CN114057745A - Preparation method and application of triazolo [1,5-a ] pyrazine - Google Patents

Preparation method and application of triazolo [1,5-a ] pyrazine Download PDF

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CN114057745A
CN114057745A CN202110857121.8A CN202110857121A CN114057745A CN 114057745 A CN114057745 A CN 114057745A CN 202110857121 A CN202110857121 A CN 202110857121A CN 114057745 A CN114057745 A CN 114057745A
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compound
formula
salt
pharmaceutically acceptable
converting
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奚倬勋
冯莹强
冯君
贺峰
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

Abstract

The disclosure relates to a triazole [1,5-a ]]Pyrazine preparation method and application thereof. In particular to a method for preparing triazole [1,5-a ]]A process for preparing a pyrazine compound (compound of formula f) comprising the step of reacting a compound of formula e with a reducing agent to form a compound of formula f,
Figure DDA0003184513390000011
the process has simple operation, high yield and high sample quality, and is suitable for large-scale production of triazolo [1,5-a]A pyrazine. In another aspect, the disclosure also provides the use of a compound of formula f in a process for preparing an HBV inhibitor, such as a compound of formula I, or a pharmaceutically acceptable salt thereof.

Description

Preparation method and application of triazolo [1,5-a ] pyrazine
Technical Field
The disclosure relates to a preparation method and application of triazole [1,5-a ] pyrazine.
Background
WO2019020070A describes a compound (S) -N5- (3, 4-difluorophenyl) -6-methyl-N3- ((R) -1,1, 1-trifluoropropan-2-yl) -6, 7-dihydro- [1,2,3] triazolo [1,5-a ] pyrazine-3, 5(4H) -dicarboxamide with HBV inhibitory activity, and pharmacodynamic experiments show that the compound has obvious inhibitory effect on normal assembly of HBV capsid protein, and the compound has good drug absorption and high bioavailability. Meanwhile, the compound with the novel structure has no influence or little influence on the in-vitro proliferation inhibition of HepG2 cells, shows better safety,
Figure BDA0003184513380000011
the preparation process is as follows:
Figure BDA0003184513380000012
wherein 6-methyl-triazolo [1,5-a ] pyrazine is used as a key intermediate for preparing the HBV inhibitor. The Click reaction is generally used for preparing a triazole structure, however, when the Click reaction forms the triazole [1,5-a ] pyrazine structure, 6-methyl ectopic products are always generated, particularly when the Click reaction is amplified to a kilogram level, the Click reaction is not favorable for the process amplification production, and the quality and the yield of the final product are also limited
Figure BDA0003184513380000013
The question of how to avoid or reduce the production of methyl-ectopic product as impurity is directly related to the process yield of the step and the quality of the subsequent product. Therefore, a new preparation method of triazole [1,5-a ] pyrazine is needed to be developed urgently.
Disclosure of Invention
The present disclosure provides a process for The preparation of a compound of formula f or a pharmaceutically acceptable salt thereof, comprising The step of reacting a compound of formula e with a reducing agent selected from borane dimethylsulfide, sodium borohydride-trifluoroboron or sodium borohydride-aluminium trichloride, preferably borane dimethylsulfide to form a compound of formula f
Figure BDA0003184513380000021
Wherein R is1Selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy (including but not limited to methoxy, ethoxy or propoxy), cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyloxy (including but not limited to formyloxy, acetoxy or propionyloxy),
R2each independently selected from alkyl (including C)1-6Alkyl radicals, e.g. methyl, ethyl, isopropyl) or cycloalkyl radicals (including C)3-8Cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl);
R3selected from hydrogen or an amino protecting group selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl;
n is an integer of 0 to 4 (including 0, 1,2,3 or 4).
In some embodiments, R in the compound of formula f1Selected from hydrogen or C1-6Alkyl groups, including but not limited to methyl, ethyl, propyl, or isopropyl.
In some embodiments, R in the compound of formula f2Selected from methyl, ethyl, cyclopropyl or cyclopentyl.
In some embodiments, R in the compound of formula f3Selected from hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl.
In some embodiments, the compound of formula e is
Figure BDA0003184513380000022
Wherein R is1～R3As defined for the compound of formula e.
In some embodiments, the compound of formula e is
Figure BDA0003184513380000031
Wherein R is1～R3As defined for the compound of formula e.
In some embodiments, the molar ratio of the compound of formula e to the reducing agent is 1:1.5 to 1:5, and can be about 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0, or any number therebetween.
In some embodiments, the compound of formula e is reacted with a reducing agent in an organic solvent selected from tetrahydrofuran, dichloromethane, t-butyl methyl ether, toluene, or the like.
Further, some embodiments provide that the process for preparing a compound of formula f, or a pharmaceutically acceptable salt thereof, further comprises the step of converting a compound of formula c to a compound of formula e,
Figure BDA0003184513380000032
wherein R is4Selected from hydrogen or an amino protecting group selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl; r5Selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each independently optionally further selected from one or more of halogen, alkyl, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyloxySubstituted by more than one substituent, preferably hydrogen or C1-6An alkyl group.
In some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000033
wherein, P1Each independently selected from amino protecting groups selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably tert-butoxycarbonyl or benzyloxycarbonyl. Further, the conversion of the compound of formula e2 into the compound of formula e1 is also encompassed,
Figure BDA0003184513380000041
in some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000042
wherein R is1、R2、R5And n is as defined for compounds of formula c. Further, the conversion of the compound of formula e2 into the compound of formula e1 is also encompassed,
Figure BDA0003184513380000043
in some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000044
wherein R is1、R2、R5And n is as defined for compounds of formula c.
In some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000045
wherein R is1、R2、R5And n is as defined for compounds of formula c.
In some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000051
wherein R is1、R2、R5And n is as defined for compounds of formula c. Further, Boc protection or Boc deprotection protocols are described in the literature ("Protective Groups in Organic Synthesis", 5Th Ed.T.W.Greene&P.g.m.wuts) and the relevant content is incorporated into the disclosure for illustration. In some embodiments, the Boc removal protecting group is an acidic condition, which may be hydrochloric acid/dioxane.
In some embodiments, the step of converting the compound of formula c to the compound of formula e is:
Figure BDA0003184513380000052
wherein R is1、R2、R5And n is as defined for compounds of formula c.
Further, ways of removing Cbz protecting Groups are described in the literature ("Protective Groups in Organic Synthesis", 5Th ed.t.w.green & p.g.m.wuts), and relevant contents are incorporated into the present disclosure for illustration. In some embodiments, the Cbz protecting group is removed by Pd/C catalyzed hydrogenation.
In another aspect, in some embodiments, the compound of formula c is obtained by reacting a compound of formula a with a compound of formula b,
Figure BDA0003184513380000053
in some embodiments, the compound of formula a is reacted with the compound of formula b under lewis acid conditions to form the compound of formula c. Further, the lewis acid is selected from copper chloride, cuprous chloride or boron trifluoride.
In other embodiments, the solvent used to react the compound of formula a with the compound of formula b is selected from toluene.
The present disclosure also provides a compound of formula e,
Figure BDA0003184513380000054
or a salt thereof, wherein R1～R3N is as previously defined.
Some embodiments provide compounds of formula e as
Figure BDA0003184513380000061
Or a salt thereof, wherein R1～R3As previously defined.
Some embodiments provide compounds of formula e as
Figure BDA0003184513380000062
Or a salt thereof, wherein R1、R2As previously defined.
In another aspect, the compounds of formula e are chiral molecules containing a 1 chiral center, having a 2 configurational isomer.
Some embodiments provide compounds of formula e as
Figure BDA0003184513380000063
Or a salt thereof.
The present disclosure also provides a compound of formula c,
Figure BDA0003184513380000064
or a salt thereof, wherein R1、R2、R4、R5N is as previously defined.
In some embodiments, the compound of formula c is
Figure BDA0003184513380000065
Or a salt thereof, wherein R1、R2、R4、R5As previously defined.
In some embodiments, the compound of formula c is
Figure BDA0003184513380000066
Or a salt thereof, wherein R1、R4、R5As previously defined.
In another aspect, the compounds of formula c are chiral molecules containing a 1 chiral center, having a 2 configurational isomer. Some embodiments provide that the compound of formula c is
Figure BDA0003184513380000071
Or a salt thereof, wherein R1、R4As previously defined.
The present disclosure also provides a process for preparing a compound of formula g or a salt thereof,
Figure BDA0003184513380000072
comprising the aforementioned process steps for the preparation of a compound of formula f and the conversion of a compound of formula f to a compound of formula g or a salt thereof, or the conversion of a compound of formula c or a salt thereof to a compound of formula g or a pharmaceutically acceptable salt thereof, or the conversion of a compound of formula e or a salt thereof to a compound of formula g or a salt thereof,
Figure BDA0003184513380000073
wherein R is1～R3And n is as defined above.
In some embodiments, the compound of formula g is
Figure BDA0003184513380000074
Or a salt thereof, wherein R1、R2And n is as defined above.
In some embodiments, the compound of formula g is
Figure BDA0003184513380000075
Or a salt thereof, wherein R1As defined above.
In another aspect, the compounds of formula g are chiral molecules containing a 1 chiral center, having a 2 configurational isomer.
In some embodiments, the compound of formula g is
Figure BDA0003184513380000081
Or a salt thereof, wherein R1As defined above.
Further, the process for preparing the compound of formula g or a salt thereof comprises removing the amino protecting group P from the compound of formula f1-12Followed by a step of converting the compound of formula f2-1 to a compound of formula g-1,
Figure BDA0003184513380000082
wherein, P2Selected from amino protecting groups selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably tert-butoxycarbonyl or benzyloxycarbonyl, R1、R2As defined for the compound of formula g.
In some embodiments, a process for preparing a compound of formula g, or a salt thereof, includes the step of converting a compound of formula f2-1 to a compound of formula g-1,
Figure BDA0003184513380000083
wherein R is1、R2As defined for the compound of formula g. Specific reaction conditions or operations can be found in journal literature WO 2019020070A.
The present disclosure also provides a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the aforementioned process for preparing a compound of formula f and the aforementioned step of converting a compound of formula f to a compound of formula I, or a pharmaceutically acceptable salt thereof, or the aforementioned process step for preparing a compound of formula g, or a salt thereof, and the aforementioned step of converting a compound of formula g to a compound of formula I, or a pharmaceutically acceptable salt thereof, or the aforementioned step of converting a compound of formula c, or a salt thereof, to a compound of formula I, or a pharmaceutically acceptable salt thereof, or the aforementioned step of converting a compound of formula e, or a salt thereof, to a compound of formula I, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula I is
Figure BDA0003184513380000084
Or a pharmaceutically acceptable salt thereof, wherein R2And n is as defined above.
In some embodiments, the compound of formula I is
Figure BDA0003184513380000091
Or a pharmaceutically acceptable salt thereof.
In another aspect, the compounds of formula I of the present disclosure are chiral molecules containing two different chiral centers, with four configurational isomers.
In some embodiments, the compound of formula I is
Figure BDA0003184513380000092
Or a pharmaceutically acceptable salt thereof.
Some embodiments provide a method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprising the step of reacting a compound of formula f with 1,1,1, -trifluoropropan 2-amine or a salt thereof to form a compound of formula h
Figure BDA0003184513380000093
Wherein R is1～R3And n is as defined in claim 1.
In some embodiments, the compound of formula h is
Figure BDA0003184513380000094
Or a salt thereof.
In some embodiments, the compound of formula h is
Figure BDA0003184513380000095
Or a salt thereof.
On the other hand, the compounds of formula h are chiral molecules containing 2 chiral centers, with 4 configurational isomers.
In some embodiments, the compound of formula h is
Figure BDA0003184513380000101
Or a salt thereof.
In some embodiments, the process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of subjecting a compound of formula e-1 to a reduction reaction to form a compound of formula f-1, converting a compound of formula f-1 to a compound of formula g-1, and reacting a compound of formula g-1 with 1,1,1, -trifluoropropan 2-amine, or a salt thereof, to form a compound of formula I-1,
Figure BDA0003184513380000102
wherein the content of the first and second substances,
R1～R3as defined above.
In some embodiments, a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of subjecting a compound of formula e-2 to a reduction reaction to form a compound of formula f-2, converting a compound of formula f-2 to a compound of formula g-2, and reacting a compound of formula g-2 with 1,1,1, -trifluoropropan 2-amine or a salt thereof to form a compound of formula I-2
Figure BDA0003184513380000103
In some embodiments, the process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the steps of reducing a compound of formula e-2a to form a compound of formula f-2a, converting a compound of formula f-2a to a compound of formula g-2a, and reacting a compound of formula g-2a with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form a compound of formula I-2a
Figure BDA0003184513380000111
In some embodiments, the process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises
Figure BDA0003184513380000112
Step d: borane dimethyl sulfide complex/tetrahydrofuran; step e: 3, 4-difluorophenyl isocyanate, or 3, 4-difluoroaniline, N-diisopropylethylamine, bis (trichloromethyl) carbonate; step f: 1) LiOH/THF-DCM-H2O, 2) HATU/DIPEA/tetrahydrofuran, the reaction conditions or manipulations are referred to in journal articles WO2019020070A, and the relevant contents are incorporated into the disclosure for illustration.
Further, the process for preparing the compound of formula I or a pharmaceutically acceptable salt thereof further comprises
Figure BDA0003184513380000113
Step b: toluene, 100 ℃; step b: for hydrochloric acid/dioxane, specific reaction conditions or operations can be found in journal literature WO2019020070A, and relevant contents are incorporated into the present disclosure for illustration.
In another aspect, a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of reducing a compound of formula e-1 to form a compound of formula f-1, reacting a compound of formula f-1 with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form a compound of formula h-1, and converting formula h-1 to a compound of formula I-1,
Figure BDA0003184513380000121
in some embodiments, the process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of reducing a compound of formula e-2 to form a compound of formula f-2, reacting the compound of formula f-2 with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form a compound of formula h-2, and converting the compound of formula h-2 to a compound of formula I-2,
Figure BDA0003184513380000122
specific reaction conditions or operations can be found in journal literature WO2019020070A, and the relevant contents are incorporated into the present disclosure for illustrative purposes.
In some embodiments, the process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of reducing a compound of formula e-2a to form a compound of formula f-2a, reacting the compound of formula f-2a with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form a compound of formula h-2a, and converting the compound of formula h-2a to a compound of formula I-2a,
Figure BDA0003184513380000123
the present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I prepared by the foregoing process, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
In some embodiments, the compound of formula I is selected from
Figure BDA0003184513380000131
Or a pharmaceutically acceptable salt thereof.
On the other hand, the disclosure also provides the application of the compound of formula I obtained by the preparation method or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for treating viral infection diseases, wherein the viruses are preferably hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the diseases are preferably hepatitis B, influenza, herpes and AIDS.
In some embodiments, the compound of formula I is selected from
Figure BDA0003184513380000132
Or a pharmaceutically acceptable salt thereof.
The methods of the present disclosure also include one or more post-treatment operations, such as filtration, extraction, concentration, column chromatography, or hand separation, to obtain the pure desired product.
On the other hand, the click reaction described in the present disclosure needs to be performed under anhydrous, oxygen-free conditions. The solvent used can be worked up in the manner described in the handbook of solvents (fourth edition) -Chenelin.
The pharmaceutically acceptable salts described in this disclosure are the products of salt formation of the compounds of formula I with an acid selected from, but not limited to, hydrochloric, sulfuric, phosphoric, methanesulfonic, malic, or oxalic acid, and the like.
The salts described in this disclosure are the products of the salt formation of the corresponding compound with an acid selected from, but not limited to, hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, oxalic acid, or the like.
The terms used in this disclosure have the following meanings, unless stated to the contrary:
the disclosure "to form" and "to convert" does not imply that the conversion reaction between two substrates is a single step, and may be a single step or a multi-step reaction between two substrates. If the intermediate contains an amino protecting group, the intermediate is subjected to a one-step deamination protective agent and then reacts with a corresponding substrate to obtain a corresponding target product.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkoxy, alkylthio, alkylamino, aryl, heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 3 to 6 ring atoms, of which 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably piperidinyl, piperazinyl, or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably phenyl and naphthyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred is a pyridyl group.
The term "alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "acyloxy" refers to-OC (O) (alkyl) or-OC (O) (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
DIPEA diisopropylethylamine
HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
DMF N, N-dimethylformamide
THF tetrahydrofuran
"amino protecting Groups" are suitable Groups known in the art for protecting hydroxyl Groups, see the literature ("Protective Groups in Organic Synthesis)is”，5Th Ed.T.W.Greene&P.g.m.wuts). By way of example, including but not limited to, carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1- (4-biphenyl) -ethoxy-carbonyl (Bpoc), tert-Butoxycarbonyl (BOC), allyloxycarbonyl (Al loc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl and nitrophenylacetyl; sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups, such as phthalimido and dithiasuccinyl.
The "therapeutically effective amount" as referred to in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
The HPLC measurements can be performed using an Agilent 1200 HPLC (Evo C184.6 x 250mm,5um, column or Xitinate C182.1 x 30mm column).
Chiral HPLC assay used Chiralpak IF 150 x 4.6mm,5um column or Lux amide-2150 x 4.6mm,5um column.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The flash column purification system used either Combiflash Rf150(TELEDYNE ISCO) or Isolara one (Biotage).
Detailed Description
The present disclosure will be described in detail below with reference to specific embodiments so that those skilled in the art can more fully understand the present disclosure, and the specific embodiments are only used for illustrating the technical solutions of the present disclosure and do not limit the present disclosure in any way.
Example 1:
Figure BDA0003184513380000161
1) dissolving the compound 1(20g, 114.14mmol) in dichloromethane (200ml), adding triethylamine (19.0ml), cooling in an ice bath, dropwise adding methylsulfonyl chloride (14.4g, 125.71mmol), and reacting at room temperature until the TLC detection reaction is complete;
after removal of dichloromethane by concentration, 300ml of ethyl acetate was added, and washed successively with 150ml of 1M dilute hydrochloric acid, 100ml of saturated aqueous sodium bicarbonate solution and 100ml of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title product 2(28.1g, white solid) in 97.2% yield.
2) Dissolving the compound 2(4.59g, 18.12mmol) in acetonitrile (40ml), adding tetrabutylammonium azide (12.8g,44.99mmol), and heating the mixture in an oil bath until the TLC detection reaction is complete;
concentration, addition of 100ml ethyl acetate, washing with (30ml) saturated aqueous sodium bicarbonate, drying over anhydrous sodium sulfate, filtration and concentration gave the title product 3(3.39g, yellow liquid) in 93.4% yield.
1H NMR(400MHz,CDCl3)δppm：1.15-1.22(m,3H)1.45(d,J＝3.76Hz,9H)3.28-3.35(m,1H)3.39(br.s.,1H)3.85(br.s.,1H)4.54(br.s.,1H)
Example 2:
Figure BDA0003184513380000162
1) dissolving the compound 3(3.39g, 16.93mmol) in toluene (50ml), dropwise adding dimethyl butynedioate (2.53g, 17.80mmol), heating in an oil bath for reaction until the TLC detection reaction is complete, concentrating, and purifying the obtained sample by column chromatography (eluent dichloromethane/n-hexane) to obtain the target product 3.3g, wherein the yield is 56.9%.
ESI[M+1]+＝343.2。
1H NMR(400MHz,CDCl3)δppm：1.20(d,J＝6.78Hz,3H)1.36(s,9H)3.95-3.99(m,3H)4.01(s,3H)4.20(br.s.,1H)4.59(dd,J＝13.68,7.91Hz,2H)4.68-4.82(m,1H)
2) Compound 5(3.3g, 9.64mmol) was added to the reaction flask, followed by addition of hydrochloric acid/1, 4-dioxane (4M, 19.4ml), reaction at room temperature until TLC detection was complete, and concentration gave target 6(2.82g, white solid) (hydrochloride salt).
ESI[M+1]+＝243.1。
3) Compound 6(2.33g, 9.62mmol) was dissolved in DMF (15ml) and refluxed in an oil bath until the TLC detection reaction was complete, concentrated, slurried with 30ml ethyl acetate and filtered to give the title product 7(1.96g, white solid) in 96.9% yield.
ESI[M+1]+＝211.1。
1H NMR(400MHz,DMSO-d6)δppm：1.22(d,J＝6.53Hz,3H)3.85(s,3H)3.99-4.10(m,1H)4.31(dd,J＝13.05,9.54Hz,1H)4.80(dd,J＝13.05,4.27Hz,1H)8.72(s,1H)。
4) Adding the compound 7(1.13g, 5.38mmol) into a reaction bottle under argon atmosphere, adding anhydrous tetrahydrofuran (25ml), adding borane dimethyl sulfide complex (2M,8.1ml), reacting at 70 ℃ in an oil bath until the TLC detection reaction is almost complete, dropwise adding 5ml of methanol to quench the reaction, concentrating, and purifying the obtained sample by column chromatography (eluent dichloromethane/methanol) to obtain the target product of 420mg with the yield of 44.5%.
1H NMR(400MHz,DMSO-d6)δppm：1.18(d,J＝6.27Hz,3H)2.72(br.s.,1H)3.02-3.15(m,1H)3.75(t,J＝11.42Hz,1H)3.82(s,3H)3.99(d,J＝17.82Hz,1H)4.27(d,J＝17.82Hz,1H)4.48(dd,J＝12.30,3.26Hz,1H)。
Example 3:
Figure BDA0003184513380000171
1) the compound 8(1.73g, 8.82mmol) is dissolved in THF (350ml), cooled in ice bath, and then 3, 4-difluorophenyl isothiocyanate (1.5g, 9.67mmol) is added dropwise, after the addition is completed, the reaction is carried out at room temperature until the TLC detection reaction is complete, the reaction is concentrated, and the obtained sample is purified by column chromatography (eluent dichloromethane/ethyl acetate) to obtain the target product 2.9g, and the yield is 93.6%. ESI [ M +1 ]]+＝352.1。
2) Compound 9(2.9g, 8.25mmol) was dissolved in THF (25ml), and lithium hydroxide monohydrate (1.04g, 24.78mmol), methanol (6ml) and water (12ml) were added and reacted at room temperature until the reaction was essentially complete by TLC. 2ml of concentrated hydrochloric acid is dropped into the reaction liquid to quench the reaction, tetrahydrofuran is removed by concentration, 1M dilute hydrochloric acid is added to adjust the pH value, the filtration and the drying are carried out to obtain 2.48g of a target product, and the yield is 89.1%.
ESI[M+1]+＝338.1。
The product of the above step (56mg, 166.03umol) was dissolved in THF (5ml), and HATU (47mg, 199.77umol) and DIPEA (43mg, 332.71umol, 57uL) were added to react at room temperature for 30 minutes. (R) -1,1, 1-trifluoro isopropyl amine hydrochloride (30mg, 200.61umol) is added, after the addition is finished, the reaction is carried out at room temperature until the TLC detection reaction is almost completed, 20ml of water is added for quenching, ethyl acetate is used for extraction (20ml multiplied by 3), 20ml of saturated sodium chloride solution is used for washing, anhydrous sodium sulfate is used for drying, filtration and concentration are carried out, and the obtained sample is purified by column chromatography (eluent dichloromethane/methanol) to obtain 60mg of a target product, and the yield is 83.6%.
ESI[M+1]+＝433.2，
1H NMR(400MHz,CD3OD)δppm 1.20(d,J＝7.03Hz,3H)1.45(d,J＝7.03Hz,3H)4.48(dd,J＝13.18,4.39Hz,1H)4.59(d,J＝13.30Hz,1H)4.72(d,J＝18.32Hz,1H)4.82-4.87(m,1H)5.01-5.13(m,1H)5.41(d,J＝18.32Hz,1H)7.07-7.22(m,2H)7.47(dd,J＝12.30,6.78Hz,1H)8.77(d,J＝9.03Hz,1H)。
Comparative example 1:
Figure BDA0003184513380000181
the 2b compound was prepared using the well-known formula "Journal of medical Chemistry, 2014,57(9),3687-
1) Compound 2a (27g, 138.28mmol), 2b (30g, 204.68mmol) and 300ml acetonitrile were added to a 500ml reaction flask, heated to reflux until the reaction was substantially complete, concentrated and purified by column chromatography (eluent dichloromethane/ethyl acetate) to afford the title product 25g, yield 40%, Rt 2.542min, m/z 306.2 by LC-MS assay.
2) Dissolving the product of the last step in a dichloromethane solvent, adding pyridine (13.2ml, 163.72mmol), cooling in an ice bath, dropwise adding thionyl chloride (8.9ml, 122.80mmol), stirring for reacting for 2-4h, adding water to quench the reaction, adding dichloromethane 500ml, washing with sodium bicarbonate, washing with saturated saline, drying, and concentrating to obtain a crude product which is directly used for the next step reaction, wherein the Rt is 2.142min and the m/z is 324.2 by LC-MS detection.
3) Adding the product of the last step into dimethylformamide, and adding NaN3(10g, 153.82mmol), heating to 80 deg.C to react until the reaction is substantially complete, cooling to room temperature, adding Pd (OH)2Heating to 80 ℃ for reaction till the reaction is complete, adding water for quenching reaction, extracting with ethyl acetate, washing with saturated saline, drying, concentrating to obtain a crude product, and purifying by column chromatography (eluent dichloromethane/ethyl acetate) to obtain the title product 5.5g, wherein the yield is 21%, and the Rt is 1.640min and the m/z is 331.2 by LC-MS detection. Methyl ectopic product 5.9g, yield 22%, LC-MS detection, Rt 1.636min, m/z 331.2.

Claims (11)

1. A process for the preparation of a compound of formula f, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula e with a reducing agent selected from borane dimethylsulfide, sodium borohydride-trifluoroboron or sodium borohydride-aluminum trichloride, preferably borane dimethylsulfide, to form a compound of formula f,
Figure FDA0003184513370000011
wherein R is1Selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyloxy, preferably hydrogen or C1-6An alkyl group;
R2each independently selected from alkyl or cycloalkyl, preferably methyl, ethyl, cyclopropyl or cyclopentyl;
R3selected from hydrogen or an amino protecting group selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl;
n is an integer of 0 to 4.
2. The method of claim 1, further comprising the step of converting the compound of formula c to a compound of formula e,
Figure FDA0003184513370000012
wherein R is4Selected from hydrogen or an amino protecting group selected from tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or benzyloxycarbonyl, preferably hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl; r5Selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each independently optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyloxy, preferably hydrogen or C1-6An alkyl group.
3. The method of claim 1 or 2, further comprising the step of reacting the compound of formula a with the compound of formula b to form a compound of formula c,
Figure FDA0003184513370000021
wherein R is1～R2N is as defined in claim 1, R4、R5As defined in claim 2.
4. The method of any one of claims 1-3, wherein the compound of formula e is
Figure FDA0003184513370000022
Preference is given to
Figure FDA0003184513370000023
Wherein R is1～R3As defined in claim 1.
5. A compound of the formula e, wherein,
Figure FDA0003184513370000024
or a salt thereof, preferably
Figure FDA0003184513370000025
Or a salt thereof, more preferably
Figure FDA0003184513370000026
Or a salt thereof, wherein R1～R3N is as defined in claim 1.
6. A compound of the formula (c),
Figure FDA0003184513370000027
or a salt thereof, preferably
Figure FDA0003184513370000028
Or a salt thereof, more preferably
Figure FDA0003184513370000029
Or a salt thereof, wherein R1、R2N is as defined in claim 1, R4、R5As defined in claim 2.
7. A process for the preparation of a compound of formula g,
Figure FDA0003184513370000031
comprising the steps of a process according to any one of claims 1 to 4 and converting the compound of formula f to a compound of formula g or a salt thereof, or converting the compound of claim 5 or 6 to a compound of formula g or a salt thereof,
Figure FDA0003184513370000032
further preference is given to compounds of the formula g
Figure FDA0003184513370000033
Or a salt thereof, more preferably
Figure FDA0003184513370000034
Or a salt thereof, wherein R1～R3And n is as defined in claim 1.
8. A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the steps of a process according to any one of claims 1 to 4 and the step of converting a compound of formula f to a compound of formula I, or a pharmaceutically acceptable salt thereof, or the step of a process according to claim 7 and the step of converting a compound of formula g to a compound of formula I, or a pharmaceutically acceptable salt thereof, or the step of converting a compound of claim 5 or 6 to a compound of formula I, or a pharmaceutically acceptable salt thereof,
Figure FDA0003184513370000035
further preference is given to compounds of the formula I
Figure FDA0003184513370000036
Or a pharmaceutically acceptable salt thereof, more preferably
Figure FDA0003184513370000041
Or a pharmaceutically acceptable salt thereof, wherein R2And n is as defined in claim 1.
9. The method of claim 8, further comprising the step of reacting the compound of formula f with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form the compound of formula h
Figure FDA0003184513370000042
Preference is given to further compounds of the formula h
Figure FDA0003184513370000043
Or a salt thereof, more preferably
Figure FDA0003184513370000044
Or a salt thereof, wherein R1～R3And n is as defined in claim 1.
10. The process of claim 8, comprising the steps of reducing the compound of formula e-1 to form the compound of formula f-1, converting the compound of formula f-1 to the compound of g-1, and reacting the compound of formula g-1 with 1,1,1, -trifluoropropan-2-amine or a salt thereof to form the compound of formula I-1
Figure FDA0003184513370000045
Further, wherein R is2Methyl is preferred.
11. The method of claim 8, comprising the steps of:
Figure FDA0003184513370000051
further, wherein R is2Methyl is preferred.
CN202110857121.8A 2020-07-29 2021-07-28 Preparation method and application of triazolo [1,5-a ] pyrazine Pending CN114057745A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
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