CN109867659A - The preparation method of benzo piperidine derivatives - Google Patents
The preparation method of benzo piperidine derivatives Download PDFInfo
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- CN109867659A CN109867659A CN201811464055.2A CN201811464055A CN109867659A CN 109867659 A CN109867659 A CN 109867659A CN 201811464055 A CN201811464055 A CN 201811464055A CN 109867659 A CN109867659 A CN 109867659A
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Abstract
本发明提供了苯并哌啶类衍生物的制备方法。具体而言，在碱性条件下，式II‑e所示化合物与式II‑d所示化合物任选在催化剂作用下进行反应得到式II‑c所示化合物的步骤，该工艺适合工业化生产。 The invention provides a preparation method of benzopiperidine derivatives. Specifically, under alkaline conditions, the compound shown in the formula II-e and the compound shown in the formula II-d are optionally reacted under the action of a catalyst to obtain the step of the compound shown in the formula II-c, and the process is suitable for industrial production.
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of preparation method of benzo piperidine derivatives.
Background technique
A kind of class cholesterol hormone secreted by endocrine system of estrogen formula, in reproductive system, bone tissue, painstaking effort
The class cholesterol hormone of pipe, immune system and central nervous system secretion, in reproductive system, bone tissue, angiocarpy, siberian crabapple
It all plays an important role in system and central nervous system.Estrogen receptor transmission system grows, breaks up and withers in adjusting cell
It plays an important role during dying.The main chemotherapy of breast cancer is with anti-estrogenic agents such as tamoxifen at present.But
Tamoxifen shows the property of female hormone agonist in uterus, to the irritating effect of the cancer cell in uterus.For this purpose, seeking
New safely and effectively treatment method is imperative.
It is disclosed selectivity estrogen receptor mediate regulator patent application include WO2014165723,
WO2014151899, WO2014141292, WO2014191726, WO2015092634, WO2014135834 and
WO2014106848 and EP113007A discloses a series of similar female hormone excitement/anticaking agent of structures.
Recently, WO2017107754 discloses the SERD for estrogen receptor access of the high-efficiency low-toxicity of a new generation.Relatively
The AZD-9496 compound that Astrazeneca AB is developed, the new structural SERD to E and the combination of ER inhibiting effect,
ER degradation and MCF7 cell Proliferation etc. all show good activity, especially have more in terms of the Emax value of ER degradation
Advantage outstanding.Structure is as follows:
The preparation method of the compound is provided in text, that is, obtain secondary amine compound in the way of reduction enamine, and then obtain
Target compound is obtained, but its product quality (such as purity) is poor, process route yield is also not ideal enough, is not suitable for industry metaplasia
It produces,
J S.Scott et al. (ACS Med.Chem.Lett., 2016,7 (1), page 94-99) reports a kind of new
Benzo piperidine compounds method is synthesized, i.e., after first constructing benzo piperidine structure, then is alkylated reaction and obtains target product,
Route is as follows:
US20010039285 discloses the new method of construction benzo piperidine structure, that is, amide compound passes through condensation reaction
Benzo piperidine structure is constructed, and then obtains target product, route is as follows:
Summary of the invention
The present invention provides a kind of method of compound shown in new preparation formula A,
It is reacted to obtain shown in formula A-c under alkaline condition with compound shown in formula A-d including compound shown in formula A-e
The step of compound,
Wherein, R2、R10Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkyl, cycloalkanes
Base, heterocycle, aryl, heteroaryl are optionally selected from alkyl (preferably C1-6Alkyl), naphthenic base (preferably C3-8Naphthenic base), heterocycle
(preferably C3-8Heterocycle), aryl (preferably C6-10Aryl) and heteroaryl (preferably C6-10Heteroaryl) in one or more substituent groups
It is replaced；
R11、R16It is respectively identical or different, it is each independently selected from hydrogen atom, hydroxyl, alkyl, halogenated alkyl, hydroxyl alkane
Base, alkoxy, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, cycloalkanes
Base, aryl and heteroaryl are optionally selected from alkyl (preferably C1-6Alkyl), halogen (such as chlorine, bromine or iodine), amino, cyano, hydroxyl,
Hydroxyalkyl (preferably C1-6Hydroxyalkyl), alkoxy (preferably C1-6Alkoxy), naphthenic base (preferably C3-8Naphthenic base), carboxyl, aldehyde radical,
Nitro, heterocycle (preferably C3-8Heterocycle), aryl (preferably C6-10Aryl) and heteroaryl (preferably C6-10Heteroaryl) in one or
Replaced multiple substituent groups；Or R11、R16Naphthenic base, heterocycle, aryl, heteroaryl are formed, wherein the naphthenic base, heterocycle
Base, aryl or heteroaryl are optionally selected from alkyl (preferably C1-6Alkyl), halogen (such as chlorine, bromine or iodine), amino, cyano, hydroxyl,
Hydroxyalkyl (preferably C1-6Hydroxyalkyl), alkoxy (preferably C1-6Alkoxy), naphthenic base (preferably C3-8Naphthenic base), carboxyl, aldehyde radical,
Nitro, heterocycle (preferably C3-8Heterocycle), aryl (preferably C6-10Aryl), heteroaryl (preferably C6-10Heteroaryl) or-R3In one
Replaced a or multiple substituent groups；
R12Selected from alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl,
Heteroaryl is optionally selected from alkyl (preferably C1-6Alkyl), naphthenic base (preferably C3-8Naphthenic base), heterocycle (preferably C3-8Heterocycle
Base), aryl (preferably C6-10Aryl), heteroaryl (preferably C6-10Heteroaryl) or-R4In one or more substituent groups replaced；
R3、R4、R5It is respectively identical or different, it is each independently selected from hydrogen atom, hydroxyl, alkyl, halogenated alkyl, hydroxyl alkane
Base, alkoxy, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, cycloalkanes
Base, aryl and heteroaryl are optionally selected from alkyl (preferably C1-6Alkyl), halogen, amino, cyano, hydroxyl, hydroxyalkyl (preferably C1-6
Hydroxyalkyl), alkoxy (preferably C1-6Alkoxy), naphthenic base (preferably C3-8Naphthenic base), carboxyl, aldehyde radical, nitro, heterocycle it is (excellent
Select C3-8Heterocycle), aryl (preferably C6-10Aryl) or heteroaryl (preferably C6-10Heteroaryl) in one or more substituent groups taken
Generation；
R13It is each independently selected from hydrogen, amino, halogen, halogenated alkyl, hydroxyl, nitro, cyano, alkyl, naphthenic base, heterocycle
Base ,-CH=CHCOOR6、-O(CH2)hNR14R15；
R6For hydrogen atom or carboxyl-protecting group, the carboxyl-protecting group is selected from alkyl (preferably C1-6Alkyl, such as methyl, second
Base) or naphthenic base (preferably C3-8Naphthenic base, such as cyclopropyl, cyclohexyl), silylation (such as front three silicon (TMS), fert-butyidimethylsilyl
Silicon (TBS) etc.) or acyl group (such as formoxyl, acetyl group or propiono)；
R14And R15Respectively identical or different, independent is hydrogen atom, alkyl, halogenated alkyl, hydroxyalkyl, alcoxyl
Base, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, naphthenic base, aryl
Optionally alkyl (preferably C is selected from heteroaryl1-6Alkyl), halogen, amino, cyano, hydroxyl, hydroxyalkyl (preferably C1-6Hydroxyl alkane
Base), alkoxy (preferably C1-6Alkoxy), naphthenic base (preferably C3-8Naphthenic base), carboxyl, aldehyde radical, nitro, heterocycle (preferably C3-8
Heterocycle), aryl (preferably C6-10Aryl) and heteroaryl (preferably C6-10Heteroaryl) in replaced one or more substituent groups；Or
Person R14、R15Heterocycle (preferably C is formed with the nitrogen-atoms being connected3-8Heterocycle), heteroaryl (preferably C6-10Heteroaryl), wherein
The heterocycle or heteroaryl are optionally selected from alkyl (preferably C1-6Alkyl), halogen, amino, cyano, hydroxyl, hydroxyalkyl (C1-6
Hydroxyalkyl), alkoxy (preferably C1-6Alkoxy), naphthenic base (preferably C3-8Naphthenic base), carboxyl, aldehyde radical, nitro, heterocycle it is (excellent
Select C3-8Heterocycle), aryl (preferably C6-10Aryl) and heteroaryl (preferably C6-10Heteroaryl) in one or more substituent groups taken
Generation；
P is-CH2,-O- ,-NH- or-S-；
X is leaving group, the leaving group be selected from halogen, sulfonyloxy, the sulfonyloxy preferably be selected from-OTs ,-
OMs,-OTf；For double bond or singly-bound；
T, k is 0,1,2 or 3；
H is 0,1,2,3,4 or 5；
Y is 0,1,2,3 or 4；
Q is 0 or 1,2 or 3.
Further, the alkali is selected from but not limited to K2CO3、K3PO4、LiOMe、NaOEt、NaOPr、NaOiPr、
LiOtBu, NaOtBu, KOtBu, DBU (11 carbon -7- alkene of 1,8- diazabicylo), DIPEA (N, N- diisopropylethylamine),
Cs2CO3, it preferably is selected from LiOtBu, NaOtBu, KOtBu.
In non-limiting embodiments, catalyst is also contained in the reaction, the catalyst is selected from but not limited to Metal Palladium
Or at least one of copper, preferably Metal Palladium, more preferable Pd2(DBA)3。
Further, catalyst ligand is also contained in the reaction, the catalyst ligand is selected from but not limited to BINAP
((±) -2,2'- couples-(diphenyl phosphine) -1,1'- dinaphthalene), X-phos (2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl),
RuPhos (2- dicyclohexyl phosphorus -2', 6'- diisopropoxy -1,1'- biphenyl), SPhos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-diformazans
Oxygroup-biphenyl), DavePhos (2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl), JohnPhos (2- (di-t-butyl
Phosphine) biphenyl), dppf (bis- (diphenylphosphine) ferrocene of 1,1'-), dppp (bis- (diphenylphosphine) propane of 1,3-) or PPh3(triphen
Base phosphorus)；The reaction dissolvent is selected from tetrahydrofuran, dioxane, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, first
At least one of benzene or acetonitrile.
Compound shown in formula A of the present invention include its tautomer, mesomer, racemic modification, enantiomter,
Or mixtures thereof diastereoisomer or its pharmaceutical salt.
In optional embodiment, the method for compound shown in preparation formula A further includes being obtained by compound shown in formula A-c
The step of compound shown in formula A,
Work as R10When for hydrogen atom,
Work as R10When not being hydrogen atom,
Specific reaction process can refer to method described in WO2015092634, and related content is introduced into the application and is implemented by reference
Example.
Compound shown in formula A-g shown in formula A-e of the present invention reacts to obtain formula A-f institute through Mitsunobu
Show compound, the step of compound deprotection base shown in subsequent formula A-f, is prepared,
Wherein, R8、R9Respectively it is identical or different, be each independently selected from nitrobenzenesulfonyl, dinitrobenzenesulfonyl,
Benzenesulfonyl or tosyl；Or R8、R9Heterocycle, the preferred Pht of heterocycle are formed with the nitrogen-atoms being connected.
In optional embodiment, compound shown in the formula A is selected from
Wherein, R2、R3、R4、R5、R6、R10, y it is as previously described；N is 0,1,2,3,4 or 5；M is 0,1,2,3 or 4.
In optional embodiment, the method for compound shown in preparation formula II includes compound shown in Formula II-e and Formula II-d
Shown compound under alkaline condition, is optionally reacted the step of obtaining compound shown in Formula II-c under the action of catalyst,
Wherein, R1For phenolic hydroxyl protecting group, it preferably is selected from alkyl, naphthenic base, silylation or acyl group, more preferably benzyl, uncle
Fourth dimethyl silicon substrate, diphenyl tert-butyl silicon substrate, trimethyl silicon substrate, triethyl group silicon substrate；R2-R4As previously described.
Further, the alkali is selected from but not limited to K2CO3、K3PO4、LiOMe、NaOEt、NaOPr、NaOiPr、
LiOtBu, NaOtBu, KOtBu, DBU (11 carbon -7- alkene of 1,8- diazabicylo), DIPEA (N, N- diisopropylethylamine),
Cs2CO3, preferably LiOtBu, NaOtBu or KOtBu；The catalyst is selected from but not limited at least one of Metal Palladium or copper, excellent
Select Metal Palladium, more preferable Pd2(DBA)3。
Further, catalyst ligand is also contained in the reaction, the catalyst ligand is selected from but not limited to BINAP
((±) -2,2'- couples-(diphenyl phosphine) -1,1'- dinaphthalene), X-phos (2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl),
RuPhos (2- dicyclohexyl phosphorus -2', 6'- diisopropoxy -1,1'- biphenyl), SPhos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-diformazans
Oxygroup-biphenyl), DavePhos (2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl), JohnPhos (2- (di-t-butyl
Phosphine) biphenyl), dppf (bis- (diphenylphosphine) ferrocene of 1,1'-), dppp (bis- (diphenylphosphine) propane of 1,3-) or PPh3(triphen
Base phosphorus)；The reaction dissolvent is selected from tetrahydrofuran, dioxane, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, first
At least one of benzene or acetonitrile.
In optional embodiment, the method for compound shown in preparation formula II further includes that compound shown in Formula II-c is changed into
The step of compound shown in Formula II-b,
Remove R1The condition of group can be but be not limited to alkalinity or acid, can refer to Greene T.W. et al. work, East China
The condition of the related phenolic hydroxyl protecting group removing of organic chemistry teaching and research group, Polytechnics (translating) " protecting group in organic synthesis ", and will
During its related content is incorporated herein.The alkali is selected from but not limited to lithium hydroxide, sodium hydroxide, and the acid is selected from but not limited to three
Methylchlorosilane, hydrochloric acid, sulfuric acid.
In some optional embodiments, work as R10When for hydrogen atom, the method for compound shown in preparation formula II further includes formula
Compound shown in II-b carries out the step of P-S (Pickett-Shi Penggele) reacts with compound shown in Formula II-a,
Wherein, R2-R6, m, n, y it is for example aforementioned described.
Wherein, catalyst can also be added, the catalyst is acidic catalyst, and the acidic catalyst preferably is selected from front three
Base chlorosilane (TMSCl), acetic acid (HOAc), Trimethylsilyl trifluoromethanesulfonate (TMSOTf), dimethyl tertiary butyl chlorosilane
(TBSCl), at least one of pyridine xylenesulfonate (PPTS) or silica gel, preferably acetic acid (HOAc).
Compound shown in formula II-g shown in Formula II-c of the present invention reacts to obtain Formula II-f through Mitsunobu
Shown compound, the step of compound deprotection base shown in subsequent Formula II-f, are prepared,
Wherein, m, R1-R3As previously mentioned, R8、R9It is respectively identical or different, it is each independently selected from but is not limited to nitro
Benzenesulfonyl, dinitrobenzenesulfonyl, benzenesulfonyl or tosyl；Or R8、R9Heterocycle is formed with the nitrogen-atoms being connected
Base, the preferred Pht of heterocycle.
In optional embodiment, II-f is had the following structure:
Further, the heterocycle is preferably Pht (phthalyl)
The Mitsunobu Reaction condition can refer to L á szl ó K ü rti et al. work, " Strategic
Applications of Named Reactions in Organic Synthesis " described in, and related content is introduced
Herein.
The reaction condition of the removing Deprotection can refer to Greene T.W. et al. work, and East China University of Science organises
Related content in teaching and research group (translating) " protecting group in organic synthesis " is learned, and is introduced into herein.In optional embodiment,
The reaction condition of Deprotection is neutral, alkalinity or acid, the removing Deprotection condition be selected from but not limited to hydrazine hydrate,
TEA、DIPEA、DBU、NaOH、LiOH、KOH、K3PO4、Na3PO4、K2CO3、Na2CO3、Cs2CO3、Li2CO3、LiOH、PhOK、
PhONa, PhOLi, PhOCs, HBr, TMSCl, hydrofluoric acid pyridiniujm, Li, Na, Mg, propylamine, SmI2Deng can also in the condition
Mercaptan, thiocarboxylic acid, thiophenol, L- cysteine etc. is added.
In a not limiting embodiment, work as R10When for hydrogen atom, the method for compound shown in preparation formula II is as described below:
Wherein, R1-R6, m, n, y it is as previously described.
Work as R10When not being hydrogen atom, the method for compound shown in preparation formula II is as described below:
Specific reaction process can be introduced into the application referring to method described in WO2015092634, and by related content to make referring to implementation
Example, wherein R1-R6, m, n, y it is as previously described.
In optional embodiment, compound shown in heretofore described Formula II is
Compound shown in the Formula II-e isInstitute
Stating compound shown in II-c isWherein, R1-R6, m, n, y it is as previously described.
Further, compound shown in the Formula II is
Compound shown in the Formula II-e isThe II-
Compound shown in c isWherein R1As previously described.
In optional embodiment, the method for compound shown in preparation formula IIA includes the following steps:
Wherein, m, R1-R3As previously described.
Further, the step of being reacted the method also includes compound shown in Formula II A-b with compound shown in Formula II-a:
Wherein, R2-R6, m, n, y it is as previously described.
Further, the method for compound shown in preparation formula IIA further includes that compound shown in Formula II-c is changed into Formula II-b
The step of shown compound,
Formula II A-e of the present invention is prepared by following route:
Wherein, R1-R3, m it is as previously described.
In a not limiting embodiment, the method for compound shown in preparation formula IIA is as described below:
Wherein, R1-R6, m, n, y it is as previously described.
In optional embodiment, compound shown in the Formula II is selected from
In non-limiting embodiments, compound shown in Formula II is
The method of compound shown in preparation formula 28, comprising:
Wherein, X, R1As previously mentioned, X described further is preferably halogen, R1Preferably benzyl or silylation, the silane
Base is selected from tertiary fourth dimethyl silicon substrate, diphenyl tert-butyl silicon substrate, trimethyl silicon substrate, triethyl group silicon substrate.
Further, compound shown in formula III of the present invention is
Further, compound shown in formula IV of the present invention is
Further, compound shown in Formula V of the present invention is
The present invention also provides a kind of method of compound shown in preparation formula II, this method includes compound shown in Formula II-b
The step of P-S (Pickett-Shi Penggele) reacts is carried out with compound shown in Formula II-a,
Wherein, R2-R6, m, n, y it is for example aforementioned described, R10For hydrogen.
Further, catalyst can also be added in aforementioned P-S (Pickett-Shi Penggele) reaction, and the catalyst is acid
Property catalyst, the acidic catalyst preferably are selected from trim,ethylchlorosilane (TMSCl), acetic acid (HOAc), trifluoromethanesulfonic acid trimethyl
At least one in estersil (TMSOTf), dimethyl tertiary butyl chlorosilane (TBSCl), pyridine xylenesulfonate (PPTS) or silica gel
Kind, preferably acetic acid (HOAc).
In non-limiting embodiments, compound shown in Formula II A-b selects acetic acid as catalysis with compound shown in Formula II-a
Agent promotes the progress of P-S (Pickett-Shi Penggele) reaction, improves the optical purity of compound shown in gained Formula II A, improves skin
The selectivity of the isomery of Carter-Shi Penggele:
Wherein, R2-R6, m, n, y it is as previously described.
The present invention also provides a kind of methods of compound shown in preparation formula I, including compound shown in aforementioned preparation formula II
Step, the step of being converted into compound shown in Formulas I it is also preferable to include compound shown in Formula II,
Wherein, R2-R6, m, n, y it is as previously described；R7Selected from hydrogen atom, alkyl, deuteroalkyl, halogenated alkyl, hydroxyalkyl, alkane
Oxygroup, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, hydroxyl, nitro, aryl and heteroaryl, the alkyl, naphthenic base,
Aryl and heteroaryl optionally from alkyl, halogen, amino, nitro, cyano, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle,
In aryl and heteroaryl replaced a kind of or multiple substituent groups；R10Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl, miscellaneous
Aryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl are optionally selected from alkyl, naphthenic base, heterocycle, aryl
With replaced one or more substituent groups in heteroaryl.Detailed reaction route can be referring to technology contents institute in WO2017107754
It states, and related content is introduced into the application by reference.
In optional embodiment, the method for compound shown in preparation formula I is as follows:
In optional embodiment, compound shown in the Formulas I is selected from
Detailed description of the invention
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, excellent
Select the alkyl containing 1 to 12 carbon atom.Non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl and its various branched isomers etc..More
Low alkyl group preferably containing 1 to 6 carbon atom, non-limiting embodiment include methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propylene
Base, 1- ethyl propyl etc..Alkyl can be it is substituted or non-substituted, when substituted, substituent group can it is any can be used
Tie point on be substituted, the substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynes
Base, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl
Base, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to
20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably include 3 to 6 carbon atoms.Monocyclic cycloalkyl it is non-limiting
Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl
Trialkenyl, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle,
It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more
Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spirocyclanes according to the number for sharing spiro-atom between ring and ring
Base or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5
Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting example of spiro cycloalkyl group includes:
Term " cycloalkyl " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system
The full carbon polycyclic moiety of carbon atom, wherein one or more rings can be containing one or more double bonds, but none ring has
The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double
Ring, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl.
The non-limiting example of cycloalkyl includes:
Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more
Cyclic group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to
14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, it is excellent
It is selected as bicyclic, tricyclic or Fourth Ring, is more selected as bicyclic or tricyclic.The non-limiting example of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure
Ring together is naphthenic base, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be
Optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane
Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl,
Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings
Atom, wherein one or more annular atoms are the hetero atom selected from nitrogen, oxygen or S (O) m (wherein m is integer 0 to 2), but are not wrapped
The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4
It is hetero atom；It more preferably include 3 to 6 annular atoms.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, imidazolidine
Base, tetrahydrofuran base, tetrahydro-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl,
Piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc., preferably piperidyl, pyrrolidinyl.Multiring heterocyclic includes loop coil, thick
The heterocycle of ring and bridged ring.
Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle
Group, wherein one or more annular atoms are the hetero atom selected from nitrogen, oxygen or S (O) m (wherein m is integer 0 to 2), remaining annular atom
For carbon.It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14
Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double according to the number for sharing spiro-atom between ring and ring
Spiro heterocyclic radical or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4
Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical includes:
Term " condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system
The polycyclic heterocyclic group of atom, one or more rings can be containing one or more double bonds, but none ring is with completely total
The pi-electron system of yoke, wherein one or more annular atoms are the miscellaneous original selected from nitrogen, oxygen or S (O) m (wherein m is integer 0 to 2)
Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic,
Tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings
Base.The non-limiting example of condensed hetero ring base includes:
Term " bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected
Group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated, one of them or
Multiple annular atoms are the hetero atom selected from nitrogen, oxygen or S (O) m (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6
To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle can be divided into according to a group cyclic number,
Bicyclic or tricyclic is more selected as at preferably bicyclic, tricyclic or Fourth Ring.The non-limiting example of bridge heterocycle includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure
The ring risen is heterocycle, and non-limiting example includes:
Deng.
Heterocycle can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro,
Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo
Base, carboxyl or carboxylate.
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared
The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.The aryl rings can be condensed in heteroaryl
On base, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limiting example packet with the ring that precursor structure links together
It includes:
Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following groups,
It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring
Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid
Ester group, preferably phenyl.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects
From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, more preferably 5- or 6-membered, such as imidazole radicals, furyl, thienyl, thiophene
Oxazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, pyrimidine radicals, thiadiazoles, pyrazinyl etc., preferably imidazole radicals,
Pyrazolyl, pyrimidine radicals or thiazolyl；More preferably pyrazolyl or thiazolyl.The heteroaryl ring can be condensed in aryl, heterocycle
On base or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes:
Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro,
Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl
Or carboxylate.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above.
The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring
Base, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably one or more
A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl,
Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur
Base, carboxyl or carboxylate.
" acyl group " of the present invention is selected from but not limited to acetyl group, benzoyl, valeryl.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " halogenated alkyl " refers to the alkyl being optionally substituted by halogen, and wherein alkyl is as defined above.
Term " deuteroalkyl " refers to the alkyl replaced by D-atom, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " carboxyl " refers to-C (O) OH.
Term " aldehyde radical " refers to-CHO.
Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl, naphthenic base are as above determined
Justice.
Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.
Term " silylation " refers to the alkyl replaced by silicon substrate, and wherein alkyl is as defined above." silylation " be selected from but
It is not limited to tertiary fourth dimethyl silicon substrate, diphenyl tert-butyl silicon substrate, trimethyl silicon substrate, triethyl group silicon substrate.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes
The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group "
But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom
Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this
Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take
Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key
Fixed.
Material or solvent used in the present invention can lead to commercial sources acquisition, prepared by the method in WO2017107754 that can also refer to
It obtains.
The compounds of this invention structure is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR displacement (moves R
It is provided with the unit of 10-6 (ppm).The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is deuterated diformazan
Base sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
The compounds of this invention purity is determined by HPLC.
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ
advantage MAX)。
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1
60101 (492.0) are dissolved in dehydrated alcohol (5L), are added bromobenzyl (535.0), Anhydrous potassium carbonate (1179.1g).
70 DEG C of heating is stirred to react 6h, is poured into water, and filters, filter cake dry product 734g after washing 3 times；Purity: 97%, yield:
98%.
Embodiment 2
Magnesium powder (2.8g) is placed in THF (40mL), 2 iodine are added, reaction is heated to 45 DEG C.60111 (20g) are molten
Solution is directly added into 1/10 into above-mentioned reaction solution in THF (40mL), and after about 10 minutes cause, remaining solution is added dropwise, and reacts
After 1 hour, -30 DEG C are cooled to, after CuCN (0.68g) is added, is added S- propylene oxide (8.8g), it is small to be warming up to 20 DEG C of reactions 1
When, add water quenching reaction, filters, be layered after ethyl acetate dilution is added, water phase is extracted with ethyl acetate again.Combined ethyl acetate
Layer, after saturated salt washing, anhydrous sodium sulfate is dry.Filtering, obtains product 17.5g through column chromatographic purifying after concentration, purity: 98%,
Yield: 95%.
Embodiment 3
60112 (16.0g) are dissolved in THF (300ml), are added phthalimide (14.6g), triphenylphosphine
(26.0g) is cooled to T=0 extremely, is added diethyl azodiformate (17.3g), reacts 3 hours, filtering, through column layer after concentration
Analysis purifies to obtain product 23.5g, purity: 98%, yield: 96%.
Embodiment 4
60113 (23.5g) are dissolved in dehydrated alcohol (500mL), is added hydrazine hydrate (20.7g), is warming up to back flow reaction
1h is cooled to 20 but, is filtered to remove insoluble matter.Product 14.5g grease is obtained through column chromatographic purifying after filtrate concentration, purity:
98%, ee value: 98%, yield: 95%.
1H-NMR(400MHz,CDCl3) δ 8.65 (dd, J=0.4, J=2.4Hz, 1H), 7.94-7.92 (dd, J=2.4, J
=8.4Hz, 1H), 7.13-7.11 (dd, J=0.8, J=8.4Hz, 1H), 5.90 (s, 2H), 2.12 (s, 6H)
Embodiment 5
Pd is added into dry flask2(DBA)3(1.1g), sodium tert-butoxide (7.3g) and t-BuXPhos (2.7g), then
Replace air therein with nitrogen, toluene (75mL) then be added into reaction flask, to cyclopropyl bromobenzene 60170 (5.0g) and
60114 (6.1g), at 80 DEG C after fully reacting, reaction solution filtering obtains product 8.8g through column chromatographic purifying after filtrate concentration, receives
Rate: 97%, purity: 98%, ee:98%.
1H-NMR (400MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.13 (t, J=8.0Hz, 1H), 6.84 (d, J=
8.4Hz, 2H), 6.77-6.75 (dd, J=1.2, J=6.4Hz, 1H), 6.75-6.70 (m, 2H), 6.47 (d, J=8.4Hz,
2H), 4.96 (s, 2H), 3.64-3.61 (m, 1H), 3.32 (br s, 1H), 2.84-2.79 (dd, J=4.8, J=13.6Hz,
1H), 2.58-2.53 (m, 1H), 1.75-1.70 (m, 1H), 1.05 (d, J=6.4Hz, 3H), 0.79-0.74 (m, 2H), 0.52-
0.44(m,2H).
Embodiment 6
Pd (OAc) is added into dry flask2(1.1g), sodium tert-butoxide (7.3g) and BINAP (4.3g), then use nitrogen
Gas replaces air therein, toluene (75mL) then is added into reaction flask, to cyclopropyl bromobenzene 60170 (5.0g) and 60114
(6.1g), at 80 DEG C after fully reacting, reaction solution filtering, filtrate concentration obtains product 6.0g through column chromatographic purifying, yield:
66%, purity: 97%.
Embodiment 7
Pd is added into dry flask2(DBA)3(1.1g), cesium carbonate (24.8g) and t-BuXPhos (2.7g), then
Replace air therein with nitrogen, toluene (75mL) then be added into reaction flask, to cyclopropyl bromobenzene 60170 (5.0g) and
60114 (6.1g), at 80 DEG C after fully reacting, reaction solution filtering, filtrate concentration obtains product 5.4g through column chromatographic purifying, receives
Rate: 60%, purity: 98%.
Embodiment 8
Pd is added into dry flask2(DBA)3(1.1g), sodium tert-butoxide (7.3g) and t-BuXPhos (2.7g), then
Air therein is replaced with nitrogen, dioxane (75mL) then is added into reaction flask, to cyclopropyl bromobenzene 60170 (5.0g)
With 60114 (6.1g), at 80 DEG C after fully reacting, reaction solution filtering, filtrate concentration obtains product 8.0g through column chromatographic purifying, receives
Rate: 88%, purity: 97%.
Embodiment 9
TMSCl (41.5g) is added in the acetonitrile solution (500mL) of 60115 (26.0g) and sodium iodide (11g).It has reacted
Complete and after being quenched, the color that sodium thiosulfate solution to the iodine of saturation is added disappears, with petroleum ether, then adjust pH value to
Alkalinity is extracted with ethyl acetate, and is concentrated to give product 19.1, yield 98%, purity 95%.
1H-NMR (400MHz, DMSO-d6) δ 9.24 (s, 1H), 7.05 (t, J=8.0Hz, 1H), 6.82 (d, J=
8.4Hz, 2H), 6.64-6.62 (m, 2H), 6.59-6.57 (dd, J=1.6, J=8.0Hz, 1H), 6.50 (d, J=8.4Hz,
2H), 5.18 (d, J=8.4Hz, 1H), 3.54-3.50 (m, 1H), 2.81-2.76 (dd, J=5.4, J=13.2Hz, 1H),
2.42-2.37 (m, 1H), 1.75-1.71 (m, 1H), 1.03 (d, J=6.4Hz, 3H), 0.80-0.76 (m, 2H), 0.52-0.44
(m,2H).
Embodiment 10
60116 (6.5g), 60160 (8.1g) (preparing referring to WO2017107754), with 240mL second are weighed in bottle
Nitrile dissolution, is added AcOH (6.2g), at 100 DEG C after fully reacting, is cooled to room temperature filtering and uses MTBE after filtrate concentration
(100mL) dissolution, washing is primary, and saturated sodium-chloride is washed, and anhydrous sodium sulfate dries, filters, after filtrate concentration, through silica gel column chromatography
Purifying obtains product 7.5g, purity 97%, yield 70%.
Embodiment 11
60116 (6.5g), 60160 (8.1g) are weighed in bottle, are dissolved with 240mL acetonitrile, are added TMSOTf (23g),
At 100 DEG C after fully reacting, it is cooled to room temperature filtering and is dissolved after filtrate concentration with MTBE (100mL), washing is primary, is saturated chlorine
To change sodium to wash, anhydrous sodium sulfate dries, filters, after filtrate concentration, it is purified by silica gel column chromatography to obtain product 4.8g, purity 95%,
Yield 45%.
1H-NMR (400MHz, CDCl3) δ 7.60 (d, J=16.0Hz, 2H), 7.35-7.49 (m, 4H), 7.17 (d, J=
8.0Hz, 1H), 6.93-6.89 (m, 2H), 6.69-6.66 (m, 3H), 6.62 (d, J=2.4Hz, 1H), 6.33 (d, J=
16.0Hz, 2H), 5.60 (s, 1H), 6.50 (d, J=8.4Hz, 2H), 4.42-4.39 (m, 1H), 3.77 (s, 3H), 3.29-
3.24 (dd, J=4.8and 15.2Hz, 1H), 2.63-2.59 (dd, J=2.8and 15.2Hz, 1H), 1.78-1.74 (m,
1H), 1.02 (d, J=6.0Hz, 3H), 0.84-0.80 (m, 2H), 0.57-0.0.53 (m, 2H)
Embodiment 12
60116 (6.5g), 60160 (8.1g) are weighed in bottle, are dissolved with 240mL acetonitrile, are added citric acid (20g),
At 100 DEG C after fully reacting, it is cooled to room temperature filtering and is dissolved after filtrate concentration with MTBE (100mL), washing is primary, is saturated chlorine
To change sodium to wash, anhydrous sodium sulfate dries, filters, after filtrate concentration, it is purified by silica gel column chromatography to obtain product 5.9g, purity 97%,
Yield 55%.
Embodiment 13
60116 (6.5g), 60160 (8.1g) are weighed in bottle, are dissolved with 240mL acetonitrile, and FeCl is added3(16.8g),
At 100 DEG C after fully reacting, it is cooled to room temperature filtering and is dissolved after filtrate concentration with MTBE (100mL), washing is primary, is saturated chlorine
To change sodium to wash, anhydrous sodium sulfate dries, filters, after filtrate concentration, it is purified by silica gel column chromatography to obtain product 4.4g, purity 96%,
Yield 41%.
Embodiment 14
28 (9.4g) are dissolved in 100mL methylene chloride, are added 2,6- lutidines (6.9g), are cooled to 0 DEG C, drop
Add trifluoromethanesulfanhydride anhydride (9.1g), after dripping, be warming up to room temperature, after fully reacting, water, liquid separation, water phase dichloromethane is added
Alkane extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated, obtains product 9.9g with column chromatographic purifying, yield:
81%, purity: 96%.
Embodiment 15
60118 (46.05g), 60180 (26.8g) are dissolved in 800mL1, the mixed solvent of 4- dioxane and 80mL water
In, potassium carbonate (33.4g) and [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride (5.9g) is added, argon gas displacement is therein
Air.It after reaction is warming up to 80 DEG C of fully reactings, is cooled to room temperature, 200mL water is added, ethyl acetate extraction merges organic
Phase, organic phase washed with water are washed, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and is concentrated, and gained residue is chromatographed through column
Product 38.9g is purified to obtain, yield: 93%, purity: 98%.
Embodiment 16
60119 (10.0g) are dissolved in 100mLTHF, sodium hydroxide (3.9g) is dissolved in 20mL water, are then added
In the solution in face, be warming up to 60 DEG C, after fully reacting, water is added in concentration of reaction solution, then with hydrochloric acid adjust water phase PH to 2~
3, it is extracted with ethyl acetate, extract liquor is washed with saturated sodium-chloride water solution, dry with sodium sulphate.It is chromatographed after filtering and concentrating through column
Product 8.5g is purified to obtain, yield: 87%, purity: 96%.
Embodiment 17
It is added into flask to cyclopropyl bromobenzene 60170 (5.0g), 60114 (6.2g), ligand (3.0g), CuI (1.0g)
And K3PO4Dimethyl sulfoxide (30mL) is added into reaction flask in (11.0g).The fully reacting at 100 DEG C will be reacted, will be cooled to room temperature
Afterwards, the water of 200mL is added, is extracted with ethyl acetate, merges organic phase, washing, anhydrous sodium sulfate dries, filters, and filtrate is concentrated
Product 3.9g is obtained through column chromatographic purifying, purity: 96%, yield: 42%.
Claims (18)
1. the method for compound shown in preparation formula A,
It is reacted to obtain chemical combination shown in formula A-c under alkaline condition with compound shown in formula A-d including compound shown in formula A-e
The step of object,
Wherein, R2、R10Respectively it is identical or different, be each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl,
Heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl are optionally selected from alkyl, naphthenic base, heterocycle, virtue
Replaced one or more substituent groups in base and heteroaryl；
R11、R16It is respectively identical or different, it is each independently selected from hydrogen atom, hydroxyl, alkyl, halogenated alkyl, hydroxyalkyl, alcoxyl
Base, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, naphthenic base, aryl
Optionally alkyl, halogen, amino, cyano, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, carboxyl, aldehyde radical, nitre are selected from heteroaryl
In base, heterocycle, aryl and heteroaryl replaced one or more substituent groups；Or R11With R16Formed naphthenic base, heterocycle,
Aryl, heteroaryl, wherein the naphthenic base, heterocycle, aryl or heteroaryl optionally by selected from alkyl, halogen, amino, cyano,
Hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, carboxyl, aldehyde radical, nitro, heterocycle, aryl, heteroaryl or-R3Middle one or more
Replaced substituent group；
R12Selected from alkyl, naphthenic base, heterocycle, aryl, heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl
Base is optionally selected from alkyl, naphthenic base, heterocycle, aryl, heteroaryl or-R4In one or more substituent groups replaced；
R3、R4、R5It is respectively identical or different, it is each independently selected from hydrogen atom, hydroxyl, alkyl, halogenated alkyl, hydroxyalkyl, alkane
Oxygroup, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, naphthenic base, virtue
Base and heteroaryl optionally by selected from alkyl, halogen, amino, cyano, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, carboxyl, aldehyde radical,
In nitro, heterocycle, aryl or heteroaryl replaced one or more substituent groups；
R13It is each independently selected from hydrogen, amino, halogen, halogenated alkyl, hydroxyl, nitro, cyano, alkyl, naphthenic base, heterocycle ,-CH
=CHCOOR6、-O(CH2)hNR14R15；
R6For hydrogen atom or carboxyl-protecting group, the carboxyl-protecting group is selected from alkyl or cycloalkyl, silylation or acyl group；
R14And R15Respectively identical or different, independent is hydrogen atom, alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, ammonia
Base, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, nitro, aryl and heteroaryl, wherein the alkyl, naphthenic base, aryl and miscellaneous
Aryl is optionally by selected from alkyl, halogen, amino, cyano, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, carboxyl, aldehyde radical, nitro, miscellaneous
In ring group, aryl and heteroaryl replaced one or more substituent groups；Or R14、R15Heterocycle is formed with the nitrogen-atoms being connected
Base, heteroaryl, wherein the heterocycle or heteroaryl are optionally selected from alkyl, halogen, amino, cyano, hydroxyl, hydroxyalkyl, alkane
In oxygroup, naphthenic base, carboxyl, aldehyde radical, nitro, heterocycle, aryl and heteroaryl replaced one or more substituent groups；
P is-CH2,-O- ,-NH- or-S-；
X is leaving group, the leaving group be selected from halogen, sulfonyloxy, the sulfonyloxy preferably be selected from-OTs ,-OMs ,-
OTf；For double bond or singly-bound；
T, k is 0,1,2 or 3；
H is 0,1,2,3,4 or 5；
Y is 0,1,2,3 or 4；
Q is 0 or 1,2 or 3.
2. according to the method described in claim 1, wherein the alkali is selected from K2CO3、LiOtBu、NaOtBu、KOtBu、DBU、
DIPEA、CS2CO3, preferably LiOtBu, NaOtBu or KOtBu.
3. method according to claim 1 or 2, wherein also containing catalyst in the reaction, the catalyst is selected from gold
Belong at least one of palladium or copper, preferably Metal Palladium, more preferable Pd2(DBA)3。
4. the catalyst ligand selects according to the method described in claim 3, wherein also containing catalyst ligand in the reaction
From BINAP, X-phos, t-BuXPhos, RuPhos, SPhos, DavePhos, JohnPhos, dppf, dppp or PPh3In extremely
Few one kind, preferably t-BuXPhos.
5. method according to any of claims 1-4, wherein the method also includes passing through compound shown in formula A-c
The step of compound shown in acquisition formula A,
6. method described in -5 any one according to claim 1, wherein formula A-g shownization shown in the formula A-e
It closes object to react to obtain compound shown in formula A-f through Mitsunobu, compound shown in subsequent formula A-f is through Deprotection the step of system
It is standby to obtain,
Wherein, R8、R9It is respectively identical or different, it is each independently selected from nitrobenzenesulfonyl, dinitrobenzenesulfonyl, benzene sulphur
Acyl group or tosyl；Or R8、R9Heterocycle, the preferred Pht of heterocycle are formed with the nitrogen-atoms being connected.
7. method described in -6 any one according to claim 1, wherein compound shown in the formula A is
Wherein, R2-R6、R10, y it is as described in claim 1；N is 0,1,2,3,4 or 5；M is 0,1,2,3 or 4.
8. the method for compound shown in preparation formula II, including compound shown in compound shown in Formula II-e and Formula II-d is in alkaline item
Under part, the step of obtaining compound shown in Formula II-c is optionally reacted under the action of catalyst,
Wherein, R1For phenolic hydroxyl protecting group, it preferably is selected from alkyl, naphthenic base, silylation or acyl group.
9. according to the method described in claim 8, wherein the alkali is selected from K2CO3、K3PO4、LiOMe、NaOEt、NaOPr、
NaOiPr、LiOtBu、NaOtBu、KOtBu、DBU、DIPEA、CS2CO3, it preferably is selected from LiOtBu, NaOtBu, KOtBu.
10. method according to claim 8 or claim 9, wherein the catalyst is selected from least one of Metal Palladium or copper, preferably
For Metal Palladium, more preferable Pd2(DBA)3。
11. according to the method described in claim 10, wherein also containing catalyst ligand, the catalyst ligand in the reaction
Selected from BINAP, X-phos, t-BuXPhos, RuPhos, SPhos, DavePhos, JohnPhos, dppf, dppp or PPh3In
At least one, preferably t-BuXPhos.
12. further including compound shown in Formula II-b and Formula II-a institute according to method described in claim 7-11 any one
Show compound optionally carry out under the action of catalyst P-S react compound shown in Formula II the step of,
Wherein, R10For hydrogen atom.
13. the acidic catalyst is preferred according to the method for claim 12, wherein the catalyst is acidic catalyst
From at least one of TMSCl, HOAc, TMSOTf, TBSCl, PPTS or silica gel, more preferable HOAc.
14. according to method described in claim 7-13 any one, wherein formula II-g institute shown in the Formula II-e
Show that compound reacts to obtain compound shown in Formula II-f through Mitsunobu, compound shown in subsequent Formula II-f is through Deprotection
Step is prepared,
Wherein, R8、R9It is respectively identical or different, it is each independently selected from nitrobenzenesulfonyl, dinitrobenzenesulfonyl, benzene sulphur
Acyl group or tosyl；Or R8、R9Heterocycle, the preferred Pht of heterocycle are formed with the nitrogen-atoms being connected.
15. according to method described in claim 8-14 any one, wherein compound shown in the Formula II isCompound shown in the Formula II-e isFormula II-the c
Shown compound is
16. according to the method for claim 15, wherein compound shown in the Formula II is
Compound shown in the Formula II-e isThe II-c institute
Show that compound is
17. the method for compound shown in preparation formula I, including method described in claim 7-16 any one, it is also preferable to include
Compound shown in Formula II is converted into the step of compound shown in Formulas I,
Wherein, R2-R6, m, n, y it is as claimed in claim 7；R7Selected from hydrogen atom, alkyl, deuteroalkyl, halogenated alkyl, hydroxyl alkane
Base, alkoxy, amino, naphthenic base, halogen, cyano, carboxyl, aldehyde radical, hydroxyl, nitro, aryl and heteroaryl, the alkyl, ring
Alkyl, aryl and heteroaryl are optionally from alkyl, halogen, amino, nitro, cyano, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, miscellaneous
In ring group, aryl and heteroaryl replaced a kind of or multiple substituent groups；R10Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, virtue
Base, heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl optionally by selected from alkyl, naphthenic base, heterocycle,
Replaced one or more substituent groups in aryl and heteroaryl.
18. preparation method according to claim 17, are as follows:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801061A (en) * | 2020-06-17 | 2021-12-17 | 上海森辉医药有限公司 | Preparation method of spiro-carboxamide derivative |
| US11339162B1 (en) | 2020-12-23 | 2022-05-24 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008036308A2 (en) * | 2006-09-18 | 2008-03-27 | Signal Pharmaceuticals, Llc | Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith |
| WO2010122578A2 (en) * | 2009-04-20 | 2010-10-28 | Msn Laboratories Limited | Process for the preparation of sitagliptin and its intermediates |
| CN102482219A (en) * | 2009-03-26 | 2012-05-30 | 盐野义制药株式会社 | Preparation method of pyrone and pyridone derivatives |
| CN103153297A (en) * | 2010-09-14 | 2013-06-12 | 安元有限公司 | Terpenoid analogues and uses thereof for treating neurological conditions |
| WO2015092634A1 (en) * | 2013-12-16 | 2015-06-25 | Novartis Ag | 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders |
| CN105229004A (en) * | 2013-05-28 | 2016-01-06 | 阿斯利康(瑞典)有限公司 | Compound |
| WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
| WO2017107754A1 (en) * | 2015-12-22 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Benzopiperidine derivative, preparation method thereof and medical use thereof |
| US20170305909A1 (en) * | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Chemical compounds |
-
2018
- 2018-12-03 CN CN201811464055.2A patent/CN109867659A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008036308A2 (en) * | 2006-09-18 | 2008-03-27 | Signal Pharmaceuticals, Llc | Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith |
| CN102482219A (en) * | 2009-03-26 | 2012-05-30 | 盐野义制药株式会社 | Preparation method of pyrone and pyridone derivatives |
| WO2010122578A2 (en) * | 2009-04-20 | 2010-10-28 | Msn Laboratories Limited | Process for the preparation of sitagliptin and its intermediates |
| CN103153297A (en) * | 2010-09-14 | 2013-06-12 | 安元有限公司 | Terpenoid analogues and uses thereof for treating neurological conditions |
| CN105229004A (en) * | 2013-05-28 | 2016-01-06 | 阿斯利康(瑞典)有限公司 | Compound |
| WO2015092634A1 (en) * | 2013-12-16 | 2015-06-25 | Novartis Ag | 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders |
| WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
| WO2017107754A1 (en) * | 2015-12-22 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Benzopiperidine derivative, preparation method thereof and medical use thereof |
| US20170305909A1 (en) * | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Chemical compounds |
Non-Patent Citations (2)
| Title |
|---|
| 梅苏宁 等: "钯催化卤代芳烃氨解反应的研究进展", 《化工进展》 * |
| 王岩 等: "过渡金属催化卤代芳烃胺化反应的研究进展", 《广东化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801061A (en) * | 2020-06-17 | 2021-12-17 | 上海森辉医药有限公司 | Preparation method of spiro-carboxamide derivative |
| US11339162B1 (en) | 2020-12-23 | 2022-05-24 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
| US11999728B2 (en) | 2020-12-23 | 2024-06-04 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
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