synthesis of Purine Nucleoside Phosphorylase Inhibitor Furapidil" (West China Journal of Pharmaceutical Sciences, 2021, 36(5): 495-500). Using N-oxidized iminosugar as a precursor, the formation of glycosidic bond was achieved by blue photocatalysis.

[0011]

[0012] However, this technology requires the use of a photocatalyst, and the photocatalyst used is selected from the following structures.

[0013]

[0014] Compared with iminosugar precursors, ketose precursors have higher stability. However, it is difficult for existing technologies to provide a method for directly using ketose precursors with higher stability to form glycosidic bonds, thereby realizing the coupling of sugar precursors and heterocyclic precursors, and further realizing the synthesis of furapidil. Summary of the Invention

[0015] Aiming at the technical bottleneck that it is difficult for existing technologies to provide a method for directly using ketose precursors with higher stability to form glycosidic bonds, thereby realizing the coupling of sugar precursors and heterocyclic precursors, and further realizing the synthesis of furapidil, the purpose of the present invention is a synthetic method, intermediate and application of furapidil.

[0016] To achieve the above invention purpose, the technical solution of the present invention is as follows:

[0017] On the one hand, the present invention provides a synthetic method of furapidil or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and the raw materials include the compounds shown in formula (I) and formula (Ra);

[0018]

[0019] Among them, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl; X 1 is selected from Cl, Br or I.

[0020] Unless otherwise indicated, the term "alkyl" as used herein includes branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, including all isomers. Common abbreviations for alkyl groups such as methyl can be represented by "Me" or CH3, ethyl by "Et" or CH2CH3, propyl by "Pr" or CH2CH2CH3, butyl by "Bu" or CH2CH2CH2CH3, etc. For example, "C 1-4 alkyl" (or "C1-C4 alkyl") refers to straight-chain or branched-chain alkyl groups having a specific number of carbon atoms, including all isomers. C 1-4 alkyl includes n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl. The term "C 1-10 alkyl" etc. has a similar meaning. In addition, common abbreviations for alkyl groups also include: isopropyl can be represented by "i-Pr", n-propyl by "n-Pr", n-butyl by "n-Bu", tert-butyl by "t-Bu", etc.

[0021] The term "alkoxy" represents straight-chain and branched-chain alkyl groups having a specified number of carbon atoms connected by an oxygen bridge.

[0022] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (or fluoro (F), chloro (Cl), bromo (Br) and iodo (I)).

[0023] The term "aryl" refers to aromatic mono- and polycarbocyclic systems, where in polycyclic systems the individual carbocyclic rings are fused or connected to each other by single bonds. Generally, aryl includes phenyl, naphthyl and biphenylyl.

[0024] The term "heterocycle" refers to a cyclic structure composed of carbon atoms and non-carbon atoms, and examples of non-carbon atoms in the ring include nitrogen, oxygen and sulfur, etc. Generally, heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone and pyrimidine.

[0025] The term "arylheterocycle" refers to a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic ring composed of carbon atoms and one or more heteroatoms selected from N, O and S. Examples of arylheterocycles include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, thiazolyl, furyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dioxazolyl, isothiazolyl and thiadiazolyl, benzotriazolyl, indolyl, isoindolyl, dihydroindolyl, iso-dihydroindolyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dienyl, imidazo(2,1-b)(1,3)thiazole and benzo-1,3-dioxolyl.

[0026] For the aryl in the term "substituted aryl", it is defined as above. When the substituents of the substituted aryl are not specified, the substituents can be selected from the following groups, including but not limited to: halogen, C1-C 20 alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C1-C6 alkyl), C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl)S(O) 0-2 -, aryl-S(O) 0-2 -, (C0-C6 alkyl)S(O) 0-2 (C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6 alkyl)2NC(O)-(C0-C6 alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O) 1-2 (C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl, heterocyclic alkyl, halogen-aryl, halogen-aralkyl, halogen-heterocycle, halogen-heterocyclic alkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclic alkyl. The term "substituted phenyl" has a similar definition.

[0027] Unless otherwise specified, all ranges listed herein are inclusive. For example, "the value of n is an integer between 0 and 2" means that n can be 0, 1, or 2.

[0028] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be readily prepared from an inorganic base or an organic base. Salts derived from such inorganic bases include salts of aluminum, ammonium, calcium, copper (cupric and cuprous), iron, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc, etc. Preferred are salts of ammonium, calcium, magnesium, potassium and sodium, etc. Salts prepared from organic bases include primary, secondary and tertiary amines from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compound of the present invention is basic, its corresponding salt can be readily prepared from an inorganic acid or an organic acid. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0029] The term "solvate" refers to a variable stoichiometric complex formed by a solute or its pharmaceutically acceptable salt and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol and acetic acid. When the solvent is water, the solvate is called a hydrate. Hydrates include, but are not limited to, hemihydrate, monohydrate, sesquihydrate, dihydrate and trihydrate.

[0030] The term "prodrug" is a functional derivative of the compound of the present invention that is readily convertible in vivo to the desired compound.

[0031] Preferably, the synthesis method includes the following synthetic route:

[0032] 。

[0033] Wherein, the product obtained in step S5 is furoldesine.

[0034] Preferably, in the synthesis method, R 1 is selected from substituted or unsubstituted C1-6 alkyl or C1-6 cycloalkyl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0035] More preferably, R 1 is selected from unsubstituted C1-6 alkyl or C1-6 cycloalkyl.

[0036] Even more preferably, and as an example of the present invention, R 1 is methyl.

[0037] Preferably, in the synthesis method, R 2 and R 3 are each independently selected from one of H, substituted or unsubstituted C1-6 alkyl, C1-6 cycloalkyl, 5-6 membered aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0038] More preferably, R 2 and R 3 are each independently selected from one of H, unsubstituted C 1-6 alkyl, C 1-6 cycloalkyl, 5-6 membered aryl.

[0039] Even more preferably, R 2 and R 3 are each independently selected from one of H, methyl, phenyl.

[0040] Further preferably, and as an example of the present invention, R 2 and R 3 are both methyl.

[0041] Preferably, in the synthesis method, R 4 is selected from substituted or unsubstituted silyl, and the substituents are selected from at least one of C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen;

[0042] More preferably, R 4 is selected from mono-substituted, di-substituted or tri-substituted silyl, and the substituents are selected from one of C1-6 alkyl, C 1-6 cycloalkyl.

[0043] Even more preferably, R 4 is tri-substituted silyl, and the substituents are selected from C1-6 alkyl, C 1-6 cycloalkyl, phenyl.

[0044] Further preferably, R 4Selected from trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

[0045] Most preferably, and as an example of the present invention, R 4 is tert-butyldimethylsilyl.

[0046] Preferably, in the synthesis method, Ar 1 is selected from substituted or unsubstituted aryl groups, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl groups containing oxygen and / or nitrogen, and 5-6 membered heterocyclic groups containing oxygen and / or nitrogen.

[0047] More preferably, Ar 1 is an unsubstituted aryl group.

[0048] Still more preferably, and as an example of the present invention, Ar 1 is phenyl.

[0049] Preferably, in the synthesis method, X 1 is Br or I.

[0050] More preferably, and as an example of the present invention, in the synthesis method X 1 is Br.

[0051] Preferably, in the synthesis method, step S1 includes the following steps:

[0052] S101. Mix the compound shown in formula (I) with a solvent, adjust the temperature, and add a n-butyllithium solution;

[0053] S102. Stir the compound solution shown in formula (Ra);

[0054] S103. Control the temperature and react;

[0055] S104. Quench and post-treat to obtain the compound shown in formula (II).

[0056] More preferably, in step S101, the solvent is a mixture of methyl tert-butyl ether and anisole, and the temperature adjustment is to adjust to -78 °C; in step S103, the temperature control is to control the temperature at -78 °C.

[0057] Still more preferably, in step S101, the solvent is a mixture of methyl tert-butyl ether and anisole with a volume ratio of 2-4:1.

[0058] Further preferably, in step S101, the solvent is a mixture of methyl tert-butyl ether and anisole with a volume ratio of 3:1.

[0059] Still more preferably, in step S101, the n-butyllithium solution is a solution of n-butyllithium in tetrahydrofuran.

[0060] Further preferably, in step S101, the n-butyllithium solution is a 2.5 mol / L solution of n-butyllithium in tetrahydrofuran.

[0061] Still more preferably, in step S101, the molar ratio of the compound represented by formula (I) to the n-butyllithium is 0.12:0.16 - 0.2.

[0062] Further preferably, and as an example of the present invention, in step S101, the molar ratio of the compound represented by formula (I) to the n-butyllithium is 0.12:0.185.

[0063] Even more preferably, in step S101, the addition is dropwise addition.

[0064] Even more preferably, in step S102, the stirring is for 0.2 - 1 h.

[0065] Further preferably, and as an example of the present invention, in step S102, the stirring is for 0.5 h.

[0066] Even more preferably, in step S102, the solution of the compound represented by formula (Ra) is a solution of the compound represented by formula (Ra) in methyl tert-butyl ether.

[0067] Still more preferably, the solution of the compound represented by formula (Ra) is a solution of the compound represented by formula (Ra) in methyl tert-butyl ether, and the concentration of the compound represented by formula (Ra) in the methyl tert-butyl ether solution is 0.3 - 1 mol / L.

[0068] Further preferably, and as an example of the present invention, the solution of the compound represented by formula (Ra) is a solution of the compound represented by formula (Ra) in methyl tert-butyl ether, and the concentration of the compound represented by formula (Ra) in the methyl tert-butyl ether solution is 0.5 mol / L.

[0069] Even more preferably, in step S102, the molar ratio of the compound represented by formula (Ra) to the compound represented by formula (I) in step S101 is 0.14 - 0.20:0.12.

[0070] Still more preferably, and as an example of the present invention, in step S102, the molar ratio of the compound represented by formula (Ra) to the compound represented by formula (I) in step S101 is 0.15:0.12.

[0071] More preferably, in step S102, the addition is dropwise addition.

[0072] Even more preferably, in step S103, the reaction is a stirring reaction at -78 °C for 2 h.

[0073] More preferably, in step S104, the quenching is carried out by adding a saturated aqueous solution of ammonium chloride.

[0074] More preferably, in step S104, the post-treatment includes the following steps:

[0075] The quenched mixture is extracted with ethyl acetate, the combined organic phases are collected, the organic phases are washed with an aqueous sodium chloride solution, the organic phases are dried to remove water, concentrated, and purified using flash silica gel chromatography.

[0076] Even more preferably, and as an example of the present invention, the flash silica gel chromatography includes the following conditions:

[0077] Biotage ® 120 g SepaFlash ® Silica flash column, gradient elution with a 0 - 100% ethyl acetate / petroleum ether gradient eluent, 80 mL / min.

[0078] Preferably, in the synthesis method, step S2 includes the following steps:

[0079] S201. Mix the solution of the compound shown in formula (II) with sodium borohydride and react;

[0080] S202. Quench and carry out post-treatment to obtain the compound shown in formula (III).

[0081] More preferably, in step S201, the solution of the compound shown in formula (II) is an ethanol solution of the compound shown in formula (II).

[0082] Even more preferably, in step S201, the solution of the compound shown in formula (II) is an ethanol solution of the compound shown in formula (II), and the concentration of the compound shown in formula (II) in the solution is 0.15 - 0.20 mol / L.

[0083] Further preferably, and as an example of the present invention, in step S201, the solution of the compound shown in formula (II) is an ethanol solution of the compound shown in formula (II), and the concentration of the compound shown in formula (II) in the solution is 0.17 mol / L.

[0084] More preferably, in step S201, the mixing is specifically: adding sodium borohydride in batches at 0 °C.

[0085] More preferably, in step S201, the molar ratio of the compound shown in the formula (II) to the sodium borohydride is 1:1.

[0086] More preferably, in step S201, the reaction is a stirring reaction at 25 °C for 1 h.

[0087] More preferably, in step S202, the quenching is carried out by adding water.

[0088] More preferably, in step S202, the post-treatment includes the following steps:

[0089] Extract the quenched mixture with ethyl acetate, collect and combine the organic phases, wash the organic phases with an aqueous sodium chloride solution, dry the organic phases to remove water, concentrate, and remove the solvent.

[0090] Preferably, in the synthesis method, step S3 includes the following steps:

[0091] S301. Mix the solution of the compound shown in the formula (III) with 2-iodoxybenzoic acid and react;

[0092] S302. Quench and post-treat to obtain the compound shown in the formula (IV).

[0093] More preferably, in step S301, the solution of the compound shown in the formula (III) is a dimethyl sulfoxide solution of the compound shown in the formula (III).

[0094] Still more preferably, in step S301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III).

[0095] Further preferably, in step S301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III), and the concentration of the compound shown in the formula (III) in the solution is 0.15 - 0.20 mol / L.

[0096] Even more preferably, and as an example of the present invention, in step S301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III), and the concentration of the compound shown in the formula (III) in the solution is 0.17 mol / L.

[0097] More preferably, in step S301, the molar ratio of the compound shown in the formula (III) to the 2-iodoxybenzoic acid is 1:5.8 - 6.5.

[0098] More preferably, and as an example of the present invention, in step S301, the molar ratio of the compound represented by the formula (III) to the 2-iodoxybenzoic acid is 1:6.

[0099] Even more preferably, in step S301, the reaction is carried out by stirring at 37 °C for 12 hours.

[0100] Even more preferably, in step S302, the quenching is carried out with water.

[0101] Even more preferably, in step S302, the post-treatment includes the following steps:

[0102] The quenched mixture is extracted with ethyl acetate, the combined organic phases are collected, the organic phase is washed with an aqueous sodium chloride solution, the organic phase is dried to remove water, concentrated, and the solvent is removed.

[0103] Preferably, in the synthesis method, step S4 includes the following steps:

[0104] S401. Mix a solution of the compound represented by the formula (IV) with molecular sieve, ammonium formate, and sodium cyanoborohydride, and react to obtain a reaction mixture;

[0105] S402. Post-treat the reaction mixture obtained in step S401 to obtain the compound represented by the formula (V).

[0106] Even more preferably, in step S401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV).

[0107] More preferably, in step S401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV), and the concentration of the compound represented by the formula (IV) in the solution is 0.1 - 0.15 mol / L.

[0108] Further preferably, and as an example of the present invention, in step S401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV), and the concentration of the compound represented by the formula (IV) in the solution is 0.128 mol / L.

[0109] Even more preferably, and as an example of the present invention, in step S401, the molecular sieve is a 4A molecular sieve.

[0110] More preferably, in step S401, the mass of the molecular sieve is equal to the mass of the compound represented by the formula (IV).

[0111] Even more preferably, in step S401, the molar ratio of the compound represented by the formula (IV), the ammonium formate, and the sodium cyanoborohydride is 12.8:110 - 150:65 - 90.

[0112] More preferably, and as an example of the present invention, in step S401, the molar ratio of the compound shown in formula (IV), ammonium formate and sodium cyanoborohydride is 12.8:122:74.9.

[0113] Even more preferably, in step S401, the reaction is carried out by stirring at 25 °C for 30 min.

[0114] Even more preferably, in step S402, the post-treatment includes the following steps:

[0115] Filter, add a mixture of water and ethyl acetate to the filtrate, separate the layers, and retain the organic phase and the aqueous phase respectively. Extract the obtained aqueous phase with ethyl acetate, collect the organic phase and combine it completely with the organic phase obtained by liquid separation. Wash the organic phase with an aqueous sodium chloride solution, dry the organic phase to remove water, and concentrate. Purify using flash silica gel chromatography.

[0116] More preferably, in the mixture of water and ethyl acetate, the volume ratio of water to ethyl acetate is 4:3 - 7.

[0117] Even more preferably, and as an example of the present invention, in the mixture of water and ethyl acetate, the volume ratio of water to ethyl acetate is 4:5.

[0118] More preferably, and as an example of the present invention, the flash silica gel chromatography includes the following conditions:

[0119] ISCO ® 20 g SepaFlash ® Silica gel column, the eluent is a 0 - 100% ethyl acetate / petroleum ether gradient, 45 mL / min.

[0120] Preferably, in the synthesis method, step S5 includes the following steps:

[0121] S501. Mix the solution of the compound shown in formula (V) with hydrochloric acid and react;

[0122] S502. Perform post-treatment to obtain furorodixin.

[0123] Even more preferably, in step S501, the solution of the compound shown in formula (V) is a methanol solution of the compound shown in formula (V).

[0124] More preferably, in step S501, the solution of the compound shown in formula (V) is a methanol solution of the compound shown in formula (V), and the concentration of the compound shown in formula (V) in the solution is 0.05 - 0.1 mol / L.

[0125] Further preferably, and as an example of the present invention, in step S501, the solution of the compound represented by formula (V) is a methanol solution of the compound represented by formula (V), and the concentration of the compound represented by formula (V) in the solution is 0.077 mol / L.

[0126] More preferably, the concentration of the hydrochloric acid in step S501 is greater than or equal to 12 mol / L.

[0127] Still more preferably, the concentration of the hydrochloric acid in step S501 is 12 mol / L.

[0128] More preferably, in step S501, the reaction is a stirring reaction at 80 °C for 12 h.

[0129] More preferably, in step S502, the post-treatment includes the following steps:

[0130] Filter and dry the reaction. Pulverize with acetonitrile, filter and collect the filter cake to obtain furorodixin.

[0131] On the other hand, the present invention provides an intermediate of furorodixin, and the intermediate is a compound represented by formula (II) or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug;

[0132]

[0133] Wherein, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl.

[0134] Preferably, R 1 is selected from substituted or unsubstituted C1-6 alkyl or C1-6 cycloalkyl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0135] More preferably, R 1 is selected from unsubstituted C1-6 alkyl or C1-6 cycloalkyl.

[0136] Still more preferably, and as an example of the present invention, R 1 is methyl.

[0137] Preferably, R 2 , R 3Each independently selected from one of H, substituted or unsubstituted C1-6 alkyl, C1-6 cycloalkyl, 5-6 membered aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0138] More preferably, R 2 , R 3 Each independently selected from one of H, unsubstituted C 1-6 alkyl, C 1-6 cycloalkyl, 5-6 membered aryl.

[0139] Still more preferably, R 2 , R 3 Each independently selected from one of H, methyl, phenyl.

[0140] Further preferably, and as an example of the present invention, R 2 , R 3 Are both methyl.

[0141] Preferably, R 4 Is selected from substituted or unsubstituted silyl, and the substituents are selected from at least one of C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen;

[0142] More preferably, R 4 Is selected from mono-substituted, di-substituted or tri-substituted silyl, and the substituents are selected from one of C1-6 alkyl, C 1-6 cycloalkyl.

[0143] Still more preferably, R 4 Is a tri-substituted silyl, and the substituents are selected from C1-6 alkyl, C 1-6 cycloalkyl, phenyl.

[0144] Further preferably, R 4 Is selected from one of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

[0145] Most preferably, and as an example of the present invention, R 4 Is tert-butyldimethylsilyl.

[0146] Preferably, Ar 1Selected from substituted or unsubstituted aryl, and the substituent is at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, and 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0147] More preferably, Ar 1 is unsubstituted aryl.

[0148] Still more preferably, and as an example of the present invention, Ar 1 is phenyl.

[0149] On the other hand, the present invention provides a method for synthesizing the intermediate, comprising the following steps:

[0150] T101. Mix the compound represented by formula (I) with a solvent, adjust the temperature, and add a solution of n-butyllithium;

[0151] T102. Stir and add a solution of the compound represented by formula (Ra);

[0152] T103. Control the temperature and react;

[0153] T104. Perform post-treatment to obtain the compound represented by formula (II);

[0154] Among them, the structural formulas of the compound represented by formula (I) in step T101 and the compound represented by formula (Ra) in step T102 are as follows:

[0155]

[0156] Among them, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl; X 1 is selected from Cl, Br or I.

[0157] More preferably, in step T101, the solvent is a mixture of methyl tert-butyl ether and anisole, and the temperature adjustment is adjusted to -78°C; in step T103, the temperature control is to control the temperature at -78°C.

[0158] Still more preferably, in step T101, the solvent is a mixture of methyl tert-butyl ether and anisole with a volume ratio of 2-4:1.

[0159] Further preferably, in step T101, the solvent is a mixture of methyl tert-butyl ether and anisole with a volume ratio of 3:1.

[0160] More preferably, in step T101, the n-butyllithium solution is a tetrahydrofuran solution of n-butyllithium.

[0161] Further preferably, in step T101, the n-butyllithium solution is a 2.5 mol / L tetrahydrofuran solution of n-butyllithium.

[0162] More preferably, in step T101, the molar ratio of the compound represented by formula (I) to the n-butyllithium is 0.12:0.16 - 0.2.

[0163] Further preferably, and as an example of the present invention, in step T101, the molar ratio of the compound represented by formula (I) to the n-butyllithium is 0.12:0.185.

[0164] Even more preferably, in step T101, the addition is dropwise addition.

[0165] Even more preferably, in step T102, the stirring is for 0.2 - 1 h.

[0166] Further preferably, and as an example of the present invention, in step T102, the stirring is for 0.5 h.

[0167] Even more preferably, in step T102, the solution of the compound represented by formula (Ra) is a methyl tert-butyl ether solution of the compound represented by formula (Ra).

[0168] More preferably, the solution of the compound represented by formula (Ra) is a methyl tert-butyl ether solution of the compound represented by formula (Ra), and the concentration of the compound represented by formula (Ra) in the methyl tert-butyl ether solution is 0.3 - 1 mol / L.

[0169] Further preferably, and as an example of the present invention, the solution of the compound represented by formula (Ra) is a methyl tert-butyl ether solution of the compound represented by formula (Ra), and the concentration of the compound represented by formula (Ra) in the methyl tert-butyl ether solution is 0.5 mol / L.

[0170] Even more preferably, in step T102, the molar ratio of the compound represented by formula (Ra) to the compound represented by formula (I) in step T101 is 0.14 - 0.20:0.12.

[0171] More preferably, and as an example of the present invention, in step T102, the molar ratio of the compound represented by formula (Ra) to the compound represented by formula (I) in step T101 is 0.15:0.12.

[0172] Even more preferably, in step T102, the addition is dropwise addition.

[0173] More preferably, in step T103, the reaction is a stirring reaction at -78 °C for 2 h.

[0174] Even more preferably, in step T104, the quenching is carried out by adding a saturated aqueous solution of ammonium chloride.

[0175] Even more preferably, in step T104, the post-treatment includes the following steps:

[0176] The quenched mixture is extracted with ethyl acetate, the combined organic phases are collected, the organic phases are washed with an aqueous solution of sodium chloride, the organic phases are dried to remove water, concentrated, and purified using flash silica gel chromatography.

[0177] More preferably, and as an example of the present invention, the flash silica gel chromatography includes the following conditions:

[0178] Biotage ® 120 g SepaFlash ® Silica gel flash column, gradient elution with a 0 - 100% ethyl acetate / petroleum ether gradient eluent at 80 mL / min.

[0179] On the other hand, the present invention provides the use of the above intermediate and the above synthesis method in the production of furoldesine intermediate products.

[0180] On the other hand, the present invention provides an intermediate of furoldesine, and the intermediate is a compound represented by formula (III) or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug;

[0181]

[0182] Wherein, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl.

[0183] Preferably, R 1 is selected from substituted or unsubstituted C1-6 alkyl or C1-6 cycloalkyl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0184] Even more preferably, R 1Selected from unsubstituted C1-6 alkyl or C1-6 cycloalkyl.

[0185] More preferably, and as an example of the present invention, R 1 is methyl.

[0186] Preferably, R 2 , R 3 are each independently selected from one of H, substituted or unsubstituted C1-6 alkyl, C1-6 cycloalkyl, 5-6 membered aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0187] Even more preferably, R 2 , R 3 are each independently selected from one of H, unsubstituted C 1-6 alkyl, C 1-6 cycloalkyl, 5-6 membered aryl.

[0188] More preferably, R 2 , R 3 are each independently selected from one of H, methyl, phenyl.

[0189] Even further preferably, and as an example of the present invention, R 2 , R 3 are both methyl.

[0190] Preferably, R 4 is selected from substituted or unsubstituted silyl, and the substituents are selected from at least one of C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen;

[0191] More preferably, R 4 is selected from mono-substituted, di-substituted or tri-substituted silyl, and the substituents are selected from one of C1-6 alkyl, C 1-6 cycloalkyl.

[0192] More preferably, R 4 is tri-substituted silyl, and the substituents are selected from C1-6 alkyl, C 1-6 cycloalkyl, phenyl.

[0193] Even further preferably, R 4 is selected from one of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

[0194] Most preferably, and as an example of the present invention, R 4 is tert-butyldimethylsilyl.

[0195] Preferably, Ar 1 is selected from substituted or unsubstituted aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, and 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0196] More preferably, Ar 1 is unsubstituted aryl.

[0197] Still more preferably, and as an example of the present invention, Ar 1 is phenyl.

[0198] On the other hand, the present invention provides a method for synthesizing the above intermediate, comprising the following steps:

[0199] T201. Mix the solution of the compound shown in formula (II) with sodium borohydride and react;

[0200] T202. Quench and perform post-treatment to obtain the compound shown in formula (III);

[0201] Among them, the structure of the compound shown in formula (II) in step T201 is as follows:

[0202] .

[0203] Among them, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl.

[0204] More preferably, in step T201, the solution of the compound shown in formula (II) is an ethanol solution of the compound shown in formula (II).

[0205] Still more preferably, in step T201, the solution of the compound shown in formula (II) is an ethanol solution of the compound shown in formula (II), and the concentration of the compound shown in formula (II) in the solution is 0.15 - 0.20 mol / L.

[0206] Further preferably, and as an example of the present invention, in step T201, the solution of the compound represented by formula (II) is an ethanol solution of the compound represented by formula (II), and the concentration of the compound represented by formula (II) in the solution is 0.17 mol / L.

[0207] More preferably, in step T201, the mixing is specifically: adding sodium borohydride in batches at 0 °C.

[0208] More preferably, in step T201, the molar ratio of the compound represented by formula (II) to the sodium borohydride is 1:1.

[0209] More preferably, in step T201, the reaction is a stirring reaction at 25 °C for 1 h.

[0210] More preferably, in step T202, the quenching is quenching with water.

[0211] More preferably, in step T202, the post-treatment includes the following steps:

[0212] Extracting the quenched mixture with ethyl acetate, collecting and combining the organic phases, washing the organic phases with an aqueous sodium chloride solution, drying the organic phases to remove water, concentrating, and removing the solvent.

[0213] On the other hand, the present invention provides the application of the above intermediate and the above synthesis method in the production of furoldesine intermediate products.

[0214] On the other hand, the present invention provides an intermediate of furoldesine, and the intermediate is a compound represented by formula (IV) or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug;

[0215]

[0216] Wherein, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl.

[0217] Preferably, R 1 is selected from substituted or unsubstituted C1-6 alkyl or C1-6 cycloalkyl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0218] More preferably, R 1 is selected from unsubstituted C1-6 alkyl or C1-6 cycloalkyl.

[0219] Even more preferably, and as an example of the present invention, R 1 is methyl.

[0220] Preferably, R 2 , R 3 are each independently selected from one of H, substituted or unsubstituted C1-6 alkyl, C1-6 cycloalkyl, 5-6 membered aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0221] More preferably, R 2 , R 3 are each independently selected from one of H, unsubstituted C 1-6 alkyl, C 1-6 cycloalkyl, 5-6 membered aryl.

[0222] Even more preferably, R 2 , R 3 are each independently selected from one of H, methyl, phenyl.

[0223] Further preferably, and as an example of the present invention, R 2 , R 3 are both methyl.

[0224] Preferably, R 4 is selected from substituted or unsubstituted silyl, and the substituents are selected from at least one of C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen;

[0225] More preferably, R 4 is selected from mono-substituted, di-substituted or tri-substituted silyl, and the substituents are selected from one of C1-6 alkyl, C 1-6 cycloalkyl.

[0226] Even more preferably, R 4 is tri-substituted silyl, and the substituents are selected from C1-6 alkyl, C 1-6 cycloalkyl, phenyl.

[0227] Further preferably, R 4Selected from trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

[0228] Most preferably, and as an example of the present invention, R 4 is tert-butyldimethylsilyl.

[0229] Preferably, Ar 1 is selected from substituted or unsubstituted aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0230] More preferably, Ar 1 is unsubstituted aryl.

[0231] Still more preferably, and as an example of the present invention, Ar 1 is phenyl.

[0232] On the other hand, the present invention provides a method for synthesizing the above intermediate, comprising the following steps:

[0233] T301. Mix the solution of the compound shown in formula (III) with 2-iodoxybenzoic acid and react;

[0234] T302. Quench and post-treat to obtain the compound shown in formula (IV);

[0235] Among them, the structure of the compound shown in formula (III) in step T301 is as follows:

[0236]

[0237] Among them, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 is selected from substituted or unsubstituted silyl; Ar 1 is selected from substituted or unsubstituted aryl.

[0238] More preferably, in step T301, the solution of the compound shown in formula (III) is a dimethyl sulfoxide solution of the compound shown in formula (III).

[0239] More preferably, in step T301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III).

[0240] Further preferably, in step T301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III), and the concentration of the compound shown in the formula (III) in the solution is 0.15 - 0.20 mol / L.

[0241] Even more preferably, and as an example of the present invention, in step T301, the solution of the compound shown in the formula (III) is an anhydrous dimethyl sulfoxide solution of the compound shown in the formula (III), and the concentration of the compound shown in the formula (III) in the solution is 0.17 mol / L.

[0242] More preferably, in step T301, the molar ratio of the compound shown in the formula (III) to the 2-iodoxybenzoic acid is 1:5.8 - 6.5.

[0243] More preferably, and as an example of the present invention, in step T301, the molar ratio of the compound shown in the formula (III) to the 2-iodoxybenzoic acid is 1:6.

[0244] More preferably, in step T301, the reaction is stirring at 37°C for 12 hours.

[0245] More preferably, in step T302, the quenching is quenching with water.

[0246] More preferably, in step T302, the post-treatment includes the following steps:

[0247] Extracting the quenched mixture with ethyl acetate, collecting and combining the organic phases, washing the organic phases with an aqueous sodium chloride solution, drying the organic phases to remove water, concentrating, and removing the solvent.

[0248] On the other hand, the present invention provides the application of the above intermediate and the above synthesis method in the production of furoldesine intermediate products.

[0249] On the other hand, the present invention provides an intermediate of furoldesine, and the intermediate is a compound shown in the formula (V) or its stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug;

[0250]

[0251] Wherein, R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl; R 2 , R 3Each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 Selected from substituted or unsubstituted silyl; Ar 1 Selected from substituted or unsubstituted aryl.

[0252] Preferably, R 1 Selected from substituted or unsubstituted C1-6 alkyl or C1-6 cycloalkyl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0253] More preferably, R 1 Selected from unsubstituted C1-6 alkyl or C1-6 cycloalkyl.

[0254] Still more preferably, and as an example of the present invention, R 1 Is methyl.

[0255] Preferably, R 2 、R 3 Each independently selected from one of H, substituted or unsubstituted C1-6 alkyl, C1-6 cycloalkyl, 5-6 membered aryl, and the substituents are at least one of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen.

[0256] More preferably, R 2 、R 3 Each independently selected from one of H, unsubstituted C 1-6 alkyl, C 1-6 cycloalkyl, 5-6 membered aryl.

[0257] Still more preferably, R 2 、R 3 Each independently selected from H, methyl, phenyl.

[0258] Further preferably, and as an example of the present invention, R 2 、R 3 Are both methyl.

[0259] Preferably, R 4 Selected from substituted or unsubstituted silyl, and the substituents are selected from at least one of C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, halogen, cyano, phenyl, 5-6 membered heteroaryl containing oxygen and / or nitrogen, 5-6 membered heterocyclic group containing oxygen and / or nitrogen;

[0260] More preferably, R 4Selected from mono-substituted, di-substituted or tri-substituted silyl groups, the substituents being selected from one of C1-6 alkyl groups, C 1-6 cycloalkyl groups.

[0261] More preferably, R 4 is a tri-substituted silyl group, the substituents being selected from C1-6 alkyl groups, C 1-6 cycloalkyl groups, phenyl groups.

[0262] Even more preferably, R 4 is selected from one of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS).

[0263] Most preferably, and as an example of the present invention, R 4 is tert-butyldimethylsilyl.

[0264] Preferably, Ar 1 is selected from substituted or unsubstituted aryl groups, the substituents being at least one of C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 haloalkyl groups, halogen, cyano groups, phenyl groups, 5-6 membered heteroaryl groups containing oxygen and / or nitrogen, 5-6 membered heterocyclic groups containing oxygen and / or nitrogen.

[0265] More preferably, Ar 1 is an unsubstituted aryl group.

[0266] Even more preferably, and as an example of the present invention, Ar 1 is phenyl.

[0267] On the other hand, the present invention provides a method for synthesizing the above intermediate, comprising the following steps:

[0268] T401. Mix a solution of the compound shown in formula (IV) with molecular sieve, ammonium formate, and sodium cyanoborohydride, and react to obtain a reaction mixture;

[0269] T402. Filter the reaction mixture obtained in step T402, and perform post-treatment to obtain the compound shown in formula (V);

[0270] wherein, the structure of the compound shown in formula (IV) in step T401 is as follows:

[0271]

[0272] wherein, R 1 is selected from substituted or unsubstituted alkyl groups, cycloalkyl groups; R 2 , R 3Each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, aryl; R 4 Selected from substituted or unsubstituted silyl; Ar 1 Selected from substituted or unsubstituted aryl.

[0273] More preferably, in step T401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV).

[0274] Still more preferably, in step T401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV), and the concentration of the compound represented by the formula (IV) in the solution is 0.1 - 0.15 mol / L.

[0275] Further preferably, and as an example of the present invention, in step T401, the solution of the compound represented by the formula (IV) is an ethanol solution of the compound represented by the formula (IV), and the concentration of the compound represented by the formula (IV) in the solution is 0.128 mol / L.

[0276] More preferably, and as an example of the present invention, in step T401, the molecular sieve is 4A molecular sieve.

[0277] Still more preferably, in step T401, the mass of the molecular sieve is equal to the mass of the compound represented by the formula (IV).

[0278] More preferably, in step T401, the molar ratio of the compound represented by the formula (IV), ammonium formate and sodium cyanoborohydride is 12.8:110 - 150:65 - 90.

[0279] Still more preferably, and as an example of the present invention, in step T401, the molar ratio of the compound represented by the formula (IV), ammonium formate and sodium cyanoborohydride is 12.8:122:74.9.

[0280] More preferably, in step T401, the reaction is carried out by stirring at 25 °C for 30 min.

[0281] More preferably, in step T402, the post-treatment includes the following steps:

[0282] Filter, add a mixture of water and ethyl acetate to the filtrate, separate the layers, and retain the organic phase and the aqueous phase respectively. Extract the obtained aqueous phase with ethyl acetate, collect the organic phase and combine it completely with the organic phase obtained by liquid separation. Wash the organic phase with an aqueous sodium chloride solution, dry the organic phase to remove water, and concentrate. Purify using flash silica gel chromatography.

[0283] Still more preferably, in the mixture of water and ethyl acetate, the volume ratio of water to ethyl acetate is 4:3 - 7.

[0284] Further preferably, and as an example of the present invention, in the mixture of water and ethyl acetate, the volume ratio of water to ethyl acetate is 4:5.

[0285] More preferably, and as an example of the present invention, the flash silica gel chromatography includes the following conditions:

[0286] ISCO ® 20 g SepaFlash ® Silica gel column, the eluent is a 0 - 100% ethyl acetate / petroleum ether gradient, 45 mL / min.

[0287] On the other hand, the present invention provides the application of the above intermediate and the above synthesis method in the production of furolixine intermediates.

[0288] On the other hand, the present invention provides the application of the intermediate of the above furolixine, the synthesis method of the above intermediate in the production of furolixine or its stereoisomers, geometric isomers, tautomers, N - oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0289] The beneficial effects of the present invention are as follows:

[0290] (1) A novel synthesis method of furolixine is provided, which directly uses a ketose precursor with higher stability to form a glycosidic bond, thereby realizing the coupling of the sugar precursor and the heterocyclic precursor, and further realizing the synthesis of furolixine, breaking through the technical bottleneck.

[0291] (2) A series of furolixine intermediates with brand - new structures and their synthesis methods are provided, which contribute to the further development of the furolixine intermediate synthesis technology.

[0292] (3) The reaction conditions of the furolixine synthesis method provided by the present invention are easy to obtain, without using expensive metal catalysts, and have broad application prospects. Brief Description of the Drawings

[0293] Figure 1 It is the liquid chromatography - mass spectrometry (LC - MS) spectrum of compound 3 prepared in Example 1.

[0294] Figure 2 It is the liquid chromatography - mass spectrometry (LC - MS) spectrum of compound 4 prepared in Example 2.

[0295] Figure 3 It is the liquid chromatography - mass spectrometry (LC - MS) spectrum of compound 5 prepared in Example 3.

[0296] Figure 4 It is the liquid chromatography - mass spectrometry (LC - MS) spectrum of compound 6 prepared in Example 4.

[0297] Figure 5 It is the liquid chromatography-mass spectrometry (LC-MS) spectrum of furoxidine prepared in Example 5. Detailed implementation manners

[0298] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary illustration of the scope claimed in this application. Those skilled in the art can make various changes and modifications to the invention of this application based on the disclosed content, and it should also fall within the scope claimed in this application.

[0299] The present invention will be further described below by way of specific examples. All kinds of chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified.

[0300] In the following examples and comparative examples, the English abbreviations involved and their Chinese interpretations are shown in the following table:

[0301]

[0302] In the following examples and comparative examples, the characterization means and characterization conditions of the compounds are shown in the following table:

[0303]

[0304] Example 1

[0305]

[0306] Dissolve the solution of 5-(benzyloxymethyl)-7-bromo-4-methoxypyrrolo[3,2-d]pyrimidine (Compound 1, 43 g, 0.12 mol) in anhydrous methyl tert-butyl ether (600 mL) and anisole (200 mL), cool to -78 °C, and dropwise add n-BuLi (2.5 mol / L tetrahydrofuran solution, 74 mL) under nitrogen. After the addition, continue stirring for 0.5 h. Then, dropwise add a solution of rac-(3aR,6aR)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-one (Compound 2, 44.8 g, 0.15 mol) in methyl tert-butyl ether (300 mL) to the above mixture. After the addition, continue stirring the reaction mixture at -78 °C for 2 h. Quench the reaction with saturated aqueous ammonium chloride solution (1.8 L). Extract the aqueous phase with ethyl acetate (800 mL × 3). Wash the combined organic phases with aqueous sodium chloride solution (800 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by flash silica gel chromatography (Biotage® 120 g SepaFlash® silica gel flash column, 0 - 100% ethyl acetate / petroleum ether gradient eluent, 80 mL / min) to obtain [5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl]-[rac-(4R,5R)-5-[2-[tert-butyl(dimethyl)silyl]oxo-1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methanone (Compound 3, 24 g, purity 80%) as a pale yellow oil.

[0307] MS (ESI) m / z of Compound 3: 572.3 [M+H] + The results of liquid chromatography-mass spectrometry detection are as Figure 1 shown.

[0308] The flow rate of the above liquid chromatography is: 2.0000 mL / min.

[0309] 1 H NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 7.81 (s, 1H), 7.36 - 7.21 (m, 5H), 5.75 (s, 2H), 4.75 - 4.62 (m, 1H), 4.45 (s, 2H), 4.10 - 3.99 (m, 2H), 3.70 - 3.65 (m, 1H), 1.20 (s, 3H), 1.17 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H).

[0310] Comparative Example 1

[0311] Compared with Example 1, “anhydrous methyl tert-butyl ether (600 mL) and anisole (200 mL)” was changed to “anhydrous tetrahydrofuran (800 mL)”, and the other conditions were the same.

[0312] In Comparative Example 1, the main by-product obtained in the experiment was: isomer [5-(benzyloxymethyl)-4-methoxy-pyrrolo[3,2-d]pyrimidin-6-yl]-[racemic-(4R,5R)-5-[2-[tert-butyl(dimethyl)silyl]oxy-1-hydroxy-ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methanone, and its structure is as follows.

[0313]

[0314] Comparative Example 2

[0315] Compared with Example 1, “after the dropping was completed, the reaction solution was continuously stirred at -78 °C for 2 hours” was changed to “after the dropping was completed, the reaction solution was stirred at -20 °C for 2 hours”, and the others were the same.

[0316] In Comparative Example 2, the main by-product obtained in the experiment was: 5-(benzyloxymethyl-4-methoxy-pyrrolo[3,2-d]pyrimidine, and its structure is as follows.

[0317]

[0318] Example 2

[0319]

[0320] Sodium borohydride (0.66 g, 17 mmol) was added in batches to an ethanol solution (100 mL) of [5-(benzyloxymethyl)-4-methoxy-pyrrolo[3,2-d]pyrimidin-7-yl]-[racemic-(4R,5R)-5-[2-[tert-butyl(dimethyl)silyl]oxy-1-hydroxy-ethyl]-2,2-dimethyl-1,3-dioxolane-4-yl]methanone (Compound 3, 10 g, 17 mmol) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. The reaction was quenched with pure water (100 mL), and the aqueous phase was extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain compound 2-[tert-butyl(dimethyl)silyl]oxy-1-[rac-(4R,5S)-5-[[5-(benzyloxymethyl)-4-methoxy-pyrrolo[3,2-d]pyrimidin-7-yl]-hydroxy-methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Compound 4, 9 g, 85%) as a colorless oil.

[0321] MS (ESI) m / z of Compound 4: 574.3 [M+H] + The detection results of liquid chromatography-mass spectrometry are as follows Figure 2 shown

[0322] The flow rate of the above liquid chromatography is: 1.0000 mL / min.

[0323] 1 H NMR (DMSO-d6, 400 MHz) δ 8.50 (s, 1H), 7.33 - 7.24 (m, 5H), 7.06 (s, 1H), 5.84 (d, J = 10.8 Hz, 1H), 5.67 (d, J = 11.0 Hz, 1H), 5.18 (dd, J = 7.2, 6.0 Hz, 1H), 4.70 (dt, J = 11.9, 0.9, 0.9 Hz, 1H), 4.60 (dt, J = 12.0, 0.9, 0.9 Hz, 1H), 4.51 (dd, J = 7.2, 4.8 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.81 - 3.68 (m, 5H), 3.64 - 3.58 (m, 2H), 3.20 - 3.14 (m, 1H), 1.36 (s, 3H), 1.25 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H).

[0324] Example 3

[0325]

[0326] To a solution of 2-[tert-butyl(dimethyl)silyl]oxy-1-[rac-(4R,5S)-5-[[5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl]-hydroxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Compound 4, 3.9 g, 6.8 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added 2-iodoxybenzoic acid (11.4 g, 40.8 mmol). The reaction mixture was stirred at 37 °C for 12 h. The reaction was quenched with pure water (50 mL), and the aqueous phase was extracted with ethyl acetate (55 mL × 3). The combined organic phases were washed with brine (55 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-[tert-butyl(dimethyl)silyl]oxy-1-[rac-(4S,5R)-5-[5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidine-7-carbonyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanone (Compound 5, 7.5 g, purity 70%) as a pale yellow oil.

[0327] MS (ESI) m / z of Compound 5: 570.2 [M+H] + The results of liquid chromatography-mass spectrometry detection were as Figure 3 shown.

[0328] The flow rate of the above liquid chromatography was: 2.0000 mL / min.

[0329] 1 H NMR (DMSO-d6, 400 MHz) δ8.64 (s, 1H), 8.62 (s, 1H), 7.25-7.21 (m,5H), 6.22 (d, J = 7.6 Hz, 1H), 5.83 (s, 2H), 5.14 (d, J = 7.2 Hz, 1H), 4.54(s, 2H), 4.43 (s, 2H), 4.09 (s, 3H), 4.05 (d, J = 2.0 Hz, 1H), 1.47 (s, 3H),1.42 (s, 3H), 0.75 (s, 9H), -0.04 (s, 3H), -0.06 (s, 3H).

[0330] Example 4

[0331]

[0332] To a solution of 2-[tert-butyl(dimethyl)silyl]oxy-1-[rac-(4S,5R)-5-[5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidine-7-carbonyl]-2,2-dimethyl-1,3-dioxolan-4-yl]ethanone (Compound 5, 7.28 g, 12.8 mmol) in ethanol (100 mL) were added 4A molecular sieve (7.28 g), ammonium formate (7.75 g, 122 mmol) and sodium cyanoborohydride (4.71 g, 74.9 mmol) respectively. The reaction mixture was stirred at 25 °C for 30 minutes. The reaction mixture was filtered, and pure water (80 mL) and EtOAc (100 mL) were added to the filtrate. The mixture was poured into a separatory funnel and separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO® 20 g SepaFlash® silica gel column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 45 mL / min) to obtain tert-butyl-dimethyl-[[rac-(3aS,4S,6R,6aR)-4-[5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-6-yl]methoxy]silane (Compound 6, 2.5 g, purity 90%) as a pale yellow oil.

[0333] MS (ESI) m / z of Compound 6: 555.2 [M+H] + The results of liquid chromatography - mass spectrometry detection are as Figure 4 shown.

[0334] The flow rate of the above liquid chromatography was: 2.0000 mL / min.

[0335] 1 H NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 7.64 (s, 1H), 7.45 - 7.22 (m, 7H), 5.91 - 5.61 (m, 2H), 4.95 (d, J = 4.8 Hz, 3H), 4.55 (s, 2H), 4.13 (s, 3H), 4.12 - 4.05 (m, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 0.95 (s, 9H), 0.17 (s, 6H).

[0336] Example 5

[0337]

[0338] To a solution of tert-butyl-dimethyl-[[rac-(3aS,4S,6R,6aR)-4-[5-(benzyloxymethyl)-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-6-yl]methoxy]silane (Compound 6, 2 g, 0.77 mmol) in methanol (10 mL) was added concentrated hydrochloric acid (12 M, 40 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction was filtered and dried, and the crude product was slurried with acetonitrile, filtered, and the cake was collected to obtain the compound rac-(2R,3R,4S,5S)-2-(hydroxymethyl)-5-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pyrrolidine-3,4-diol (Frolodiside, 1 g, purity 90%) as a pale yellow solid.

[0339] The MS (ESI) m / z of frolodiside: 267.1 [M+H] + The results of liquid chromatography-mass spectrometry detection were as Figure 5 shown.

[0340] The flow rate of the above liquid chromatography was: 1.0000 mL / min.

[0341] 1 H NMR (DMSO- d 6, 400 MHz) δ 7.98 (s, 1H), 7.80 (s, 1H), 4.83 (d, J = 4.8 Hz, 1H), 4.43 (dd, J = 4.2, 7.2 Hz, 1H), 4.24 (t, J = 4.4 Hz, 1H), 3.76 - 3.73 (m, 2H), 3.67 - 3.64 (m, 2H).

[0342] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Simple modifications or equivalent replacements made by those of ordinary skill in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing forodesine or a pharmaceutically acceptable salt thereof, characterized in that: The following synthetic routes are included: ； Step S1 includes the following steps: S101, mixing the compound represented by formula (I) with a solvent, adjusting the temperature, and adding an n-butyl lithium solution; S102, stirring, adding a solution of a compound represented by formula (Ra); S103, control temperature, reaction; S104, quenching and post-treatment to obtain a compound represented by formula (II); In step S101, the solvent is a mixture of methyl tert-butyl ether and anisole; Among them, R 1 is selected from substituted or unsubstituted C 1-6 Alkyl or C 1-6 Cycloalkyl, the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 , R 3 are each independently selected from H, substituted or unsubstituted C 1-6 Alkyl, C 1-6 One of cycloalkyl and 5-6 membered aryl, wherein the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; R 4 is tert-butyldimethylsilyl; Ar 1 is selected from substituted or unsubstituted phenyl, wherein the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; X 1 is selected from Cl, Br or I.

2. The synthesis method according to claim 1, characterized in that R 1 Selected from unsubstituted C 1-6 Alkyl or C 1-6 Cycloalkyl; R 2 , R 3 are each independently selected from H, unsubstituted C 1-6 Alkyl, C 1-6 One of cycloalkyl and 5-6 membered aryl; Ar 1 is an unsubstituted phenyl group; X 1 For Br.

3. The synthesis method according to claim 1, characterized in that R 1 , R 2 , R 3 All are methyl, X 1 For Br.

4. The synthesis method according to claim 1, characterized in that Step S2 includes the following steps: S201, mixing a solution of the compound represented by formula (II) with sodium borohydride to react; S202, quenching, post-treatment, to obtain a compound represented by formula (III); Step S3 includes the following steps: S301, mixing a solution of the compound represented by formula (III) with 2-iodoacylbenzoic acid to react; S302, quenching and post-treatment to obtain a compound represented by formula (IV); Step S4 includes the following steps: S401, mixing a solution of the compound represented by formula (IV) with 4AMS, ammonium formate and sodium cyanoborohydride, and reacting the mixture to obtain a reaction mixture; S402, post-treating the reaction mixture obtained in step S401 to obtain a compound represented by formula (V); Step S5 includes the following steps: S501, mixing a solution of the compound represented by formula (V) with hydrochloric acid for reaction; S502, post-processing to obtain Forodesine.

5. The synthesis method according to claim 4, characterized in that In step S101, the adjustment temperature is adjusted to -78°C; in step S103, the control temperature is controlled at -78°C.

6. A method for synthesizing an intermediate (II) of forodesine, characterized in that: The structure of intermediate (II) is as follows: ； The following steps are involved: T101, mixing the compound represented by formula (I) with a solvent, adjusting the temperature, and adding an n-butyl lithium solution; T102, stirring, adding the solution of the compound represented by formula (Ra); T103, control temperature, reaction; T104, post-treatment to obtain a compound represented by formula (II); Wherein, the structures of the compound represented by formula (I) in step T101 and the compound represented by formula (Ra) in step T102 are as follows: ； Among them, R 1 is selected from substituted or unsubstituted C 1-6 Alkyl or C 1-6 Cycloalkyl, the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; R 2 , R 3 are each independently selected from H, substituted or unsubstituted C 1-6 Alkyl, C 1-6 One of cycloalkyl and 5-6 membered aryl, wherein the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; R 4 is tert-butyldimethylsilyl; Ar 1 is selected from substituted or unsubstituted phenyl, wherein the substituent is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 At least one of a haloalkyl group, a halogen group, a cyano group, a phenyl group, a 5-6-membered aromatic heterocyclic group containing oxygen and / or nitrogen, and a 5-6-membered heterocyclic group containing oxygen and / or nitrogen; X 1 is selected from Cl, Br or I; In step T101, the solvent is a mixture of methyl tert-butyl ether and anisole.

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