Method for preparing carbocyclic nucleosides using amides

Abstract

The present disclosure describes methods for preparing carbanucleosides.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims priority to International Application No. PCT / CN2021 / 087731, filed on April 16, 2021, with the title "METHODS OF PREPARING CARBANUCLEOSIDES USING AMIDES".

Background Art

[0002] The compound 7 - ((3S,4R,5R)-3,4 - bis(benzyloxy)-5 - ((benzyloxy)methyl)tetrahydrofuran - 2 - yl)pyrrolo[2,1 - f][1,2,4]triazin - 4 - amine and its substituted compounds are important synthetic intermediates (see, for example, WO 2016 / 069825). There is a continuing need for improved methods for preparing such intermediates and other carbonucleosides.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0004] In one embodiment, the present disclosure is a method for preparing a compound of formula (II - a) or formula (II - b), comprising:

Chemical Formula

Chemical Formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0005] I. General Overview The present disclosure describes methods for preparing carbocyclic nucleosides. The methods described herein can relate to efficient and scalable processes that can be carried out on any scale. In some embodiments, the method comprises preparing a compound of formula (II-a) or formula (II-b) from a compound of formula (V),

Chemical formula

Chemical formula

[0006] When referring to a value, "about" includes the recited value plus or minus 10% of the recited value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to each of the recited values at each end of the range plus or minus 10% of the recited value. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3.

[0007] As used herein, "feed mixture" refers to a mixture of one or more reagents and / or solvents entering a reactor.

[0008] As used herein, "output mixture" refers to a mixture of one or more reagents and / or solvents exiting the reactor.

[0009] "Reactor" refers to a vessel configured such that chemicals and reagents are added as an input mixture and the conversion of chemicals, reagents, and other dependent variables occurs within the reactor. Each reactor may be, separately, a round-bottom flask, a batch reactor, a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, a continuous stirred tank reactor, a mixed flow reactor, a semi-batch reactor, or a combination thereof. In the methods of the present disclosure, one or more reactors can be used. If multiple reactors are present, the reactors may be of the same or different types.

[0010] "Catalyst" refers to a chemical reactant that increases the reaction rate without itself being consumed.

[0011] "Lewis acid" refers to a chemical group that can accept an electron pair from a second chemical group that can donate an electron pair. Lewis acids include, but are not limited to, inorganic compounds such as boron salts such as boron trifluoride or aluminum salts such as aluminum trichloride; organic compound salts such as trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate or TMSOTf); or metal complexes containing organic and / or inorganic ligands such as indium(III) chloride or dichlorodiisopropoxytitanium(IV). Exemplary Lewis acids include boron trifluoride diethyl etherate (BF 3 ·Et 2 O), trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate or TMSOTf), TiCl 4 , SnCl 4 , and FeCl 3 , but are not limited thereto.

[0012] "Bronsted acid", "Bronsted acid", or "Bronsted-Lowry acid" refers to an acid that can donate a proton and form a conjugate base. Examples of Bronsted acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen tetrafluoroborate, and sulfuric acid; and organic acids such as carboxylic acids like acetic acid and trifluoroacetic acid (TFA), or sulfonic acids like p-toluenesulfonic acid and trifluoromethanesulfonic acid, but are not limited thereto. Exemplary Bronsted acids include, but are not limited to, formic acid, acetic acid, dichloroacetic acid, and trifluoroacetic acid.

[0013] "Inorganic acid" or "mineral acid" is an acid derived from one or more inorganic compounds. Inorganic acids form hydrogen ions and conjugate bases when dissolved in water. Exemplary inorganic acids include, but are not limited to, hydrochloric acid and phosphoric acid.

[0014] "Organic acid" is an organic compound that is a compound containing a carbon-hydrogen bond and having an acidic moiety. Organic acids include alkane carboxylic acids whose acidity is related to the carboxyl group -COOH, and arylsulfonic acids containing an -SO 2 OH group, but are not limited thereto. Exemplary organic acids include, but are not limited to, acetic acid and p-toluenesulfonic acid.

[0015] "Protecting group" refers to a moiety of a compound that shields or modifies the properties of a functional group or the compound as a whole. The chemical structures of protecting groups vary widely. One function of a protecting group is to function as an intermediate in the synthesis of a desired compound. Chemical protecting groups and strategies for protection / deprotection are well-known in the art. See also Protective Groups in Organic Chemistry, Peter G.M. Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often used to shield the reactivity of a particular functional group to assist the effectiveness of a desired chemical reaction, e.g., to regularly and systematically form and cleave chemical bonds. "Amine protecting group" refers to a protecting group useful for protecting an amine having at least one uncharged hydrogen.

[0016] "Protecting agent" is a chemical reactant capable of effecting the attachment of a protecting group. "Amine protecting agent" is a reactant capable of effecting the attachment of an amine protecting group to an amine.

[0017] "Metalating agent" is a chemical reactant capable of effecting the transfer of an organic ligand from a compound, where the ligand has a carbon bonded to a metal atom on the compound. III. Preparation Methods

[0018] This specification provides methods for preparing compounds of formula (II-a) or formula (II-b) on various scales, such as multi-gram or kilogram scale. In some embodiments, the present disclosure is a method for preparing a compound of formula (II-a) or formula (II-b), comprising:

Chemical formula

Chemical formula

Chem.

Chem.

[0019] In some embodiments, the disclosure is a method for preparing a compound of formula (II-a) or formula (II-b),

Chem.

Chem.

Chem.

Chem.

[0020] In some embodiments, the disclosure is a method of preparing a compound of formula (II-a) or formula (II-b), comprising

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] In some embodiments, a method for preparing a compound of formula (II-a) or formula (II-b) comprises:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0022] In some embodiments, the method for preparing a compound of formula (II-a) or formula (II-b) is [Chemical formula] (a) preparing a first input mixture in a first reactor, the first input mixture comprising an amine protecting agent, a first base, a metalating agent, and a compound of formula (IV), [Chemical formula] the first reactor providing a first output mixture, (b) adding the first output mixture and a compound of formula (V) to form a second input mixture in a second reactor, the compound of formula (V) having the following structure, [Chemical formula] wherein R a is [Chemical formula] and M a is Li or MgX a and X a is Cl, Br, or I, X b is Cl, Br, or I, the metalating agent is R 2 MgX 2 or R 2 Li, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, X2 is Cl, Br, or I, The second reactor provides a second output mixture comprising a compound of formula (II-a) or formula (II-b).

[0023] In some embodiments, the method for preparing a compound of formula (II-a) or formula (II-b) comprises

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0024] In some embodiments, X a is Cl, Br, or I. In some embodiments, X a is Br or I. In some embodiments, X a is Cl. In some embodiments, X a is Br. In some embodiments, X a is I.

[0025] In some embodiments, M a is Li or MgX a . In some embodiments, M a is Li. In some embodiments, M a is MgX a . In some embodiments, M a is MgCl. In some embodiments, M a is MgBr. In some embodiments, M a is MgI.

[0026] In some embodiments, X bis Cl, Br, or I. In some embodiments, X b is Br or I. In some embodiments, X b is Cl. In some embodiments, X b is Br. In some embodiments, X b is I.

[0027] In some embodiments, the compound of formula (IV) has the following structure.

Chemical formula

Chemical formula

Chemical formula

[0028] In some embodiments, R a is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0029] In some embodiments, the compound of formula (V) has the following structure. [Chemical formula] In some embodiments, the compound of formula (V) has the following structure. [Chemical formula] In some embodiments, the compound of formula (V) has the following structure. [Chemical formula] In some embodiments, the compound of formula (V) has the following structure. [Chemical formula]

[0030] When preparing the compound of formula (II-a) or formula (II-b), any suitable amine protecting agent well-known in the art can be used. In some embodiments, the amine protecting agent is an anhydride, a silyl halide, or a silyl trifluoromethanesulfonate. Suitable anhydrides include, but are not limited to, trifluoroacetic anhydride and di(tert-butyl) dicarbonate. Silyl halides include trimethylsilyl halide (TMS-X 4 ), triethylsilyl halide (TES-X 4 ), triisopropylsilyl halide (TIPS-X 4 ), tert-butyldimethylsilyl halide (TBDMS-X 4 ), tert-butyldiphenylsilyl halide (TBDPS-X 4 ), triphenylsilyl halide (TPS-X 4 ), 1,2-bis(halodimethylsilyl)ethane (X 4 Me 2 SiCH 2 -CH 2 SiMe 2 X 4 ), but are not limited thereto, wherein X4 is Cl, Br, or I. Examples of silyl trifluoromethanesulfonates include, but are not limited to, trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), tert-butyldiphenylsilyl trifluoromethanesulfonate (TBDPSOTf), and triphenylsilyl trifluoromethanesulfonate. In some embodiments, the amine protecting agent is trifluoroacetic anhydride, di(tert-butyl) dicarbonate, trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis(chlorodimethylsilyl)ethane. In some embodiments, the amine protecting agent is trimethylsilyl chloride (TMSCl).

[0031] When preparing a compound of formula (II-a) or formula (II-b), any suitable first base capable of deprotonating the compound of formula (IV) can be used. In some embodiments, the first base is an alkylmagnesium halide optionally complexed with a lithium halide, such as a Grignard reagent like iPrMgCl or iPrMgCl-LiCl; an alkyllithium reagent; an aryllithium reagent; or an inorganic hydride such as sodium hydride or potassium hydride. In some embodiments, the first base is R 1 MgX 1 or R 1 Li. R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl, Br, or I.

[0032] ​In some embodiments, the first base is R 1 MgX 1 or R 1 Li, where R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl, Br, or I, provided that when R 1 is methyl, X 1 is Cl or I. In some embodiments, the first base is R 1 MgX 1 or R 1 Li, where R 1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl, Br, or I. In some embodiments, the first base is R 1 MgX 1 or R 1 Li, where R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl or I. In some embodiments, the first base is R 1 MgX 1 or R 1 Li, where R 1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl or I.

[0033] In some embodiments, the first base is R 1 MgX 1 where R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl, Br, or I, provided that when R 1 is methyl, X 1 is Cl or I. In some embodiments, the first base is R 1 MgX 1 where R 1is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl, Br, or I. In some embodiments, the first base is R 1 MgX 1 where R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl or I. In some embodiments, the first base is R 1 MgX 1 where R 1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 1 is Cl or I.

[0034] In some embodiments, the first base is R 1 MgX 1 wherein in some embodiments, R 1 is isopropyl or phenyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is phenyl. In some embodiments, X 1 is Cl. In some embodiments, the first base is iPrMgCl or PhMgCl. In some embodiments, the first base is iPrMgCl. In some embodiments, the first base is PhMgCl.

[0035] When preparing a compound of formula (II-a) or formula (II-b), any suitable metalating agent that can effect a metal exchange reaction of the compound of formula (IV) can be used. For example, the metalating agent can be an alkylmagnesium halide optionally complexed with a lithium halide, such as a Grignard reagent like iPrMgCl or iPrMgCl-LiCl; an alkyllithium reagent; or an aryllithium reagent. In some embodiments, the metalating agent is R 2 MgX 2 or R 2 Li, where R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 2 is Cl, Br, or I. In some embodiments, the metallating agent is R 2 MgX 2 . In some embodiments, R 2 is isopropyl or phenyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is phenyl. In some embodiments, X 2 is Cl. In some embodiments, the metallating agent is iPrMgCl or PhMgCl. In some embodiments, the metallating agent is iPrMgCl. In some embodiments, the metallating agent is PhMgCl.

[0036] In some embodiments, the first base and the metallating agent are each an alkyllithium reagent. In some embodiments, one of the first base and the metallating agent is an alkyllithium reagent and the other is a Grignard reagent. In some embodiments, the first base and the metallating agent are each a Grignard reagent. In some embodiments, the first base is PhMgCl and the metallating agent is iPrMgCl. In some embodiments, the first base is PhMgCl and the metallating agent is iPrMgCl-LiCl. In some embodiments, the first base is iPrMgCl and the metallating agent is PhMgCl. In some embodiments, the first base is iPrMgCl and the metallating agent is iPrMgCl. In some embodiments, the first base is iPrMgCl-LiCl and the metallating agent is iPrMgCl-LiCl.

[0037] In some embodiments, the first base is PhMgCl, the metallating agent is iPrMgCl, and M a is MgCl. In some embodiments, the first base is PhMgCl, the metallating agent is iPrMgCl-LiCl, and M ais MgCl. In some embodiments, the first base is iPrMgCl, the metallating agent is PhMgCl, M a is MgCl. In some embodiments, the first base is iPrMgCl, the metallating agent is iPrMgCl, M a is MgCl. In some embodiments, the first base is iPrMgCl-LiCl, the metallating agent is iPrMgCl-LiCl, M a is MgCl.

[0038] In some embodiments, the amine protecting agent is trimethylsilyl chloride (TMSCl), the first base is PhMgCl, the metallating agent is iPrMgCl, M a is MgCl. In some embodiments, the amine protecting agent is triethylsilyl chloride (TESCl), the first base is PhMgCl, the metallating agent is iPrMgCl, M a is MgCl. In some embodiments, the amine protecting agent is triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis(chlorodimethylsilyl)ethane, the first base is PhMgCl, the metallating agent is iPrMgCl, M a is MgCl.

[0039] In some embodiments, the first input mixture further comprises a first solvent. In some embodiments, the first output mixture further comprises a first solvent. In some embodiments, the first solvent is added to the first reactor. In some embodiments, the first solvent is added to the second reactor. When preparing the compound of formula (II-a) or formula (II-b), any suitable solvent can be used as the first solvent. Suitable solvents include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene and n-heptane; and halogenated solvents such as 1,2-dichloroethane, chloroform, and chlorobenzene, but are not limited thereto. In some embodiments, the first input mixture further comprises a first solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof. In some embodiments, the first solvent is tetrahydrofuran (THF).

[0040] To prepare the compound of formula (II-a) or formula (II-b), any suitable reactor or combination of reactors well known in the art can be used. Exemplary reactors that can be used to prepare the compound of formula (II-a) or formula (II-b) include, but are not limited to, batch reactors, continuous flow reactors, plug flow reactors, continuous tubular reactors, continuous stirred tank reactors, mixed flow reactors, semi-batch reactors, or combinations thereof. In some embodiments, one reactor is used. In some embodiments, two reactors are used. In some embodiments, three reactors are used.

[0041] In some embodiments, the first reactor and the second reactor are different reactors. In some embodiments, the first reactor and the second reactor are the same type of reactor. In some embodiments, the first reactor and the second reactor are different types of reactors. In some embodiments, the first reactor and the second reactor are a single reactor. In some embodiments, the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor. In some embodiments, the first reactor is a first reaction zone within a single reactor, and the second reactor is a second reaction zone within the single reactor.

[0042] In some embodiments, to prepare a compound of formula (II-a) or formula (II-b), one reactor having a first reaction zone and a second reaction zone is used. The first input mixture can be prepared in the first reaction zone of the reactor over a first time at a first set of reaction conditions including a first temperature and a first pressure. The first input mixture can be reacted to provide a first output mixture as it moves from the first reaction zone to the second reaction zone. A compound of formula (V) can be added to the second reaction zone of the reactor over a second time at a second set of reaction conditions including a second temperature and a second pressure. In some embodiments, one reactor having a first reaction zone and a second reaction zone is a plug flow reactor. In some embodiments, one reactor having a first reaction zone and a second reaction zone is a continuous tubular reactor. In some embodiments, one reactor having a first reaction zone and a second reaction zone includes a recirculation loop. In some embodiments, the first input mixture and the compound of formula (V) are added separately. In some embodiments, the first input mixture is added to the first reaction zone and the compound of formula (V) is added to the second reaction zone. In some embodiments, the first input mixture and the compound of formula (V) are added simultaneously to the first reaction zone.

[0043] In some embodiments, to prepare a compound of formula (II-a) or formula (II-b), one reactor having one reaction zone is used. The first input mixture and the compound of formula (V) can be added to one reaction zone over a first time period under a first set of reaction conditions including a first temperature and a first pressure. Then, one reaction zone of the one reactor can be shifted to a second set of reaction conditions including a second temperature and a second pressure over a second time period. In some embodiments, the one reactor having one reaction zone is a batch reactor. In some embodiments, the first input mixture is added to one reaction zone under a first set of reaction conditions, then the compound of formula (V) is added to the one reaction zone, and the one reactor is shifted to a second set of reaction conditions. In some embodiments, the one reactor having one reaction zone is a semi-batch reactor. In some embodiments, the first input mixture and the compound of formula (V) are added to one reaction zone at a temperature of about -20°C to about 20°C, at a pressure of about 0.1 bar to about 10 bar, over a time period of about 1 hour to about 24 hours to produce a compound of formula (II-a) or formula (II-b).

[0044] In some embodiments, to prepare a compound of formula (II-a) or formula (II-b), two reactors including a first reactor and a second reactor are used. The first reactor can operate under a first set of reaction conditions including a first temperature and a first pressure. The second reactor can operate under a second set of reaction conditions including a second temperature and a second pressure. In some embodiments, the first reactor and the second reactor are the same type of reactor. In some embodiments, the first reactor and / or the second reactor is a batch reactor. In some embodiments, the first reactor and / or the second reactor is a different type of reactor. In some embodiments, the first reactor and / or the second reactor is a semi-batch reactor. In some embodiments, the first reactor and the second reactor are continuous stirred tank reactors.

[0045] To prepare a compound of formula (II-a) or formula (II-b), any suitable temperature can be used in the first reactor. The first reactor is maintained at a first temperature suitable for providing the first output mixture at an appropriate time and yield. In some embodiments, the first reactor is maintained at a first temperature of about -78°C to about 20°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about 0°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about -5°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C to about -10°C. In some embodiments, the first reactor is cooled to a first temperature of about -20°C.

[0046] The method for preparing a compound of formula (II-a) or formula (II-b) can be carried out at any suitable pressure. For example, the first reactor can have a first pressure. Suitable first pressures can be less than atmospheric pressure, atmospheric pressure, or greater than atmospheric pressure. Other suitable first pressures can be, but are not limited to, 0.1 to 10 bar, 0.2 to 9 bar, 0.3 to 8 bar, 0.4 to 7 bar, 0.5 to 6 bar, 0.6 to 5 bar, 0.7 to 4 bar, 0.8 to 3 bar, 0.9 to 2 bar, or about 1 bar. In some embodiments, the first pressure can be atmospheric pressure. In some embodiments, the first pressure can be about 1 bar.

[0047] The method for preparing a compound of formula (II-a) or formula (II-b) can be carried out at any suitable time. For example, the first time for preparing a compound of formula (II-a) or formula (II-b) can be, but is not limited to, 1 to 600 minutes, 30 to 600 minutes, 60 to 600 minutes, 60 to 300 minutes, 60 to 240 minutes, 60 to 180 minutes, 90 to 150 minutes, or about 120 minutes. In some embodiments, the first time for preparing a compound of formula (II-a) or formula (II-b) can be about 120 minutes. In some embodiments, the first time for preparing a compound of formula (II-a) or formula (II-b) can be about 90 minutes.

[0048] In some embodiments, the second input mixture further comprises a second solvent. In some embodiments, the second output mixture further comprises a second solvent. In some embodiments, the second solvent is added to the second reactor. In some embodiments, the second solvent is the same as the first solvent. In some embodiments, the second solvent is different from the first solvent. When preparing the compound of formula (II-a) or formula (II-b), any suitable solvent can be used as the second solvent. Suitable solvents include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene and n-heptane; and halogenated solvents such as 1,2-dichloroethane, chloroform, and chlorobenzene, but are not limited thereto. In some embodiments, the second input mixture further comprises a second solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof. In some embodiments, the second solvent is tetrahydrofuran (THF).

[0049] Any suitable temperature can be used in the second reactor to prepare the compound of formula (II-a) or formula (II-b). The second reactor is maintained at a temperature suitable to provide the second output mixture containing the compound of formula (II-a) or formula (II-b) at an appropriate time and yield. In some embodiments, the second reactor is maintained at a temperature of about -20°C to about 40°C. In some embodiments, the second reactor is maintained at a temperature of about 10°C to about 30°C. In some embodiments, the second reactor is maintained at a temperature of about 20°C.

[0050] The method for preparing the compound of formula (II-a) or formula (II-b) can be carried out at any suitable pressure. For example, the second reactor can have a second pressure. The suitable second pressure can be less than atmospheric pressure, atmospheric pressure, or greater than atmospheric pressure. Other suitable first pressures can be 0.1 to 10 bar, 0.2 to 9 bar, 0.3 to 8 bar, 0.4 to 7 bar, 0.5 to 6 bar, 0.6 to 5 bar, 0.7 to 4 bar, 0.8 to 3 bar, 0.9 to 2 bar, or about 1 bar, but are not limited thereto. In some embodiments, the first pressure can be atmospheric pressure. In some embodiments, the first pressure can be about 1 bar.

[0051] The method for preparing the compound of formula (II-a) or formula (II-b) can be carried out at any suitable time. For example, the second time for preparing the compound of formula (II-a) or formula (II-b) can be 1 to 50 hours, 1 to 48 hours, 1 to 40 hours, 1 to 30 hours, 1 to 24 hours, 2 to 12 hours, 4 to 12 hours, 6 to 10 hours, 6 to 24 hours, 10 to 20 hours, or 12 to 18 hours, but are not limited thereto. In some embodiments, the second time for preparing the compound of formula (II-a) or formula (II-b) can be about 8 hours. In some embodiments, the second time for preparing the compound of formula (II-a) or formula (II-b) can be 12 to 18 hours.

[0052] The compound of formula (II-a) or formula (II-b) can be isolated by any suitable method well-known in the art, including concentration, extraction, grinding, crystallization, and / or chromatography.

[0053] In some embodiments, the method further comprises combining a second output mixture with an acid. In some embodiments, the acid comprises a Bronsted acid. In some embodiments, the acid comprises an organic acid or a mineral acid, or a combination thereof. In some embodiments, the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, benzoic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid, or a combination thereof. In some embodiments, the acid comprises an organic acid. In some embodiments, the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, or benzoic acid. In some embodiments, the acid comprises acetic acid.

[0054] In some embodiments, the method for preparing a compound of formula (II-a) or formula (II-b) further comprises preparing a compound of formula (V), and the method comprises: (a1) a compound of formula (III),

Chemical formula

[0055] In some embodiments, the amine has the following formula.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0056] In some embodiments, X 3 is Cl, Br, or I. In some embodiments, X 3 is Br or I. In some embodiments, X 3 is Cl. In some embodiments, X 3 is Br. In some embodiments, X 3 is I.

[0057] In some embodiments, the third base is R 3 MgX 3 wherein R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 3 is Cl, Br, or I. In some embodiments, the third base is R 3 MgX 3 wherein R 3 is methyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X 3 is Cl or Br. In some embodiments, the third base is R 3 MgCl, and R 3 is methyl, isopropyl, tert-butyl, or phenyl. In some embodiments, the third base is MeMgCl, iPrMgCl, or t-BuMgCl. In some embodiments, the third base is iPrMgCl.

[0058] In some embodiments, the amine has the following formula,

Chemical formula

[0059] When preparing the compound of formula (V) by the method described herein, any suitable solvent can be used. In some embodiments, the third reaction mixture further comprises a third solvent that is an ether solvent or a chlorinated solvent. In some embodiments, the third reaction mixture further comprises a third solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof. In some embodiments, the third reaction mixture further comprises a third solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, or a combination thereof. In some embodiments, the third solvent is tetrahydrofuran (THF).

[0060] When preparing the compound of formula (V), any suitable temperature can be used. In some embodiments, the third reaction mixture is maintained at a temperature of about -78°C to about 40°C. In some embodiments, the third reaction mixture is maintained at a temperature of about -20°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 0°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 10°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 15°C to about 25°C. In some embodiments, the third reaction mixture is maintained at a temperature of about 20°C.

[0061] In some embodiments, the method comprises (a1) a compound of formula (III) having the following structure: [Chemical formula] An amine having the following formula, [Chemical formula] forming a third reaction mixture containing iPrMgCl, thereby forming a compound of formula (V) having the following structure, [Chemical formula] (a) preparing a first input mixture in a first reactor, the first input mixture containing TMS-Cl, PhMgCl, iPrMgCl, and a compound of formula (IV) having the following structure, [Chemical formula] the first reactor providing a first output mixture, (b) adding the first output mixture and the compound of formula (V) to a second reactor, thereby forming a compound of formula (II-a) or formula (II-b) having the following structure. [Chemical formula]

[0062] The compound of formula (II-a) having the following structure is [Chemical formula] also known as (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol.

[0063] As is generally understood in the art, the compound of formula (II-a) having the following structure is [Chemical formula] present in equilibrium with a compound of formula (II-b) having the following structure. [Chemical formula] Accordingly, as used herein, a compound of formula (II-a) having the above structure, when recited alone, is understood to mean a compound of formula (II-a) and / or a compound of formula (II-b) or any combination of two species.

[0064] The methods of the present disclosure are suitable for the synthesis of gram to kilogram amounts of compounds of formula (II-a) or formula (II-b) from compounds of formula (III). In some embodiments, the third reaction mixture comprises at least 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 10 kg, 20 kg, 30 kg, 40 kg, 50 kg, 100 kg, 200 kg, 500 kg, or at least 1000 kg or more of a compound of formula (III). In some embodiments, the third reaction mixture comprises at least 1 kg of a compound of formula (III). In some embodiments, the third reaction mixture comprises from about 50 g to about 100 kg, such as from about 50 g to about 20 kg, or from about 30 g to about 20 kg of a compound of formula (III). In some embodiments, the third reaction mixture comprises from about 5 kg to about 15 kg of a compound of formula (III). For example, in some embodiments, the third reaction mixture comprises about 10 kg of a compound of formula (III).

[0065] A compound of formula (III) having the following structure is

Chemical formula

[0066] A compound of formula (IV) having the following structure is

Chemical formula

[0067] The method of the present disclosure can provide the compound of formula (II-a) or formula (II-b) in any suitable yield from the compound of formula (III) or the compound of formula (V). For example, the compound of formula (II-a) or formula (II-b) can be prepared in a yield of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or at least 99%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 60% to about 100%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 70% to about 80% or from about 75% to about 85%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is about 60%, about 70%, about 72%, about 74%, about 75%, about 76%, about 78%, about 80%, about 82%, about 84%, about 85%, about 86%, about 88%, about 90%, about 95%, about 97%, about 98%, or about 99%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is about 79%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 60% to about 90%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 70% to about 90%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 70% to about 80%. In some embodiments, the yield of the compound of formula (II-a) or formula (II-b) is from about 75% to about 85%.

[0068] The method of the present disclosure can provide a compound of formula (II-a) or formula (II-b) in any suitable purity from a compound of formula (III) or a compound of formula (V). For example, the compound of formula (II-a) or formula (II-b) can be prepared with a purity of about 90% to about 100%, such as about 95% to about 100%, or about 98% to about 100%. In some embodiments, the purity of the compound of formula (II-a) or formula (II-b) is about 98% to about 100%. In some embodiments, the compound of formula (II-a) or formula (II-b) is prepared with a purity of about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.9%, about 99.99%, about 99.999%, about 99.9999%, or about 99.99999%. In some embodiments, the compound of formula (II-a) or formula (II-b) is prepared with a purity of about 99.92%. In some embodiments, the compound of formula (II-a) or formula (II-b) is prepared with a purity of about 95% to about 99.999%, about 98% to about 99.999%, about 98% to about 99.99%, or about 99% to about 99.99%. In some embodiments, the purity of the compound of formula (II-a) or formula (II-b) is about 90% to about 100%. IV.

Examples

[0069] Example 1. Synthesis of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

Chem.

[0070] The foregoing disclosure has been described in some detail for purposes of explanation and illustration to clarify understanding. However, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the extent that each reference is individually incorporated by reference as if set forth herein in full. In the event of a conflict between this application and the references provided herein, this application shall control. According to a preferred embodiment of the present invention, for example, the following is provided. (Item 1) A method for preparing a compound of formula (II-a) or formula (II-b), comprising:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

**Claim 1** A method for preparing a compound of formula (II-a) or formula (II-b), comprising: 【Chemical Formula 66】 (a) preparing a first input mixture to provide a first output mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metalating agent, and a compound of formula (IV); 【Chemical 67】 and (b) preparing a second input mixture comprising the first output mixture and a compound of formula (V) to provide a second output mixture comprising the compound of formula (II-a) or formula (II-b), wherein the compound of formula (V) has the following structure: 【Chemical Formula 68】 wherein R ａ is 【Chemical Formula 69】 and M ａ is MgX ａ and X ａ is Cl, Br, or I, X ｂ is Cl, Br, or I, wherein the first base is PhMgCl; the metalating agent is R₂MgX₂; R₂ is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X₂ is Cl, Br, or I. A method. **Claim 2** For preparing the compound of formula (II-a) or formula (II-b), (a) preparing the first input mixture in a first reactor, wherein the first input mixture comprises the amine protecting agent, the first base, the metalating agent, and the compound of formula (IV), and the first reactor provides the first output mixture; and (b) adding the first output mixture and the compound of formula (V) to form the second input mixture in a second reactor. The method according to claim 1, wherein the second reactor provides the second output mixture comprising the compound of formula (II-a) or formula (II-b). **Claim 3** The method according to claim 1 or claim 2, wherein the amine protecting agent is trifluoroacetic anhydride, di(tert-butyl) dicarbonate, trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis(chlorodimethylsilyl)ethane. **Claim 4** The method according to claim 3, wherein the amine protecting agent is trifluoroacetic anhydride or di(tert-butyl) dicarbonate. **Claim 5** The method according to claim 1, wherein the metalating agent is iPrMgCl. **Claim 6** The amine protecting agent is trimethylsilyl chloride (TMSCl), The metallating agent is iPrMgCl, M ａ The method according to claim 1, wherein M is MgCl.

7. The method according to claim 1, wherein the first input mixture further comprises a first solvent which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

8. The method according to claim 7, wherein the first solvent is tetrahydrofuran (THF).

9. The method according to claim 2, wherein the first reactor is maintained at a temperature of about -78°C to about 20°C.

10. The method according to claim 2, wherein the first reactor is cooled to a temperature of about -20°C to about 0°C.

11. The method according to claim 1, wherein the second input mixture further comprises a second solvent which is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

12. The method according to claim 11, wherein the second solvent is tetrahydrofuran (THF).

13. The method according to claim 2, wherein the second reactor is maintained at a temperature of about -20°C to about 40°C.

14. The method according to claim 2, wherein the second reactor is maintained at a temperature of about 10°C to about 30°C.

15. The method according to claim 2, wherein the second reactor is maintained at a temperature of about 20°C.

16. The method according to claim 1, further comprising combining the second output mixture with an acid.

17. The method according to claim 16, wherein the acid comprises an organic acid or an inorganic acid, or a combination thereof.

18. The method according to claim 16, wherein the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, benzoic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid, or a combination thereof.

19. The method according to claim 18, wherein the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, benzoic acid, phosphoric acid, sulfuric acid, or a combination thereof.

20. The method according to claim 16, wherein the acid comprises an organic acid.

21. The method according to claim 16, wherein the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, or benzoic acid.

22. The method according to claim 16, wherein the acid comprises acetic acid.

23. The method further comprising preparing the compound of formula (V), the method comprising: (a1) a compound of formula (III), 【Chemical 88】 Formula H-R ａ amine, and R ３ MgX ３ or R ３ forming a third reaction mixture comprising a third base which is Li wherein: R ３ is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl, and X ３ is Cl, Br, or I, thereby providing the compound of formula (V), the method according to claim 1.

24. The method according to claim 23, wherein the amine has the following formula. 【Chemical 89】

25. The method according to claim 24, wherein the third base is iPrMgCl.

26. The method according to claim 23, wherein the third reaction mixture further comprises a third solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

27. The method according to claim 26, wherein the third solvent is tetrahydrofuran (THF).

28. The method according to claim 23, wherein the third reaction mixture is maintained at a temperature of about -78°C to about 40°C.

29. The method according to claim 23, wherein the third reaction mixture is maintained at a temperature of about -20°C to about 25°C.

30. The method comprises: (a1) the compound of formula (III) having the following structure, 【Chemical Formula 91】 the amine having the following formula, 【Chemical Formula 92】 forming the third reaction mixture comprising iPrMgCl, thereby forming the compound of formula (V) having the following structure, and 【Chemical Formula 93】 (a) adding the first input mixture to the first reactor, the first input mixture comprising TMS-Cl, PhMgCl, iPrMgCl, and the compound of formula (IV) having the following structure, 【Chemical Formula 94】 the first reactor providing the first output mixture, (b) adding the first output mixture and the compound of formula (V) to the second reactor, thereby forming the compound of formula (II-a) or formula (II-b) having the following structure, the method according to claim 2. 【Chemical Formula 95】

31. The method according to claim 1, wherein the yield of the compound of formula (II-a) or formula (II-b) is about 60% to about 90%.

32. The method according to claim 1, wherein the purity of the compound of formula (II-a) or formula (II-b) is from about 90% to about 100%.

33. The method according to claim 2, wherein the first reactor and the second reactor are different reactors.

34. The method according to claim 2, wherein the first reactor and the second reactor are reactors of the same type.

35. The method according to claim 2, wherein the first reactor and the second reactor are reactors of different types.

36. The method according to claim 2, wherein the first reactor and the second reactor are a single reactor.

37. The method according to claim 36, wherein the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor.

38. The method according to claim 36, wherein the first reactor is a first reaction zone within the single reactor, and the second reactor is a second reaction zone within the single reactor.

Images