CN109810047A - (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani - Google Patents

(R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani Download PDF

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CN109810047A
CN109810047A CN201910134281.2A CN201910134281A CN109810047A CN 109810047 A CN109810047 A CN 109810047A CN 201910134281 A CN201910134281 A CN 201910134281A CN 109810047 A CN109810047 A CN 109810047A
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phenylpiperidine
added
reaction
synthetic method
acid
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刘振德
高河勇
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Shanghai Bo Bang Pharmaceutical Technology Co Ltd
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Shanghai Bo Bang Pharmaceutical Technology Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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Abstract

Target product (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine has successfully been made as starting material in the 3- piperidones that the synthetic method that first aspect present invention provides is protected using N；The synthetic method that second aspect of the present invention provides with identical starting material, and it is ingenious organosilicon reagent is utilized, target product (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine has also been made.(S) -3- Phenylpiperidine synthesizes chiral intermediate α, β and γ of Ni Lapani in terms of can pressing third of the invention, the 4th and the 5th respectively.In a word, the synthetic method of chiral intermediate α, β and γ of the synthetic method and Ni Lapani of (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine provided by the present invention significantly reduce production cost, are conducive to the large-scale industrial production of Ni Lapani drug.

Description

(R) chirality of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani The synthetic method of intermediate
Technical field
The invention belongs to technical field of organic synthesis, in particular to (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine Synthetic method, further relate to the synthetic method of the chiral intermediate of Ni Lapani.
Background technique
Entitled 2- { 4- [(3S) -3- piperidyl] the phenyl } -2H- Yin of chemistry of Ni Lapani (Niraparib, MK-4827) Azoles -7- formamide (11), chemical structural formula is as follows:
It is well known that the anticancer drug Ni Lapani (Niraparib, the MK- that are developed by Tesaro biotechnology company It 4827) is a kind of novel oral selective Poly adenosine diphosphate-ribose polymerase-1 (PARP) inhibitor, which passes through dry It disturbs DNA repair process in cell and plays a role, this will make tumour become more sensitive to the DNA chemotherapeutics being damaged.Mesh The preceding drug just carries out the treatment that clinical test is used for different tumours in the U.S., including two 3 clinical trial phases, for controlling Treat 1. platinum class sensibility oophoroma (U.S. clinical trial number of registration NCT01847274)；2. HER2 is negative, the positive cream of BRCA1/2 Gland cancer (U.S. clinical trial number of registration NCT01905592).In addition, Tesaro biotechnology company declared on June 11st, 2014 Other two III phase clinic of the cloth program launched Niraparib for oophoroma first-line treatment and Small Cell Lung Cancer first-line treatment is ground Study carefully.
It is reported according to pertinent literature, the synthetic route of Ni Lapani mainly has following three kinds at present:
One, route 1 (Scheme 4) (referring to WO2008084261, Journal of Medicinal Chemistry, 2009,52(22),7170-7185)；Organic Process Research&Development,2011,15(4),831- 840.): aminocarbonyl phenyl piperidinyl-1 3 being reacted with 3- formoxyl -2- nitrobenzoic acid first 12 using (the S) -3- that BOC is protected, is formed Group with imine moiety 14, then with NaN3/ DMF reaction after nitro is replaced by azido, continues cyclisation in a heated condition and obtains centre Body 15, intermediate 15 carry out ammonia exchange reaction in methanolic ammonia solution, obtain amide intermediate 16, finally take off in the presence of HCl Except BOC blocking group, Ni Lapani 11 is obtained.However, the overall yield of reaction of the route is not high, and product is isolated and purified and is relatively stranded It is difficult.
Scheme 4:
Two, route 2 (Scheme 5) (referring to WO2008084261): benzopyrazoles intermediate 17 and fluorobenzene 18 is anti- It answers, obtains intermediate 19, then Suzuki coupling reaction is occurred into for intermediate 19 and 3- pyridine boronic acid, generate intermediate 20；It is intermediate The pyridine ring of body 20 restores to obtain racemic compound 21, and further chiral resolution obtains chiral Ni Lapani 11.
Scheme 5:
In the route, Suzuki coupling reaction and reduction this two step of pyridine ring have used expensive transition metal, at This is higher；Especially, it splitting to obtain chiral product in final step, at least half of enantiomter becomes waste, thus Yield is caused to reduce, cost increase is not suitable for large-scale industrial production.
Three, route 3 (Scheme 6) (WO2018/088983, Org.Process Res.Dev., 2014,18 (1), 215- 227): using catalysed reaction of copper, benzopyrazoles intermediate 22 and BOC (the S) -3- p-bromophenyl piperidines 23 protected are subjected to idol Connection reaction, obtains intermediate 24, then in xylene solvent, methanesulfonic acid deprotection obtains final products Ni Lapani 11.It is logical Analysis is crossed it is found that this route inexpensive catalyst, reaction condition is mild, and yield is higher, therefore, this route is to be relatively more suitable for The route of industrialized production.
Scheme 6:
By analyzing the above synthetic route in the prior art, it is known that the 3- Phenylpiperidine for the S configuration that phenyl contraposition replaces It is one of the key intermediate for synthesizing Ni Lapani.Wherein, (the S) -3- that route one has used BOC to protect is to aminocarbonyl phenyl piperidines 13 are used as reactant, and (S) -3- p-bromophenyl piperidines 23 that route three has used BOC to protect is as reactant；But in document The synthetic method for two side chains recorded is simultaneously uneconomical, using valuable transition metal-catalyzed in reaction process, or is urged using enzyme The very low production methods of reaction efficiencies such as change can all cause production cost high.
In addition, additionally provide in the prior art (the S) -3- of BOC protection to the synthetic method of aminocarbonyl phenyl piperidinyl-1 3 (referring to WO2008084261, Journal of Medicinal Chemistry, 2009,52 (22), 7170-7185)；Organic Process Research&Development, 2011,15 (4), 831-840.), synthetic route is as shown in Scheme 7.
As it can be seen that starting material 3- pyridine boronic acid used in the route is not easy to prepare, and stability is poor, preservation condition requirement Height, it is expensive；Continuous two step carries out chiral resolution using expensive transition metal (palladium and platinum), in final step, equally has The enantiomter of about half is not used, if therefore according to the route be mass produced intermediate 13, will cause high Production cost.
Scheme 7:
In the prior art, BOC protection (S) -3- p-bromophenyl piperidines 23 synthesis used transaminase (referring to WO2018/088983, Org.Process Res.Dev., 2014,18 (1), 215-227.), synthesis uses such as Scheme Route shown in 8 or Scheme 9:
Scheme 8:
However, the route of (S) -3- p-bromophenyl piperidines 23 of above two synthesis BOC protection must be anti-by transaminase It answers, production efficiency is low, it is clear that cost is excessively high.
In conclusion the production cost of Ni Lapani is excessively high in the prior art, this is mainly due to its chiral 3- phenyl The synthesis cost of piperidine sidechains is high；The existing several method for synthesizing the side-chain radical, can not be suitable for large-scale industry Metaplasia produces.Therefore, it is urgent to provide a kind of completely new synthesis technologies of Ni Lapani key intermediate (S) -3- Phenylpiperidine, to logical It crosses cheap reagent and mild reaction condition obtains higher product yield, convenient for (S) -3- Phenylpiperidine is each for synthesizing The crucial chiral intermediate of kind is (for example, (the S) -3- of BOC protection is to (S) -3- of aminocarbonyl phenyl piperidinyl-1 3 and BOC protection to bromobenzene Phenylpiperidines 23), to be conducive to the large-scale industrial production for finally realizing Ni Lapani.
Summary of the invention
In order to promote the large-scale industrial production of anticancer drug Ni Lapani, overcome existing synthesis technology cost excessively high Technological deficiency, present invention is directed primarily to provide a kind of new method for synthesizing (S) -3- Phenylpiperidine, this method uses common honest and clean Valence reagent is reacted, and reaction condition is mild, and every step reaction yield is higher, so as to effectively control the piperidines of Ni Lapani The production cost of side chain；(S) -3- Phenylpiperidine can pass through simple chemical conversion, further synthesize in various crucial chiralitys Therefore mesosome is conducive to the production of anticancer drug Ni Lapani.
Specifically, first aspect present invention provides the conjunction of one kind (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine At method comprising following synthetic route Scheme 1:
Wherein, step (a) are as follows: the 3- piperidones (2) and contraposition R of N protection2It is anti-that grignard occurs for substituted phenyl-magnesiumhalide It answers, generates 3- hydroxyl -3- Phenylpiperidine (3)；
Wherein, step (b) are as follows: 3- hydroxyl -3- Phenylpiperidine (3) occur alcoholic extract hydroxyl group elimination reaction, generate compound (4) and The mixture of compound (5)；
Wherein, step (c) are as follows: transition-metal catalyst catalysis under, the mixture of compound (4) and compound (5) and Hydrogenation reduction occurs for hydrogen source, generates the 3- Phenylpiperidine (6) of N protection；
Wherein, step (d) are as follows: 3- Phenylpiperidine (6) deprotection base R of N protection1, generate racemic 3- phenyl piperazine Pyridine (1)；
Wherein, step (e) are as follows: in chemical resolution solvent, using acid resolving agent to racemic 3- Phenylpiperidine (1) into Row is split, and obtains (R) -3- Phenylpiperidine ((R) -1) or/and (S) -3- Phenylpiperidine ((S) -1).
Preferably, in above-mentioned synthetic method, R1Selected from following any: trityl, benzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyls, tert-butyl, trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, t-Butyldimethylsilyl, Tert-butyl diphenyl silicon substrate.
Preferably, in above-mentioned synthetic method, R2Selected from following any: H, methoxyl group, ethyoxyl, isopropoxy, just Propoxyl group, allyl oxygroup, normal-butyl oxygroup, isobutyl group oxygroup, tert-butoxy, methoxymethoxy, ethoxymethyl) epoxide, first Oxygroup ethyoxyl, 2- tetrahydro-pyran oxy, trimethyl silicane base oxethyl methoxyl group, t-Butyldimethylsilyl ethyoxyl methoxy Base, trimethylsiloxy group, triethyl group siloxy, tri isopropyl siloxany, tertiary butyl dimethyl Si base, tert-butyl diphenyl silicon Oxygroup, benzyloxy, to methoxybenzyl oxygroup, 2,4- dimethoxybenzyloxycarbonyl bases.
Preferably, in the step (c) of above-mentioned synthetic method, the transition-metal catalyst is selected from following any Kind: Raney's nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.The transition-metal catalyst is more preferably palladium carbon.
Preferably, in the step (e) of above-mentioned synthetic method, the chemical resolution solvent be selected from it is following any or A variety of combination: methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, tetrahydrofuran, ethyl acetate, methylene chloride.The chemistry Resolution solvent is further preferably from following any one or more combination: methanol, ethyl alcohol, isopropanol, tetrahydrofuran, acetic acid second Ester.
Preferably, in the step (e) of above-mentioned synthetic method, the acidity resolving agent is selected from following any: wine Stone acid, dibenzoyl tartaric acid, two pairs of toluyl tartaric acid, malic acid, camphorsulfonic acid, camphoric acid, mandelic acid, quinine Acid.The acidity resolving agent is further preferably from following any: tartaric acid, dibenzoyl tartaric acid, two pairs of methylbenzene first Acyl tartaric acid, malic acid, camphorsulfonic acid.
In short, successively to carry out grignard reaction, elimination reaction, hydrogenating reduction anti-for synthetic method described in first aspect present invention It answers, deprotection base R1, chiral resolution, target product (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine has successfully been made, Each step reaction yield is higher, wherein the chirality that (S) -3- Phenylpiperidine can also be further used in synthesis Ni Lapani is intermediate Body.
Also, second aspect of the present invention provides the conjunction of another (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine At method comprising following synthetic route Scheme 1-1:
Wherein, step (a) are as follows: the 3- piperidones (2) and contraposition R of N protection2It is anti-that grignard occurs for substituted phenyl-magnesiumhalide It answers, generates 3- hydroxyl -3- Phenylpiperidine (3)；
Wherein, step (f) are as follows: 3- hydroxyl -3- Phenylpiperidine (3) and (CnH2n+1)3SiH reaction directly generates N protection 3- Phenylpiperidine (6)；Wherein, the integer that n is 1~4；
Wherein, step (d) are as follows: 3- Phenylpiperidine (6) deprotection base R of N protection1, generate racemic 3- phenyl piperazine Pyridine (1)；
Wherein, step (e) are as follows: in chemical resolution solvent, using acid resolving agent to racemic 3- Phenylpiperidine (1) into Row is split, and obtains (R) -3- Phenylpiperidine ((R) -1) or/and (S) -3- Phenylpiperidine ((S) -1).
As it can be seen that the synthetic method of another kind (the R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine has rationally been utilized Machine silica reagent (i.e. (CnH2n+1)3SiH), directly the hydroxyl in 3- hydroxyl -3- Phenylpiperidine (3) is removed, then deprotection base R1, target product (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine is made eventually by chiral resolution, each step reaction is received Rate is higher, wherein (S) -3- Phenylpiperidine can also be further used in the chiral intermediate of synthesis Ni Lapani.
Preferably, in the step (f) of above-mentioned synthetic method, (the CnH2n+1)3SiH is selected from following any: three Ethylsilane, three n-propyl silane, tri isopropyl silane.
Preferably, in the step (f) of above-mentioned synthetic method, the chemical resolution solvent be selected from it is following any or A variety of combination: methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, tetrahydrofuran, ethyl acetate, methylene chloride.
Preferably, in the step (f) of above-mentioned synthetic method, the acidity resolving agent is selected from following any: wine Stone acid, dibenzoyl tartaric acid, two pairs of toluyl tartaric acid, malic acid, camphorsulfonic acid, camphoric acid, mandelic acid, quinine Acid.
Meanwhile third aspect present invention provides the synthetic method of the chiral intermediate α of Ni Lapani a kind of, synthesizes road Line is as follows:
Scheme 2:
And, comprising the following steps:
S1: according to a first aspect of the present invention or synthetic method described in second aspect prepares (S) -3- Phenylpiperidine ((S) - 1), wherein R2For H；
S2: nitration reaction is occurred into for (S) -3- Phenylpiperidine ((S) -1-1) and nitrating agent, generates (S) -3- p-nitrophenyl Piperidines (6-1)；
S3: (S) -3- p-nitrophenyl phenylpiperidines (6-1) and reduction system are subjected to nitro-reduction reaction, -3- pairs of generation (S) Aminocarbonyl phenyl piperidines (7), i.e. the chiral intermediate α of Ni Lapani.
Preferably, in the synthetic method of the chiral intermediate α of above-mentioned Ni Lapani, the nitrating agent is selected from following any Kind: nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, chloro-nitric acid, Butylnitrate ester, methyl nitrate, NO2BF4, NO2PF6.Further preferably Ground, the nitrating agent are selected from following any: nitric acid, potassium nitrate, NO2BF4And methyl nitrate.
Preferably, in the synthetic method of the chiral intermediate α of above-mentioned Ni Lapani, the reduction system is selected from following It is a kind of: ferric trichloride/hydrazine hydrate, Fe/HCl, Zn/HCl, LiAlH4, transition-metal catalyst/hydrogen, sodium dithionite；Its In, the transition-metal catalyst is selected from following any: Raney's nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
In addition, fourth aspect present invention additionally provides the synthetic method of the chiral intermediate β of Ni Lapani a kind of, synthesis Route is as follows:
Scheme3:
Wherein, protecting group PG is selected from following any: alkyl, acyl group, sulfonyl；For example, protecting group PG is preferred are as follows: acetyl Base, propiono, bytyry, benzenesulfonyl；
And, comprising the following steps:
P1: according to a first aspect of the present invention or synthetic method described in second aspect prepares (S) -3- Phenylpiperidine ((S) - 1-1), wherein R2For H；
P2: (S) -3- Phenylpiperidine ((S) -1) and N protection reagent are reacted, (S) -3- phenyl of N-protected is generated Piperidines (8)；
P3: bromo-reaction is occurred into for (the S) -3- Phenylpiperidine (8) of N-protected and brominated reagent, generates (S)-of N-protected 3- p-bromophenyl piperidines (9)；
P4: (S) -3- p-bromophenyl piperidines (9) of N-protected is subjected to deprotection reaction, that is, sloughs protecting group PG, is generated (S) -3- p-bromophenyl piperidines (10), i.e. the chiral intermediate β of Ni Lapani.
Preferably, in the synthetic method of the chiral intermediate β of above-mentioned Ni Lapani, the N protection reagent is selected from following It is any: chloroacetic chloride, propionyl chloride, butyl chloride, benzene sulfonyl chloride, BOC acid anhydrides.
Preferably, in the synthetic method of the chiral intermediate β of above-mentioned Ni Lapani, the brominated reagent is selected from following It is a kind of: NBS, Br2, HBr, excessively pyridinium bromide hydrobromide, C5H6Br2N2O2,2,4,4,6- tetrabromobisphenols, 5- cyclohexadienone.
Finally, fifth aspect present invention additionally provides the synthetic method of the chiral intermediate γ of Ni Lapani a kind of, close It is as follows at route:
Scheme 3-1:
Wherein, protecting group PG is selected from following any: alkyl, acyl group, sulfonyl；For example, protecting group PG is preferred are as follows: acetyl Base, propiono, bytyry, benzenesulfonyl；
And, comprising the following steps:
P'1: according to a first aspect of the present invention or synthetic method described in second aspect prepares (S) -3- Phenylpiperidine ((S) - 1), wherein R2Selected from following any: methoxyl group, ethyoxyl, isopropoxy, positive propoxy, allyl oxygroup, normal-butyl oxygen Base, isobutyl group oxygroup, tert-butoxy, methoxymethoxy, ethoxymethyl) epoxide, methoxy ethoxy, 2- tetrahydro-pyran oxy, Trimethyl silicane base oxethyl methoxyl group, t-Butyldimethylsilyl ethoxymethyl) epoxide, trimethylsiloxy group, triethyl group silicon oxygen Base, tri isopropyl siloxany, tertiary butyl dimethyl Si base, tert-butyl diphenyl siloxy, benzyloxy, to methoxyl group benzyloxy Base, 2,4- dimethoxybenzyloxycarbonyl bases；
P'2: (S) -3- Phenylpiperidine ((S) -1) and N protection reagent are reacted, (S) -3- phenyl of N-protected is generated Piperidines (8)；
P'3: by (S) -3- Phenylpiperidine (8) eliminating hydroxide protecting group of N-protected, (S) -3- (4- hydroxyl of N-protected is generated Base phenyl)-piperidines (9 ')；
P'4: (S) -3- (4- hydroxy phenyl)-piperidines (9 ') of N-protected and activated sulfonyl chlorine or active sulphonic acid anhydride is anti- It answers, generates active ester (10 '), i.e. the chiral intermediate γ of Ni Lapani.
Preferably, in the synthetic method of the chiral intermediate γ of above-mentioned Ni Lapani, the N protection reagent is selected from following It is any: chloroacetic chloride, propionyl chloride, butyl chloride, benzene sulfonyl chloride, BOC acid anhydrides.
Preferably, in the synthetic method of the chiral intermediate γ of above-mentioned Ni Lapani, the activated sulfonyl chlorine be selected from Under it is any: mesyl chloride, paratoluensulfonyl chloride, benzene sulfonyl chloride；The activity sulphonic acid anhydride is trifluoromethanesulfanhydride anhydride.
In conclusion technical solution provided by the present invention at least has compared with synthesis technology well known in the prior art Have it is following the utility model has the advantages that
The 3- piperidones that synthetic method shown in Scheme 1 is protected using N successively carries out grignard reaction, disappears as starting material Dereaction, hydrogenation reduction, deprotection base R1, chiral resolution, be successfully made target product (R) -3- Phenylpiperidine or/ (S) -3- Phenylpiperidine；Synthetic method shown in Scheme 1-1 is advanced equally using the 3- piperidones of N protection as starting material Row grignard reaction, then dexterously directly removed hydroxyl using organosilicon reagent, then deprotection base R1, and eventually by hand Property split target product (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine be made；Also, shown in either Scheme 1 Synthetic method shown in synthetic method or Scheme1-1, wherein used in reaction reagent it is more cheap, it is each walk reaction yield compared with Height, and reaction condition is mild, is therefore particularly suitable for large-scale industrial production.
In addition, (S) -3- Phenylpiperidine can also synthesize (S) -3- to aminocarbonyl phenyl piperazine according to route shown in Scheme 2 Pyridine, or (S) -3- p-bromophenyl piperidines is synthesized according to route shown in Scheme 3, or according to shown in Scheme 3-1 Route synthesizing activity ester；It is worth noting that (S) -3- as described herein is to aminocarbonyl phenyl piperidines, (S) -3- p-bromophenyl piperidines It is the key intermediate for preparing Ni Lapani with active ester.
In short, the synthetic method of (R) -3- Phenylpiperidine provided by the present invention or/and (S) -3- Phenylpiperidine and Buddhist nun draw The synthetic method of chiral intermediate α, β, γ of pa Buddhist nun significantly reduce production cost, to be conducive to Ni Lapani drug Large-scale industrial production.
Specific embodiment
The present invention is further elaborated With reference to embodiment, but the present invention is not limited to following embodiment party Formula.
Also, the operating procedure in following embodiments is unless otherwise specified Conventional procedures；Following embodiments Used in instrument, material, reagent etc., unless otherwise specified, can be obtained from public commercial source.
The synthesis of embodiment 1:3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)
By phenyl-magnesium-bromide Grignard Reagent (2mol/L in THF, 240mL), anhydrous tetrahydro furan (300mL) is added to In reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, and N- benzyl -3- piperidones (2-1,60.0g, 317.0mmol) is used nothing Water tetrahydrofuran (300mL) dilution, is added in dropping funel, is slowly dropped in reaction flask, and temperature control is at 0-5 DEG C, 60min drop It is complete, continue to be stirred to react 1 hour after being added dropwise, TLC detects raw material fully reacting, is added with stirring saturated ammonium chloride water Solution (300mL), then extracted with ethyl acetate (200mL × 3), after extraction three times, merges organic layer, appropriate anhydrous slufuric acid is added Sodium dries, filters, and is spin-dried for solvent and obtains product crude product (3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)) 76.5g, yield 90.2%；1H-NMR(400MHz,D2O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J=12.4Hz), 4.21 (1H, D, J=13.2Hz), 3.60 (1H, d, J=11.2Hz), 3.28 (1H, d, J=12.4Hz), 3.15-3.13 (2H, m), 2.22- 2.19 (1H, m), 1.99-1.87 (3H, m) .MS-ESI (m/z): 268.3 [(M+H)+]；The crude product can be directly used for anti-in next step It answers.
The synthesis of embodiment 2:3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)
By phenyl-magnesium-bromide Grignard Reagent (2mol/L in THF, 240mL), anhydrous ether (300mL) is added to reaction In bottle, nitrogen protection, ice-water bath is cooled to 0 DEG C, by the anhydrous second of N- benzyl -3- piperidones (2-1,60.0g, 317.0mmol) Ether (300mL) dilution, is added in dropping funel, is slowly dropped in reaction flask, and at 0-5 DEG C, 60min is dripped off temperature control, is added dropwise After continue to be stirred to react 1 hour, TLC detect raw material fully reacting, be added with stirring saturated aqueous ammonium chloride (300mL), then extracted with ethyl acetate (200mL × 3), after extraction three times, merge organic layer, then add into combined organic layer Enter appropriate anhydrous sodium sulfate to dry, filter, is spin-dried for solvent and obtains product crude product (3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)) 74.1g, yield 87.4%；1H-NMR (400MHz, D2O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J= 12.4Hz), 4.21 (1H, d, J=13.2Hz), 3.60 (1H, d, J=11.2Hz), 3.28 (1H, d, J=12.4Hz), 3.15- 3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m) .MS-ESI (m/z): 268.3 [(M+H)+]；The crude product can It is directly used in and reacts in next step.
The synthesis of embodiment 3:3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)
By phenyl-magnesium-chloride Grignard Reagent (2mol/L in THF, 240mL), anhydrous tetrahydro furan (300mL) is added to In reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2,60.0g, 317.0mmol) with anhydrous Tetrahydrofuran (300mL) dilution, is added in dropping funel, is slowly dropped in reaction flask, and temperature control is at 0-5 DEG C, 50min drop It is complete, continue to be stirred to react 1.5 hours after being added dropwise, TLC detects raw material fully reacting, is added with stirring saturated ammonium chloride Aqueous solution (300mL), then extracted with ethyl acetate (200mL × 3), after extraction three times, merge organic layer, then to the organic of merging Appropriate anhydrous sodium sulfate is added in layer to dry, filter, is spin-dried for solvent and obtains product crude product (3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)) 75.5g, yield 89.0%；1H-NMR(400MHz,D2O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J= 12.4Hz), 4.21 (1H, d, J=13.2Hz), 3.60 (1H, d, J=11.2Hz), 3.28 (1H, d, J=12.4Hz), 3.15- 3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m) .MS-ESI (m/z): 268.3 [(M+H)+]；The crude product can It is directly used in and reacts in next step.
The synthesis of embodiment 4:3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)
By phenyl-magnesium-chloride Grignard Reagent (2mol/L in THF, 240mL), anhydrous ether (300mL) is added to reaction In bottle, nitrogen protection, ice-water bath is cooled to 0 DEG C, and N- benzyl -3- piperidones (2,60.0g, 317.0mmol) is used anhydrous ether (300mL) dilution, is added in dropping funel, is slowly dropped in reaction flask, at 0-5 DEG C, 30min is dripped off temperature control, is dripped Continue to be stirred to react 1 hour after finishing, TLC detects raw material fully reacting, is added with stirring saturated aqueous ammonium chloride (300mL), then extracted with ethyl acetate (200mL × 3), after extraction three times, merge organic layer, then add into combined organic layer Enter appropriate anhydrous sodium sulfate to dry, filter, is spin-dried for solvent and obtains product crude product (3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1)) 77.4g, yield 91.3%；1H-NMR(400MHz,D2O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J= 12.4Hz), 4.21 (1H, d, J=13.2Hz), 3.60 (1H, d, J=11.2Hz), 3.28 (1H, d, J=12.4Hz), 3.15- 3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m) .MS-ESI (m/z): 268.3 [(M+H)+]；The crude product can It is directly used in and reacts in next step.
Embodiment 5: the synthesis of compound (4-1) and compound (5-1)
By 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), glacial acetic acid (400mL, 6.67mol), chloroacetic chloride (400mL, 5.66mol) is added in reaction flask, heating, and TLC detects raw material after back flow reaction 90min Fully reacting stops reaction, acetic acid is evaporated under reduced pressure, and 20% sodium hydrate aqueous solution is then added to residue, adjusts PH value of solution=8-9 is saved, (200mL × 3) are then extracted with ethyl acetate, collected organic layer is dried with anhydrous sodium sulfate, mistake Solvent is spin-dried for obtaining crude product (mixture of compound (4-1) and compound (5-1)) 64.7g by filter, yield 88.3%, directly For reacting in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 6: the synthesis of compound (4-1) and compound (5-1)
3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), formic acid (700mL, 18.6mol) are added Enter into reaction flask, heat, TLC detects raw material fully reacting after back flow reaction 3h, stops reaction, formic acid is spin-dried for, is first added Water (250mL) adds 20% sodium hydrate aqueous solution, adjusts pH value of solution=8-9, (250mL is then extracted with ethyl acetate × 3), collected organic layer is dried with anhydrous sodium sulfate, and solvent is spin-dried for obtaining crude product 50.1g (compound (4-1) by filtering With the mixture of compound (5-1)), yield 70.3% is directly used in and reacts in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 7: the synthesis of compound (4-1) and compound (5-1)
By 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), toluene (700mL), to toluene sulphur Sour (27g, 142.1mmol) is added in reaction flask, is heated, and TLC detects raw material fully reacting after back flow reaction 12h, is stopped anti- It answers, after revolving, water (100mL) first is added, adds 20% sodium hydrate aqueous solution, adjusts pH value of solution=8-9, then uses second Acetoacetic ester extracts (200mL × 3), and collected organic layer is dried with anhydrous sodium sulfate, filters, solvent is spin-dried for obtain crude product 40.2g (mixture of compound (4-1) and compound (5-1)), yield 56.2% are directly used in and react in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 8: the synthesis of compound (4-1) and compound (5-1)
3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), acetic acid (700mL, 11.6mol) are added Entering into reaction flask, heats, TLC detects raw material fully reacting after back flow reaction 2.5h, stops reaction, acetic acid decompression is steamed, Water (300mL) first is added, adds 20% sodium hydrate aqueous solution, adjusts pH value of solution=8-9, is then extracted with ethyl acetate (200mL × 3), collected organic layer are dried with anhydrous sodium sulfate, and solvent is spin-dried for obtaining crude product 50.2g (chemical combination by filtering The mixture of object (4-1) and compound (5-1)), yield 70.3% is directly used in and reacts in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 9: the synthesis of compound (4-1) and compound (5-1)
By 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), the 1,4- dioxane of 4M hydrochloric acid Solution (76.5mL), Isosorbide-5-Nitrae-dioxane (200mL) are added in reaction flask, heating, and TLC detects raw material after back flow reaction 10h Fully reacting stops reaction, and Isosorbide-5-Nitrae-dioxane decompression is steamed, water (200mL) first is added, adds 20% sodium hydroxide Aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (200mL × 3), collected organic layer, with anhydrous sodium sulfate into Row dries, filters, and solvent is spin-dried for obtain crude product 52.2g (mixture of compound (4-1) and compound (5-1)), yield 72.4%, it is directly used in and reacts in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 10: the synthesis of compound (4-1) and compound (5-1)
By 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), the tetrahydrofuran solution of 4M hydrochloric acid (700mL) is added in reaction flask, heating, and TLC detects raw material fully reacting after back flow reaction 14h, stops reaction, by tetrahydro furan It mutters and is spin-dried for, water (100mL) first is added, add 20% sodium hydrate aqueous solution, adjust pH value of solution=8-9, then use acetic acid Ethyl ester extracts (100mL × 3), and collected organic layer is dried with anhydrous sodium sulfate, filters, solvent is spin-dried for obtain crude product 48.3g (mixture of compound (4-1) and compound (5-1)), yield 69.1% are directly used in and react in next step.MS-ESI (m/z): 250.3 (M+H)+。
Embodiment 11: the synthesis of compound (4-1) and compound (5-1)
By 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,76.5g, 286.5mmol), triethylamine (70mL, 503.1mmol), methylene chloride (DCM) (500mL) is added in reaction flask, and after cooling to 0 DEG C, methylsufonyl chloride is slowly added dropwise (30mL, 392.8mmol), 30min is added dropwise, and then, is warming up to room temperature, continues to be stirred to react 1h, TLC detects raw material reaction Completely, stop reaction, DCM is spin-dried for, then 500mL anhydrous DMF is added into residue and adds sodium hydrogen after residue dissolved clarification (60%, 14g, 0.35mol) is heated to 75 DEG C, reacts 2h, and TLC detects raw material end of reaction, stops reaction, reaction solution is fallen Enter in ice water (100mL)；(100mL × 3) are extracted with ethyl acetate, collected organic layer is dried with anhydrous sodium sulfate, mistake Filter, solvent is spin-dried for obtaining crude product 60.3g (mixture of compound (4-1) and compound (5-1)), yield 85.6%, directly For reacting in next step.MS-ESI (m/z): 250.3 (M+H)+。
The synthesis of embodiment 12:3- Phenylpiperidine (1-1)
By the mixture (64.7g, 259.8mmol) of compound (4-1) and compound (5-1), palladium carbon (13g, 20%), nothing Water methanol (300mL), glacial acetic acid (12mL) are added in autoclave, and are passed through the hydrogen of 1atm, are heated to 60 DEG C, react 16h, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (200mL) is added after being spin-dried in solvent, and uses ethyl acetate (200mL × 3) are extracted, collected organic layer is dried, filtered with anhydrous sodium sulfate, and solvent is spin-dried for obtain product 3- phenyl Piperidines (1-1) 35.1g, yield 88.3% are directly used in and react in next step.1H-NMR (400MHz, DMSO-d6) δ: 7.30- 7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m) .13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+。
Embodiment 13:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in isopropanol (50mL), it will be dissolved with L-TARTARIC ACID Isopropanol (200mL) solution of (93.16g, 622.2mmol) is added drop-wise in the aqueous isopropanol of racemic 3- Phenylpiperidine, is stirred 2h is mixed, filters, obtains tartrate；Then, methanol (10L) is added to the tartrate, is heated to after being completely dissolved, stops stirring It mixes；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains crude white solid, and 1N sodium hydrate aqueous solution is added (50mL) is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to get white wax Shape solid 30.1g, i.e. (S) -3- Phenylpiperidine, yield 30.1%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR (100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS- ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, ee=95.39%.
Embodiment 14:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in methanol (50mL), it will be dissolved with L- (-)-dibenzoyl wine Methanol (200mL) solution of stone acid (222.93g, 622.2mmol) is added drop-wise in the methanol solution of racemic 3- Phenylpiperidine, is stirred 2h is mixed, filters, obtains dibenzoyl tartaric acid salt；Then, ethyl alcohol (8L) is added to the dibenzoyl tartaric acid salt, has been heated to After fully dissolved, stop stirring；Be slow cooling to room temperature, -10 DEG C crystallization 5 days, filtering obtains crude white solid, and 1N hydrogen is added Aqueous solution of sodium oxide (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, anhydrous sodium sulfate dries, filters, dense Contracting obtains white waxy solid 28.3g, i.e. (S) -3- Phenylpiperidine, yield 28.3%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H, m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, ee=92.41%.
Embodiment 15:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in ethyl acetate (50mL), it will be dissolved with L- (-)-hexichol first Ethyl acetate (200mL) solution of acyl tartaric acid (222.93g, 622.2mmol) is added drop-wise to the acetic acid of racemic 3- Phenylpiperidine In ethyl ester solution, 2h is stirred, filtering obtains dibenzoyl tartaric acid salt；Then, methanol is added to the dibenzoyl tartaric acid salt (10L) is heated to after being completely dissolved, and stops stirring；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains white solid Crude product is added 1N sodium hydrate aqueous solution (50mL), is extracted with ethyl acetate (100mL × 2), merges organic phase, anhydrous slufuric acid Sodium dries, filters, and is concentrated to get white waxy solid 25.3g, i.e. (S) -3- Phenylpiperidine, yield 25.3%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H,m),1.67-1.46(3H,m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96, 45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, ee=93.21%.
Embodiment 16:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in ethyl acetate (30mL), it will be dissolved with L- bis- to methylbenzene Ethyl acetate (200mL) solution of formyl tartaric acid (205.53g, 622.2mmol) is added drop-wise to the second of racemic 3- Phenylpiperidine In acetate solution, 2h is stirred, filtering obtains two pairs of toluyl tartrates；Then, to two pairs of toluyl wine Ethyl acetate (15L) is added in stone hydrochlorate, is heated to after being completely dissolved, and stops stirring；Be slow cooling to room temperature, 0 DEG C crystallization 2 days, Filtering obtains crude white solid, is added 1N sodium hydrate aqueous solution (50mL), is extracted with ethyl acetate (25mL × 2), merges Organic phase, anhydrous sodium sulfate dry, filter, and are concentrated to get white waxy solid 20.5g, i.e. (S) -3- Phenylpiperidine, yield 20.5%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08, 126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, Ee=93.82%.
Embodiment 17:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in tetrahydrofuran (60mL), it will be dissolved with L MALIC ACID Tetrahydrofuran (250mL) solution of (83.43g, 622.2mmol) is added drop-wise to the tetrahydrofuran solution of racemic 3- Phenylpiperidine In, 2h is stirred, filtering obtains malate；Then, tetrahydrofuran (8L) is added to the malate, is heated to being completely dissolved Afterwards, stop stirring；Be slow cooling to room temperature, -10 DEG C crystallization 3 days, filtering obtains crude white solid, and 1N sodium hydroxide is added Aqueous solution (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate is dried, filtered, is concentrated to get White waxy solid 18.7g, i.e. (S) -3- Phenylpiperidine, yield 18.7%.1H-NMR (400MHz, DMSO-d6) δ: 7.30- 7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m) .13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, ee=92.49%.
Embodiment 18:(S) -3- Phenylpiperidine ((S) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in ethyl alcohol (50mL), it will be dissolved with L- camphorsulfonic acid Ethyl alcohol (150mL) solution of (145.8g, 622.2mmol) is added drop-wise in the ethanol solution of racemic 3- Phenylpiperidine, stirs 2h, Filtering, obtains camsilate；Then, methanol (5L) is added to the camsilate, is heated to after being completely dissolved, stops stirring It mixes；Be slow cooling to room temperature, 0 DEG C crystallization 2 days, filtering obtains crude white solid, and 1N sodium hydrate aqueous solution is added (50mL) is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to get white wax Shape solid 18.1g, i.e. (S) -3- Phenylpiperidine, yield 18.1%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR (100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS- ESI(m/z):162.2(M+H)+；Mp=14.5-15.5 DEG C, ee=89.19%.
Embodiment 19:(R) -3- Phenylpiperidine ((R) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in isopropanol (50mL), it will be dissolved with D- tartaric acid Isopropanol (200mL) solution of (93.16g, 622.2mmol) is added drop-wise in the aqueous isopropanol of racemic 3- Phenylpiperidine, is stirred 2h is mixed, filters, obtains tartrate；Then, methanol (10L) is added to the tartrate, is heated to after being completely dissolved, stops stirring It mixes；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains crude white solid, and 1N sodium hydrate aqueous solution is added (50mL) is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to get white wax Shape solid 29.7g, i.e. (R) -3- Phenylpiperidine, yield 29.7%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR (100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS- ESI(m/z):162.2(M+H)+；Ee94.85%.
Embodiment 20:(R) -3- Phenylpiperidine ((R) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in methanol (50mL), it will be dissolved with D- (+)-dibenzoyl wine Methanol (200mL) solution of stone acid (222.93g, 622.2mmol) is added drop-wise in the methanol solution of racemic 3- Phenylpiperidine, is stirred 2h is mixed, filters, obtains dibenzoyl tartaric acid salt；Then, ethyl alcohol (8L) is added to the dibenzoyl tartaric acid salt, has been heated to After fully dissolved, stop stirring；Be slow cooling to room temperature, -10 DEG C crystallization 5 days, filtering obtains crude white solid, and 1N hydrogen is added Aqueous solution of sodium oxide (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, anhydrous sodium sulfate dries, filters, dense Contracting obtains white waxy solid 28.3g, i.e. (R) -3- Phenylpiperidine, yield 28.3%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H, m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+；Ee=93.64%.
Embodiment 21:(R) -3- Phenylpiperidine ((R) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in ethyl acetate (30mL), it will be dissolved with D- bis- to methylbenzene Ethyl acetate (200mL) solution of formyl tartaric acid (205.53g, 622.2mmol) is added drop-wise to the second of racemic 3- Phenylpiperidine In acetate solution, 2h is stirred, filtering obtains two pairs of toluyl tartrates；Then, to two pairs of toluyl wine Ethyl acetate (15L) is added in stone hydrochlorate, is heated to after being completely dissolved, and stops stirring；Be slow cooling to room temperature, 0 DEG C crystallization 2 days, Filtering obtains crude white solid, is added 1N sodium hydrate aqueous solution (50mL), is extracted with ethyl acetate (25mL × 2), merges Organic phase, anhydrous sodium sulfate dry, filter, and are concentrated to get white waxy solid 23.5g, i.e. (R) -3- Phenylpiperidine, yield 23.5%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08, 126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H)+；Ee=95.32%.
Embodiment 22:(R) -3- Phenylpiperidine ((R) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in tetrahydrofuran (60mL), it will be dissolved with D-malic acid Tetrahydrofuran (250mL) solution of (83.43g, 622.2mmol) is added drop-wise to the tetrahydrofuran solution of racemic 3- Phenylpiperidine In, 2h is stirred, filtering obtains malate；Then, tetrahydrofuran (8L) is added to the malate, is heated to being completely dissolved Afterwards, stop stirring；Be slow cooling to room temperature, -10 DEG C crystallization 3 days, filtering obtains crude white solid, and 1N sodium hydroxide is added Aqueous solution (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate is dried, filtered, is concentrated to get White waxy solid 17.9g, i.e. (R) -3- Phenylpiperidine, yield 17.9%.1H-NMR (400MHz, DMSO-d6) δ: 7.30- 7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m) .13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+；Ee=90.20%.
Embodiment 23:(R) -3- Phenylpiperidine ((R) -1-1) preparation
3- Phenylpiperidine (1-1,100g, 621.1mmol) is dissolved in ethyl alcohol (50mL), it will be dissolved with D- camphorsulfonic acid Ethyl alcohol (150mL) solution of (145.8g, 622.2mmol) is added drop-wise in the ethanol solution of racemic 3- Phenylpiperidine, stirs 2h, Filtering, obtains camsilate；Then, methanol (5L) is added to the camsilate, is heated to after being completely dissolved, stops stirring It mixes；Be slow cooling to room temperature, 0 DEG C crystallization 2 days, filtering obtains crude white solid, and 1N sodium hydrate aqueous solution is added (50mL) is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to get white wax Shape solid 19.3g, i.e. (R) -3- Phenylpiperidine, yield 19.3%.1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16 (5H, m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m).13C-NMR (100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS- ESI(m/z):162.2(M+H)+；Ee=87.31%.
Embodiment 24:(S) -3- p-nitrophenyl phenylpiperidines (6-1) synthesis
(S) -3- Phenylpiperidine ((S) -1-1,35.1g, 218.0mmol), glacial acetic acid (300mL) are added to reaction flask In, be then slowly added dropwise the concentrated sulfuric acid (12mL), stir 10min after, cool to 0 DEG C, then be slowly dropped into fuming nitric aicd (9.6mL, 218.2mmol), continue to stir 10min, the concentrated sulfuric acid (180mL) is then slowly added dropwise, after being added dropwise, 0 DEG C is stirred to react 7h, TLC detects raw material fully reacting, stops reaction；With 20% sodium hydroxide solution, reaction solution pH=10-12 is adjusted, then It is extracted with ethyl acetate (200mL × 2), collected organic layer, anhydrous sodium sulfate is added and dries, filters, is spin-dried for solvent and obtains product (S) -3- p-nitrophenyl phenylpiperidines (6-1) 31.9g, yield 71.0%；MS-ESI (m/z): 207.2 (M+H)+。
Embodiment 25:(S) -3- p-nitrophenyl phenylpiperidines (6-1) synthesis
By (S) -3- Phenylpiperidine ((S) -1-1,35.1g, 218.0mmol), potassium nitrate (25.7g, 254.45mmol), dense Sulfuric acid (180mL) is added in reaction flask, is warming up to 58 DEG C of reactions 8h, TLC and is detected raw material fully reacting, stops reaction；With 20% sodium hydroxide solution adjusts reaction solution pH=10-12, (250mL × 2) is then extracted with ethyl acetate, collection has Machine layer is added anhydrous sodium sulfate and dries, filters, is spin-dried for solvent and obtains product (S) -3- p-nitrophenyl phenylpiperidines (6-1) 32.9g, Yield 73.2%；MS-ESI (m/z): 207.2 (M+H)+。
Embodiment 26:(S) -3- p-nitrophenyl phenylpiperidines (6-1) synthesis
Reaction flask is added in (S) -3- Phenylpiperidine ((S) -1-1,31.9g, 197.84mmol), nitromethane (150mL) In, reaction solution is cooled to 0 DEG C, boron trifluoride etherate (32.96g, 232.28mmol) first is added, then methyl nitrate is added dropwise (35.77g, 464.55mmol) after being added dropwise, is warming up to 25 DEG C of reactions.After reaction, methylene chloride (300mL) is added, (3 × 100mL) is washed with saturated sodium bicarbonate aqueous solution, collected organic layer, anhydrous sodium sulfate dries, filters, and is spin-dried for solvent, mistake Column point is pure to obtain 28.8g product (S) -3- p-nitrophenyl phenylpiperidines (6-1), and product is light tan solid, yield 70.6%.MS- ESI (m/z): 207.2 (M+H)+。
Embodiment 27:(S) -3- p-nitrophenyl phenylpiperidines (6-1) synthesis
(S) -3- Phenylpiperidine ((S) -1-1,31.9g, 197.84mmol) is dissolved in methylene chloride (200mL), is reacted Liquid is cooled to 0 DEG C, and NO is added portionwise2BF4(27.6g, 207.73mmol) after addition, is to slowly warm up to 25 DEG C of reactions.Instead After answering, (3 × 50mL) is washed with saturated sodium bicarbonate aqueous solution, collected organic layer, anhydrous sodium sulfate dries, filters, rotation Dry solvent, column point is pure excessively obtains 36.00g product (S) -3- p-nitrophenyl phenylpiperidines (6-1), and product is light tan solid, yield 88.2%.MS-ESI (m/z): 207.2 (M+H)+。
Embodiment 28:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
By (S) -3- p-nitrophenyl phenylpiperidines (6-1,30g, 145.6mmol), active carbon (3g, 10%), ferric trichloride (1.335g, 3.5%), 80% hydrazine hydrate (19mL, 2.18mol), dehydrated alcohol (300mL) are added in reaction flask, are heated, and are returned After stream reaction 20h, stop reaction；First water (100mL) is added in filtering, concentrated solvent, then be extracted with ethyl acetate (200mL × 3), merge organic layer, anhydrous sodium sulfate dries, filters, and is concentrated to get solid crude product, silica gel column chromatography obtains (S) -3- to amine Base Phenylpiperidine (7) 15.2g, yield 65.0%；Mp=96-98 DEG C,1H-NMR(400MHz,CD3OD) δ: 7.04 (2H, d, J= 8.4Hz), 6.72 (2H, d, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m), 2.88-2.84 (1H, m), 2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+。13C-NMR(100MHz,CDCl3)δ: 144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.2 9.MS-ESI (m/z): 177.2 (M +H)+。
Embodiment 29:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
Water (200mL) is added into reaction flask, under stirring state, be sprinkled into batches 60-80 mesh iron powder (24.46g, 436.80mmol), hydrochloric acid is added, adjusts after reacting liquid pH value is 4-5 or so, be heated to it is slightly boiled, then by (S) -3- (4- nitro) Phenylpiperidine (6-1,30g, 145.6mmol) slowly instills, and after being added dropwise, extends the reaction time, until raw material has reacted.Stop Reaction adjusts pH value of solution=9-10 with saturated aqueous sodium carbonate, is extracted with ethyl acetate (100mL × 3), merges organic layer, Anhydrous sodium sulfate dries, filters, and is concentrated to get solid crude product, and silica gel column chromatography obtains (S) -3- to aminocarbonyl phenyl piperidines (7) 14.0g, yield 55.0%；Mp=96-98 DEG C,1H-NMR(400MHz,CD3OD) δ: 7.04 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m), 2.88-2.84 (1H, m), 2.07-1.98 (2H, m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+。13C-NMR(100MHz,CDCl3)δ:144.60,135.20, (127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI m/z): 177.2 (M+H)+。
Embodiment 30:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
By (S) -3- (4- nitro) Phenylpiperidine (6-1,31.9g, 154.85mmol), anhydrous tetrahydro furan (300mL) adds It in entering into reaction flask, is added portionwise Lithium Aluminium Hydride (5.9g, 154.95mmol), after reacting 3h, TLC detection raw material has reacted Entirely, stop reaction, cool to 0 DEG C, be slowly added dropwise water (6mL), then water layer pH is transferred to 8- with 15% sodium hydrate aqueous solution 9, water (18mL) then is added dropwise, 1h is stirred at room temperature.Anhydrous magnesium sulfate (50g) stirring 15, min is added, filtering, concentration removes THF, (200mL × 3) are extracted with ethyl acetate again, collected organic layer, anhydrous sodium sulfate dries, filters, and is spin-dried for solvent, silica gel column layer Analysis, obtains 13.6g product (S) -3- to aminocarbonyl phenyl piperidines (7), yield 50.2%；Mp=96-98 DEG C,1H-NMR(400MHz, CD3OD) δ: 7.04 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+.13C- NMR(100MHz,CDCl3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36, 27.29.MS-ESI (m/z): 177.2 (M+H)+。
Embodiment 31:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
By (S) -3- (4- nitro) Phenylpiperidine (6-1,31.9g, 154.85mmol), palladium carbon (1.6g, 5%), without water beetle Alcohol (300mL) is added in autoclave, is passed through 1atm hydrogen, and after reacting 2h, TLC detects raw material fully reacting, stops reaction, mistake Filter, solvent is spin-dried for, and is added 1N hydrochloric acid (100mL), then (100mL) is extracted with ethyl acetate, and is collected water layer, is discarded organic layer, Water layer pH is transferred to 8-9 with 10% sodium hydrate aqueous solution again, is then extracted with ethyl acetate (200mL × 3), is collected organic Layer, anhydrous sodium sulfate dry, filter, and are spin-dried for solvent, silica gel column chromatography obtains 17.3g product (S) -3- to aminocarbonyl phenyl piperidines (7), yield 63.2%；Mp=96-98 DEG C,1H-NMR(400MHz,CD3OD) δ: 7.04 (2H, d, J=8.4Hz), 6.72 (2H, D, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m), 2.88-2.84 (1H, m), 2.07-1.98 (2H, m), 1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+.13C-NMR(100MHz,CDCl3)δ:144.60,135.20, (127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI m/z): 177.2 (M+H)+。
Embodiment 32:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
By (S) -3- (4- nitro) Phenylpiperidine (6-1,31.9g, 154.85mmol), platinum dioxide (1.6g, 5%), nothing Water methanol (250mL) is added in autoclave, is passed through 1atm hydrogen, and after reacting 1.5h, TLC detects raw material fully reacting, is stopped Reaction, filtering, solvent is spin-dried for, and is added 1N hydrochloric acid (100mL), then (100mL) is extracted with ethyl acetate, and is collected water layer, is discarded Organic layer, then water layer pH is transferred to 8-9 with 10% sodium hydrate aqueous solution, (200mL × 3) are then extracted with ethyl acetate, Collected organic layer, anhydrous sodium sulfate dry, filter, and are spin-dried for solvent, and silica gel column chromatography obtains 17.8g product (S) -3- to amido Phenylpiperidine (7), yield 65.2%；Mp=96-98 DEG C,1H-NMR(400MHz,CD3OD) δ: 7.04 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m), 2.88-2.84 (1H, m), 2.07-1.98 (2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+.13C-NMR(100MHz,CDCl3)δ:144.60, 135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ES I (m/z): 177.2 (M+H)+。
Embodiment 33:(S) the synthesis of -3- to aminocarbonyl phenyl piperidines (7)
By (S) -3- (4- nitro) Phenylpiperidine (6-1,31.9g, 154.85mmol), Raney's nickel (0.957g, 3%), 80% hydrazine hydrate (20mL, 2.32mol), dehydrated alcohol (320mL) are added in reaction flask, and after reacting 8h, it is anti-that TLC detects raw material Reaction should be stopped completely, solvent is spin-dried for by filtering, and dilute hydrochloric acid (100mL) first is added, and is stirred 30min, is added ethyl acetate It extracts (200mL), collects water layer, discard organic layer, then water layer pH is transferred to 8-9 with 10% sodium hydrate aqueous solution, then (200mL × 3) are extracted with ethyl acetate, collected organic layer, anhydrous sodium sulfate dries, filters, it is spin-dried for solvent, silica gel column chromatography, 17.7g product (S) -3- is obtained to aminocarbonyl phenyl piperidines (7), yield 65.2%；Mp=96-98 DEG C,1H-NMR(400MHz, CD3OD) δ: 7.04 (2H, d, J=8.4Hz), 6.72 (2H, d, J=8.4Hz), 3.44-3.33 (2H, m), 3.05-2.97 (2H, m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H)+；13C- NMR(100MHz,CDCl3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36, 27.29.MS-ESI (m/z): 177.2 (M+H)+。
The synthesis of embodiment 34:N- benzyl -3- Phenylpiperidine (6-2)
Under room temperature, by 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,75g, 279.85mmol), DCM (500mL), Boron trifluoride ether (38mL) is added in reaction flask, and ice-water bath is cooled to 0 DEG C, be slowly added dropwise triethylsilane (75mL, 474.78mmol), 30min is added dropwise, and is warming up to room temperature, reacts 3h, and TLC detects raw material fully reacting, stops reaction, slowly It is added water (200mL), adds NaOH solution and adjust water layer as alkalinity, stir 20min, liquid separation, by organic layer anhydrous slufuric acid Sodium dries, filters, and is spin-dried for solvent, and silica gel column chromatography obtains product N- benzyl -3- Phenylpiperidine (6-2) 56.4g, yield 80.3%；MS-ESI (m/z): 252.4 (M+H)+。
The synthesis of embodiment 35:N- benzyl -3- Phenylpiperidine (6-2)
Under room temperature, by 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,75g, 279.85mmol), DCM (500mL), Trifluoroacetic acid (32mL) is added in reaction flask, and ice-water bath is cooled to 0 DEG C, be slowly added dropwise triethylsilane (75mL, 474.78mmol), 30min is added dropwise, and is warming up to room temperature, reacts 2.5h, and TLC detects raw material fully reacting, stops reaction, delays It is slow that water (200mL) is added, it adds NaOH solution and adjusts water layer as alkalinity, stir 20min, liquid separation, by the anhydrous sulphur of organic layer Sour sodium dries, filters, and is spin-dried for solvent, and silica gel column chromatography obtains product N- benzyl -3- Phenylpiperidine (6-2) 50.1g, yield 71.2%；MS-ESI (m/z): 252.4 (M+H)+。
The synthesis of embodiment 36:N- benzyl -3- Phenylpiperidine (6-2)
Under room temperature, by 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,75g, 279.85mmol), THF (500mL), Boron trifluoride ether (38mL) is added in reaction flask, and ice-water bath is cooled to 0 DEG C, be slowly added dropwise triethylsilane (75mL, 474.78mmol), 30min is added dropwise, and is warming up to room temperature, reacts 3h, and TLC detects raw material fully reacting, stops reaction, slowly It is added water (200mL), adds NaOH solution and adjust water layer as alkalinity, stir 20min, liquid separation, by organic layer anhydrous slufuric acid Sodium dries, filters, and is spin-dried for solvent, and silica gel column chromatography obtains product N- benzyl -3- Phenylpiperidine (6-2) 55.4g, yield 79.2%；MS-ESI (m/z): 252.4 (M+H)+。
The synthesis of embodiment 37:N- benzyl -3- Phenylpiperidine (6-2)
Under room temperature, by 3- hydroxyl -3- phenyl -1- benzyl piepridine (3-1,75g, 279.85mmol), THF (500mL), Trifluoroacetic acid (32mL) is added in reaction flask, and ice-water bath is cooled to 0 DEG C, be slowly added dropwise triethylsilane (75mL, 474.78mmol), 30min is added dropwise, and is warming up to room temperature, reacts 2.5h, and TLC detects raw material fully reacting, stops reaction, delays It is slow that water (200mL) is added, it adds NaOH solution and adjusts water layer pH=8, stir 20min, liquid separation, by organic layer anhydrous slufuric acid Sodium dries, filters, and is spin-dried for solvent, and silica gel column chromatography obtains product N- benzyl -3- Phenylpiperidine (6-2) 49.4g, yield 70.3%；MS-ESI (m/z): 252.4 (M+H)+。
The synthesis of embodiment 38:3- Phenylpiperidine (1)
By N- benzyl -3- Phenylpiperidine (6-2,65g, 258.96mmol), palladium carbon (12g, 18%), dehydrated alcohol (300mL), glacial acetic acid (11mL) are added in reaction flask, are passed through the hydrogen of 1atm, are heated to 60 DEG C, after reacting 12h, TLC inspection Raw material fully reacting is surveyed, stops reaction, palladium carbon is filtered, solvent is spin-dried for, and water (250mL) then is added, and extracted with ethyl acetate (250mL × 3) are taken, collected organic layer is dried, filtered with anhydrous sodium sulfate, and solvent is spin-dried for, and silica gel column chromatography obtains product 3- Phenylpiperidine (1) 35.2g, yield 89.3% are directly used in and react in next step；1H-NMR (400MHz, DMSO-d6) δ: 7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H, m).13C-NMR(100MHz,D2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80, 26.21.MS-ESI(m/z):162.2(M+H)+。
Embodiment 39:(S)-N- acetyl group -3- Phenylpiperidine (8-1) synthesis
By (S) -3- Phenylpiperidine ((S) -1-1,50g, 310.55mmol), DCM (100mL), triethylamine (43.8g, It 315.1mmol) is added in reaction flask, after ice salt bath cools to 0 DEG C, chloroacetic chloride (24.7g, 315.1mmol) is slowly added dropwise, 30min is added dropwise, and stops reaction；Saturated sodium bicarbonate aqueous solution (100mL) extraction is added, collects organic phase, anhydrous slufuric acid Sodium is dry, and concentrated solvent, silica gel column chromatography obtains colourless oil liquid 58.2g, i.e. (S)-N- acetyl group -3- Phenylpiperidine (8- 1), yield 92.1%；MS-ESI (m/z): 204.3 (M+H)+。
Embodiment 40:(S)-N- benzenesulfonyl -3- Phenylpiperidine (8-2) synthesis
By (S) -3- Phenylpiperidine ((S) -1-1,50g, 310.55mmol), methylene chloride (300mL), triethylamine (62.7g, 621.10mmol) is added in reaction flask, is added dropwise benzene sulfonyl chloride (55.65g, 315.1mmol), is added dropwise, and 25 DEG C anti- Answer 3h, end of reaction；Reaction solution is washed with water (100mLx3), collects organic phase, and anhydrous sodium sulfate is dry, and concentrated solvent obtains Product 88.1g, i.e. (S)-N- benzenesulfonyl -3- Phenylpiperidine (8-2), yield 94.1%；MS-ESI (m/z): 302.4 (M+H)+。
Embodiment 41:(S)-N- acetyl group -3- (the bromo- phenyl of 4-) piperidines (9-1) synthesis
By (S)-N- acetyl group -3- Phenylpiperidine (8-1,147.78mmol), glacial acetic acid (60mL), NBS (26.3g, It 147.75mmol) is added in reaction flask, is heated to 65 DEG C, react 2h, stop reaction；Vacuum distillation removes acetic acid, is then added Saturated sodium bicarbonate aqueous solution (100mL), and (30mL × 3) are extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate is dry Dry, concentration, crude product silica gel column chromatography obtains colourless oil liquid 35.1g, i.e. (S)-N- acetyl group -3- (the bromo- phenyl of 4-) piperazine Pyridine (9-1), yield 85.3%；MS-ESI (m/z): 282.2,284.2 (M+H)+。
Embodiment 42:(S)-N- benzenesulfonyl -3- (the bromo- phenyl of 4-) piperidines (9-2) synthesis
Reaction is added in (S)-N- benzenesulfonyl -3- Phenylpiperidine (8-2,147.78mmol), methylene chloride (120mL) Bromine (24.8g, 155.17mmol) is diluted with methylene chloride (180mL) and is slowly dropped in reaction flask by bottle, and drop finishes, room temperature 10h is reacted, reaction is stopped.Reaction solution is washed with water (80mL × 3), anhydrous sodium sulfate dries, filters, concentration, crude product silicon Plastic column chromatography obtains colourless oil liquid 50.7g, i.e. (S)-N- benzenesulfonyl -3- (the bromo- phenyl of 4-) piperidines (9-2), yield 90.3%；MS-ESI (m/z): 380.1,382.1 (M+H)+。
Embodiment 43:(S) -3- p-bromophenyl piperidines (10) synthesis
By (S)-N- acetyl group -3- (the bromo- phenyl of 4-) piperidines (9-1,106.76mmol), the aqueous hydrochloric acid solution of 6N (150mL) is added in reaction flask, heating, and back flow reaction 12h stops reaction；2N sodium hydrate aqueous solution is added dropwise, adjusts reaction Liquid pH=9, then (35mL × 3) are extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate is dry, concentration, crude product silicagel column Chromatography, obtains colourless oil liquid 20.1g, i.e. (S) -3- p-bromophenyl piperidines (10), yield 78.4%；MS-ESI (m/z): 240.1,242.1 (M+H)+。
Embodiment 44:(S) -3- p-bromophenyl piperidines (10) synthesis
By (S)-N- benzenesulfonyl -3- (the bromo- phenyl of 4-) piperidines (9-2,106.76mmol), 40% HBr solution (100mL) and glacial acetic acid (100mL) is added in reaction flask, is to slowly warm up to 70 DEG C of reactions.After reaction, it is concentrated under reduced pressure molten Agent.Residue is dissolved with water, and it is 10-12 that NaOH solution, which adjusts pH, then extracts (100mLx3) with DCM, merges organic layer, nothing Aqueous sodium persulfate is dry, and concentration, crude product silica gel column chromatography obtains colourless oil liquid 15.1g, i.e. (S) -3- p-bromophenyl piperidines (10), yield 58.4%；MS-ESI (m/z): 240.1,242.1 (M+H)+。
The synthesis of embodiment 45:3- hydroxyl -3- p-methoxyphenyl -1- benzyl piepridine (3-2)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), It is added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1,6.0g, 31.7mmol) With anhydrous tetrahydro furan (30mL) dilute, be added in dropping funel, be slowly dropped in reaction flask, temperature control at 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is added with stirring saturation Aqueous ammonium chloride solution (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, appropriate nothing is added Aqueous sodium persulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography, obtains that (3- hydroxyl -3- is to methoxyl group Phenyl -1- benzyl piepridine (3-2)) 8.7g, yield 92.2%；MS-ESI (m/z): 298.3 [(M+H)+]。
The synthesis of embodiment 46:3- hydroxyl -3- p-methoxyphenyl -1- tritylpiperidine (3-3)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2,10.9g, It 31.9mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Methoxyphenyl -1- tritylpiperidine (3-3)) 14.1g, yield 98.3%；MS-ESI (m/z): 450.6 [(M+H)+]。
The synthesis of embodiment 47:3- hydroxyl -3- p-methoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-4)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- piperidones (2-3, 8.0g, 32.1mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, control At 0-5 DEG C, 60min is dripped off temperature, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, stirring Lower addition saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merge organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- p-methoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-4)) 11.0g, yield 96.1%；MS-ESI (m/z): 358.5[(M+H)+]。
The synthesis of embodiment 48:3- hydroxyl -3- p-methoxyphenyl -1- tert-butylpiperidin (3-5)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- tert-butyl -3- piperidones (2-4,5.0g, It 32.2mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL) quenching, then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- p-methoxyphenyl -1- tert-butylpiperidin (3-5)) 7.9g, yield 93.2%；MS-ESI (m/z): 264.3 [(M+H)+]。
The synthesis of embodiment 49:3- hydroxyl -3- p-methoxyphenyl -1- trimethyl silicane phenylpiperidines (3-6)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- trimethyl silicon substrate -3- piperidones (2-5,5.5g, It 32.1mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL) quenching, then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl -3- P-methoxyphenyl -1- trimethyl silicane phenylpiperidines (3-6)) 8.2g, yield 91.4%；MS-ESI (m/z): 280.4 [(M+H)+]。
The synthesis of embodiment 50:3- hydroxyl -3- p-methoxyphenyl -1- t-Butyldimethylsilyl piperidines (3-7)
By p-methoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- tert-butyl -3- piperidones (2-6,6.8g, It 31.9mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL) quenching, then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- p-methoxyphenyl -1- t-Butyldimethylsilyl piperidines (3-7)) 9.8g, yield 95.8%；MS-ESI (m/z): 322.5 [(M+H)+]。
Synthesis of the embodiment 51:3- hydroxyl -3- to ethoxyl phenenyl -1- benzyl piepridine (3-8)
It will be to ethoxyl phenenyl magnesium bromide Grignard Reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1,6.0g, It 31.7mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Ethoxyl phenenyl -1- benzyl piepridine (3-8)) 9.2g, yield 93.2%；MS-ESI (m/z): 312.4 [(M+H)+]。
Synthesis of the embodiment 52:3- hydroxyl -3- to ethoxyl phenenyl -1- tritylpiperidine (3-9)
Will to ethoxyl phenenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2,10.9g, It 31.9mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Ethoxyl phenenyl -1- tritylpiperidine (3-9)) 13.8g, yield 93.2%；MS-ESI (m/z): 464.6 [(M+H)+]。
Synthesis of the embodiment 53:3- hydroxyl -3- to ethoxyl phenenyl -1- (2,4- dimethoxy) benzyl piepridine (3-10)
Will to ethoxyl phenenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- piperidones (2-3, 8.0g, 32.1mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, control At 0-5 DEG C, 60min is dripped off temperature, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, stirring Lower addition saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merge organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- is to ethoxyl phenenyl -1- (2,4- dimethoxy) benzyl piepridine (3-10)) 11.2g, yield 94.3%；MS-ESI (m/z): 372.5[(M+H)+]。
Synthesis of the embodiment 54:3- hydroxyl -3- to ethoxyl phenenyl -1- t-Butyldimethylsilyl piperidines (3-11)
Will to ethoxyl phenenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- t-Butyldimethylsilyl -3- piperidones (2-6, 6.8g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, control At 0-5 DEG C, 60min is dripped off temperature, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, stirring Lower addition saturated aqueous ammonium chloride (50mL) quenching, then extracted with ethyl acetate (20mL × 3), after extraction three times, it is associated with Machine layer is added appropriate anhydrous sodium sulfate and dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- Hydroxyl -3- is to ethoxyl phenenyl -1- t-Butyldimethylsilyl piperidines (3-11)) 9.8g, yield 91.2%；MS-ESI (m/z): 336.6[(M+H)+]。
Synthesis of the embodiment 55:3- hydroxyl -3- to tert .- butoxyphenyl -1- benzyl piepridine (3-12)
It will be to tert .- butoxyphenyl magnesium bromide Grignard Reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1,6.0g, It 31.7mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Tert .- butoxyphenyl -1- benzyl piepridine (3-12)) 10.4g, yield 96.5%；MS-ESI (m/z): 343.5 [(M+H)+]。
Synthesis of the embodiment 56:3- hydroxyl -3- to tert .- butoxyphenyl -1- tritylpiperidine (3-13)
It will be to tert .- butoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2, 10.9g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, At 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is stirred Lower addition saturated aqueous ammonium chloride (50mL) is mixed, then is extracted with ethyl acetate (20mL × 3), after extraction three times, is merged organic Layer, is added appropriate anhydrous sodium sulfate and dries, filters, be spin-dried for solvent and obtain product crude product, crude product silica gel column chromatography obtains (3- hydroxyl Base -3- is to tert .- butoxyphenyl -1- tritylpiperidine (3-13)) 14.6g, yield 92.9%；MS-ESI (m/z): 492.6 [(M+H)+]。
Synthesis of the embodiment 57:3- hydroxyl -3- to tert .- butoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-14)
It will be to tert .- butoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- piperidines Ketone (2-3,8.0g, 32.1mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped to reaction In bottle, at 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and it is reacted complete that TLC detects raw material Entirely, it is added with stirring saturated aqueous ammonium chloride (50mL), then is extracted with ethyl acetate (20mL × 3), after extraction three times, merged Organic layer is added appropriate anhydrous sodium sulfate and dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl -3- is to tert .- butoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-14)) 12.2g, yield 95.2%；MS- ESI (m/z): 400.5 [(M+H)+]。
Synthesis of the embodiment 58:3- hydroxyl -3- to tert .- butoxyphenyl -1- t-Butyldimethylsilyl piperidines (3-15)
It will be to tert .- butoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by the tertiary fourth dimethyl silicon substrate -3- piperidones (2- of N- 6,6.8g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, At 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is stirred Lower addition saturated aqueous ammonium chloride (50mL) quenching is mixed, then is extracted with ethyl acetate (20mL × 3), after extraction three times, is merged Organic layer is added appropriate anhydrous sodium sulfate and dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl -3- is to the tertiary fourth dimethyl-silicon phenylpiperidines of tert .- butoxyphenyl -1- (3-15)) 10.5g, yield 90.2%；MS-ESI (m/z): 364.6 [(M+H)+]。
Synthesis of the embodiment 59:3- hydroxyl -3- to methoxymethoxyphenyl -1- benzyl piepridine (3-16)
It will be to methoxymethoxyphenyl magnesium bromide Grignard Reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1,6.0g, It 31.7mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Methoxymethoxyphenyl -1- benzyl piepridine (3-16)) 9.9g, yield 95.2%；MS-ESI (m/z): 328.5 [(M+H)+]。
Synthesis of the embodiment 60:3- hydroxyl -3- to methoxymethoxyphenyl -1- tritylpiperidine (3-17)
It will be to methoxymethoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2, 10.9g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, At 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is stirred Lower addition saturated aqueous ammonium chloride (50mL) is mixed, then is extracted with ethyl acetate (20mL × 3), after extraction three times, is merged organic Layer, is added appropriate anhydrous sodium sulfate and dries, filters, be spin-dried for solvent and obtain product crude product, crude product silica gel column chromatography obtains (3- hydroxyl Base -3- is to methoxymethoxyphenyl -1- tritylpiperidine (3-17)) 14.5g, yield 94.6%；MS-ESI (m/z): 480.6[(M+H)+]。
Embodiment 61:3- hydroxyl -3- is to methoxymethoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-18) Synthesis
It will be to methoxymethoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- piperidines Ketone (2-3,8.0g, 32.1mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped to reaction In bottle, at 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and it is reacted complete that TLC detects raw material Entirely, it is added with stirring saturated aqueous ammonium chloride (50mL), then is extracted with ethyl acetate (20mL × 3), after extraction three times, merged Organic layer is added appropriate anhydrous sodium sulfate and dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl -3- is to methoxymethoxyphenyl -1- (2,4- dimethoxy) benzyl piepridine (3-18)) 11.8g, yield 94.8%； MS-ESI (m/z): 388.5 [(M+H)+]。
Conjunction of the embodiment 62:3- hydroxyl -3- to methoxymethoxyphenyl -1- t-Butyldimethylsilyl piperidines (3-19) At
It will be to methoxymethoxyphenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by the tertiary fourth dimethyl silicon substrate -3- piperidones (2- of N- 6,6.8g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, At 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is stirred Lower addition saturated aqueous ammonium chloride (50mL) quenching is mixed, then is extracted with ethyl acetate (20mL × 3), after extraction three times, is merged Organic layer is added appropriate anhydrous sodium sulfate and dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl -3- is to the tertiary fourth dimethyl-silicon phenylpiperidines of methoxymethoxyphenyl -1- (3-19)) 10.2g, yield 91.1%；MS- ESI (m/z): 352.6 [(M+H)+]。
Synthesis of the embodiment 63:3- hydroxyl -3- to tertiary butyl dimethyl Si base phenyl -1- benzyl piepridine (3-20)
Will to tertiary butyl dimethyl Si base phenyl-magnesium-bromide Grignard Reagent (1.8mol/L in THF, 20mL), anhydrous four Hydrogen furans (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1, 6.0g, 31.7mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, control At 0-5 DEG C, 60min is dripped off temperature, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, stirring Lower addition saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merge organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- is to tertiary butyl dimethyl Si base phenyl -1- benzyl piepridine (3-20)) 12.1g, yield 96.5%；MS-ESI (m/z): 398.6[(M+H)+]。
Synthesis of the embodiment 64:3- hydroxyl -3- to tertiary butyl dimethyl Si base phenyl -1- tritylpiperidine (3-21)
It will be to tertiary butyl dimethyl Si base phenyl-magnesium-bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro Furans (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2, 10.9g, 31.9mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, At 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, is stirred Lower addition saturated aqueous ammonium chloride (50mL) is mixed, then is extracted with ethyl acetate (20mL × 3), after extraction three times, is merged organic Layer, is added appropriate anhydrous sodium sulfate and dries, filters, be spin-dried for solvent and obtain product crude product, crude product silica gel column chromatography obtains (3- hydroxyl Base -3- is to tertiary butyl dimethyl Si base phenyl -1- tritylpiperidine (3-21)) 16.7g, yield 95.1%；MS-ESI(m/ Z): 550.8 [(M+H)+]。
Embodiment 65:3- hydroxyl -3- is to tertiary butyl dimethyl Si base phenyl -1- (2,4- dimethoxy) benzyl piepridine The synthesis of (3-22)
It will be to tertiary butyl dimethyl Si base phenyl-magnesium-bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro Furans (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- Piperidones (2-3,8.0g, 32.1mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped to In reaction flask, at 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and it is anti-that TLC detects raw material It should be added with stirring saturated aqueous ammonium chloride (50mL), then be extracted with ethyl acetate (20mL × 3) completely, after extraction three times, Merge organic layer, appropriate anhydrous sodium sulfate is added and dries, filters, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography, (3- hydroxyl -3- is to tertiary butyl dimethyl Si base phenyl -1- (2,4- dimethoxy) benzyl piepridine (3-22)) 13.6g is obtained, is received Rate 92.5%；MS-ESI (m/z): 458.7 [(M+H)+]。
Embodiment 66:3- hydroxyl -3- is to tertiary butyl dimethyl Si base phenyl -1- t-Butyldimethylsilyl piperidines (3- 23) synthesis
It will be to tertiary butyl dimethyl Si base phenyl-magnesium-bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro Furans (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by the tertiary fourth dimethyl silicon substrate -3- piperidines of N- Ketone (2-6,6.8g, 31.9mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped to reaction In bottle, at 0-5 DEG C, 60min is dripped off temperature control, continues to be stirred to react 1 hour after being added dropwise, and it is reacted complete that TLC detects raw material Entirely, it is added with stirring saturated aqueous ammonium chloride (50mL) quenching, then is extracted with ethyl acetate (20mL × 3), after extraction three times, Merge organic layer, appropriate anhydrous sodium sulfate is added and dries, filters, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography, Obtain (3- hydroxyl -3- is to the tertiary fourth dimethyl silica phenylpiperidines of t-Butyldimethylsilyl phenyl -1- (3-23)) 12.5g, yield 93.0%；MS-ESI (m/z): 422.8 [(M+H)+]。
Synthesis of the embodiment 67:3- hydroxyl -3- to benzyloxy-phenyl -1- benzyl piepridine (3-24)
It will be to benzyloxy-phenyl magnesium bromide Grignard Reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydro furan (30mL), is added in reaction flask, nitrogen protection, and ice-water bath is cooled to 0 DEG C, by N- benzyl -3- piperidones (2-1,6.0g, It 31.7mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Benzyloxy-phenyl -1- benzyl piepridine (3-24)) 11.2g, yield 94.8%；MS-ESI (m/z): 374.5 [(M+H)+]。
Synthesis of the embodiment 68:3- hydroxyl -3- to benzyloxy-phenyl -1- tritylpiperidine (3-25)
Will to benzyloxy-phenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- trityl -3- piperidones (2-2,10.9g, 31.9mmol) diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, be added Appropriate anhydrous sodium sulfate dries, filters, and is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (- 3- pairs of 3- hydroxyl Benzyloxy-phenyl -1- tritylpiperidine (3-25)) 16.0g, yield 95.1%；MS-ESI (m/z): 526.7 [(M+H)+]。
Synthesis of the embodiment 69:3- hydroxyl -3- to benzyloxy-phenyl -1- (2,4- dimethoxy) benzyl piepridine (3-26)
Will to benzyloxy-phenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by N- (2,4- dimethoxy) benzyl -3- piperidones (2-3, 8.0g, 32.1mmol) it is diluted with anhydrous tetrahydro furan (30mL), it is added in dropping funel, is slowly dropped in reaction flask, control At 0-5 DEG C, 60min is dripped off temperature, continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, stirring Lower addition saturated aqueous ammonium chloride (50mL), then extracted with ethyl acetate (20mL × 3), after extraction three times, merge organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- is to benzyloxy-phenyl -1- (2,4- dimethoxy) benzyl piepridine (3-26)) 13.5g, yield 97.2%；MS-ESI (m/z): 434.5[(M+H)+]。
Synthesis of the embodiment 70:3- hydroxyl -3- to benzyloxy-phenyl -1- t-Butyldimethylsilyl piperidines (3-27)
Will to benzyloxy-phenyl magnesium bromide Grignard Reagent (2mol/L in THF, 18mL), anhydrous tetrahydro furan (30mL), Be added in reaction flask, nitrogen protection, ice-water bath is cooled to 0 DEG C, by the tertiary fourth dimethyl silicon substrate -3- piperidones of N- (2-6,6.8g, It 31.9mmol) is diluted with anhydrous tetrahydro furan (30mL), is added in dropping funel, is slowly dropped in reaction flask, temperature control exists 0-5 DEG C, 60min is dripped off, and continues to be stirred to react 1 hour after being added dropwise, and TLC detects raw material fully reacting, and stirring is lower to be added Enter saturated aqueous ammonium chloride (50mL) quenching, then extracted with ethyl acetate (20mL × 3), after extraction three times, merges organic layer, Appropriate anhydrous sodium sulfate is added to dry, filter, is spin-dried for solvent and obtains product crude product, crude product silica gel column chromatography obtains (3- hydroxyl- 3- is to the tertiary fourth dimethyl-silicon phenylpiperidines of benzyloxy-phenyl -1- (3-27)) 11.7g, yield 92.6%；MS-ESI (m/z): 398.6 [(M+H)+]。
Embodiment 71:1- benzyl -5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-2) and 1- benzyl -5- are to methoxy The synthesis of base phenyl -1,2,3,4- tetrahydropyridine (5-2)
By 3- hydroxyl -3- p-methoxyphenyl -1- benzyl piepridine (3-2,8.0g, 26.9mmol), glacial acetic acid (40mL, 0.67mol), chloroacetic chloride (40mL, 0.56mol) is added in reaction flask, heating, and TLC detection raw material is anti-after back flow reaction 90min Should reaction be stopped, acetic acid is evaporated under reduced pressure completely, 20% sodium hydrate aqueous solution is then added to residue, adjusts (20mL × 3) are then extracted with ethyl acetate in pH value of solution=8-9, and collected organic layer is dried with anhydrous sodium sulfate, filtering, Solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (mixture of compound (4-2) and compound (5-2)) 6.5g, Yield 86.8%；MS-ESI (m/z): 280.4 (M+H)+。
Embodiment 72:5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-3) and p-methoxyphenyl -1,2,3 5-, The synthesis of 4- tetrahydropyridine (5-3)
By 3- hydroxyl -3- p-methoxyphenyl -1- tritylpiperidine (3-3,12.0g, 26.7mmol), glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, and TLC is detected after back flow reaction 90min Raw material fully reacting stops reaction, acetic acid is evaporated under reduced pressure, and the sodium hydroxide for being then added 20% to residue is water-soluble Liquid adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer is done with anhydrous sodium sulfate Dry, solvent is spin-dried for obtaining crude product (mixture of compound (4-3) and compound (5-3)), by gained crude product silica gel by filtering Column chromatography, obtains the mixture 4.2g of compound (4-3) and compound (5-3), yield 83.9%, and MS-ESI (m/z): 189.3 (M+H)+。
Embodiment 73:1- (2,4- dimethoxy-benzyl) -5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-4) and The synthesis of 1- (2,4- dimethoxy-benzyl) -5- p-methoxyphenyl -1,2,3,4- tetrahydropyridine (5-4)
By 3- hydroxyl -3- p-methoxyphenyl -1- (2,4- dimethoxy-benzyl)-piperidines (3-4,10.0g, 28.0mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) are added in reaction flask, heating, and reflux is anti- It answers TLC after 90min to detect raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, be then added 20% to residue Sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 3), collected organic layer, with nothing Aqueous sodium persulfate is dried, filtering, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-4) and change Close the mixture of object (5-4)) 8.1g, yield 85.6%；MS-ESI (m/z): 340.4 (M+H)+。
- 5- pairs of embodiment 74:1- tert-butyl -5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-5) and 1- tert-butyl The synthesis of methoxyphenyl -1,2,3,4- tetrahydropyridine (5-5)
By 3- hydroxyl -3- p-methoxyphenyl -1- tert-butyl-piperidine (3-5,7.8g, 29.6mmol), glacial acetic acid (40mL, 0.67mol), chloroacetic chloride (40mL, 0.56mol) is added in reaction flask, heating, and TLC detection raw material is anti-after back flow reaction 90min Should reaction be stopped, acetic acid is evaporated under reduced pressure completely, 20% sodium hydrate aqueous solution is then added to residue, adjusts (20mL × 3) are then extracted with ethyl acetate in pH value of solution=8-9, and collected organic layer is dried with anhydrous sodium sulfate, filtering, Solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (mixture of compound (4-5) and compound (5-5)) 6.3g, Yield 86.7%；MS-ESI (m/z): 246.4 (M+H)+。
Embodiment 75:5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-3) and p-methoxyphenyl -1,2,3 5-, The synthesis of 4- tetrahydropyridine (5-3)
By 3- hydroxyl -3- p-methoxyphenyl -1- trimethyl silicane phenylpiperidines (3-6,8.0g, 28.6mmol), glacial acetic acid (40mL, 0.67mol), chloroacetic chloride (40mL, 0.56mol) are added in reaction flask, heating, and TLC is detected after back flow reaction 90min Raw material fully reacting stops reaction, acetic acid is evaporated under reduced pressure, and the sodium hydroxide for being then added 20% to residue is water-soluble Liquid adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer is done with anhydrous sodium sulfate Dry, solvent is spin-dried for obtaining crude product (mixture of compound (4-3) and compound (5-3)), by gained crude product silica gel by filtering Column chromatography, obtains the mixture 4.5g of compound (4-3) and compound (5-3), yield 83.3%, and MS-ESI (m/z): 189.3 (M+H)+。
Embodiment 76:5- p-methoxyphenyl -1,2,3,6- tetrahydropyridine (4-3) and p-methoxyphenyl -1,2,3 5-, The synthesis of 4- tetrahydropyridine (5-3)
By 3- hydroxyl -3- p-methoxyphenyl -1- t-Butyldimethylsilyl piperidines (3-7,8.8g, 27.4mmol), ice Acetic acid (40mL, 0.67mol), chloroacetic chloride (40mL, 0.56mol) are added in reaction flask, heating, TLC after back flow reaction 90min Raw material fully reacting is detected, stops reaction, acetic acid is evaporated under reduced pressure, 20% sodium hydroxide water is then added to residue Solution adjusts pH value of solution=8-9, is then extracted with ethyl acetate (20mL × 3), collected organic layer, is carried out with anhydrous sodium sulfate It dries, filters, solvent is spin-dried for obtain crude product (mixture of compound (4-3) and compound (5-3)), by gained crude product silicon Rubber column gel column purifying, obtains the mixture 4.5g of compound (4-3) and compound (5-3), yield 86.6%.MS-ESI (m/z): 189.3(M+H)+。
Embodiment 77:1- benzyl -5- is to ethoxyl phenenyl -1,2,3,6- tetrahydropyridine (4-6) and 1- benzyl -5- to ethoxy The synthesis of base phenyl -1,2,3,4- tetrahydropyridine (5-6)
By 3- hydroxyl -3- to ethoxyl phenenyl -1- benzyl piepridine (3-8,9.0g, 28.9mmol), glacial acetic acid (40mL, 0.67mol), chloroacetic chloride (40mL, 0.56mol) is added in reaction flask, heating, and TLC detection raw material is anti-after back flow reaction 90min Should reaction be stopped, acetic acid is evaporated under reduced pressure completely, 20% sodium hydrate aqueous solution is then added to residue, adjusts (20mL × 3) are then extracted with ethyl acetate in pH value of solution=8-9, and collected organic layer is dried with anhydrous sodium sulfate, filtering, Solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (mixture of compound (4-6) and compound (5-6)) 7.2g, Yield 85.0%, MS-ESI (m/z): 294.4 (M+H)+。
Embodiment 78:1- (2,4- dimethoxy-benzyl) -5- to ethoxyl phenenyl -1,2,3,6- tetrahydropyridine (4-7) and Synthesis of 1- (2,4- the dimethoxy-benzyl) -5- to ethoxyl phenenyl -1,2,3,4- tetrahydropyridine (5-7)
By 3- hydroxyl -3- to ethoxyl phenenyl -1- (2,4- dimethoxy-benzyl)-piperidines (3-10,10.0g, 26.92mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) are added in reaction flask, are heated, reflux TLC detects raw material fully reacting after reacting 90min, stops reaction, acetic acid is evaporated under reduced pressure, and is then added to residue 20% sodium hydrate aqueous solution adjusts pH value of solution=8-9, is then extracted with ethyl acetate (20mL × 3), collected organic layer, It is dried with anhydrous sodium sulfate, filters, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-7) With the mixture of compound (5-7)) 8.2g, yield 86.3%.MS-ESI (m/z): 354.4 (M+H)+。
Embodiment 79:1- benzyl -5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-8) and 1- benzyl -5- para hydroxybenzene The synthesis of base -1,2,3,4- tetrahydropyridine (5-8)
By 3- hydroxyl -3- to tert .- butoxyphenyl -1- benzyl piepridine (3-12,10.0g, 29.5mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) are added in reaction flask, heating, and TLC is detected after back flow reaction 90min Raw material fully reacting stops reaction, acetic acid is evaporated under reduced pressure, and the sodium hydroxide for being then added 20% to residue is water-soluble Liquid adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer is done with anhydrous sodium sulfate Dry, solvent is spin-dried for obtaining crude product, crude product silica gel column chromatography obtains the (mixing of compound (4-8) and compound (5-8) by filtering Object) 6.4g, yield 81.4%, MS-ESI (m/z): 266.4 (M+H)+。
Embodiment 80:1- (2,4- dimethoxy-benzyl) -5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-9) and 1- The synthesis of (2,4- dimethoxy-benzyl) -5- p-hydroxybenzene -1,2,3,4- tetrahydropyridine (5-9)
By 3- hydroxyl -3- to tert .- butoxyphenyl -1- (2,4- dimethoxy-benzyl)-piperidines (3-14,12.0g, 30.0mmol), glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, and reflux is anti- It answers TLC after 90min to detect raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, be then added 20% to residue Sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 3), collected organic layer, with nothing Aqueous sodium persulfate is dried, filtering, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-9) and change Close the mixture of object (5-9)) 8.2g, yield 84.2%, MS-ESI (m/z): 326.4 (M+H)+。
Embodiment 81:5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-10) and 5- p-hydroxybenzene -1,2,3,4- four The synthesis of pyridinium hydroxide (5-10)
By 3- hydroxyl -3- to tert .- butoxyphenyl -1- t-Butyldimethylsilyl-piperidines (3-15,10.0g, 27.5mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) are added in reaction flask, heating, and reflux is anti- It answers TLC after 90min to detect raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, be then added 20% to residue Sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 5), collected organic layer, with nothing Aqueous sodium persulfate is dried, filtering, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-10) and change Close the mixture of object (5-10)) 4.0g, yield 83.9%, MS-ESI (m/z): 176.2 (M+H)+。
Embodiment 82:1- benzyl -5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-8) and 1- benzyl -5- para hydroxybenzene The synthesis of base -1,2,3,4- tetrahydropyridine (5-8)
By 3- hydroxyl -3- to methoxymethoxyphenyl -1- benzyl piepridine (3-16,9.5g, 29.0mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) are added in reaction flask, heating, and TLC is detected after back flow reaction 90min Raw material fully reacting stops reaction, acetic acid is evaporated under reduced pressure, and the sodium hydroxide for being then added 20% to residue is water-soluble Liquid adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer is done with anhydrous sodium sulfate Dry, solvent is spin-dried for obtaining crude product, crude product silica gel column chromatography obtains the (mixing of compound (4-8) and compound (5-8) by filtering Object) 7.2g, yield 85.0%, MS-ESI (m/z): 266.4 (M+H)+。
Embodiment 83:1- (2,4- dimethoxy-benzyl) -5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-9) and 1- The synthesis of (2,4- dimethoxy-benzyl) -5- p-hydroxybenzene -1,2,3,4- tetrahydropyridine (5-9)
By 3- hydroxyl -3- to methoxymethoxyphenyl -1- (2,4- dimethoxy-benzyl)-piperidines (3-18,11.5g, 29.7mmol), glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, and reflux is anti- It answers TLC after 90min to detect raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, be then added 20% to residue Sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 3), collected organic layer, with nothing Aqueous sodium persulfate is dried, filtering, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-9) and change Close the mixture of object (5-9)) 7.9g, yield 82.3%, MS-ESI (m/z): 326.4 (M+H)+。
Embodiment 84:1- benzyl -5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-8) and 1- benzyl -5- para hydroxybenzene The synthesis of base -1,2,3,4- tetrahydropyridine (5-8)
By 3- hydroxyl -3- to tertiary butyl dimethyl Si base phenyl -1- benzyl piepridine (3-20,11.8g, 29.7mmol), Glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, after back flow reaction 90min TLC detects raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, and 20% hydroxide is then added to residue Sodium water solution adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer uses anhydrous sodium sulfate It is dried, filters, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-8) and compound (5-8) Mixture) 6.3g, yield 79.8%, MS-ESI (m/z): 266.4 (M+H)+。
Embodiment 85:5- p-hydroxybenzene -1,2,3,6- tetrahydropyridine (4-10) and 5- p-hydroxybenzene -1,2,3,4- four The synthesis of pyridinium hydroxide (5-10)
By 3- hydroxyl -3- to tertiary butyl dimethyl Si base phenyl -1- t-Butyldimethylsilyl piperidines (3-23, 12.2g, 28.9mmol), glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) be added in reaction flask, heat, TLC detects raw material fully reacting after back flow reaction 90min, stops reaction, acetic acid is evaporated under reduced pressure, is then added to residue Enter 20% sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 5), collects organic Layer, is dried with anhydrous sodium sulfate, is filtered, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4- 10) and the mixture of compound (5-10)) 4.1g, yield 80.8%, MS-ESI (m/z): 176.2 (M+H)+。
Embodiment 86:1- benzyl -5- is to benzyloxy-phenyl -1,2,3,6- tetrahydropyridine (4-11) and 1- benzyl -5- to benzyl The synthesis of phenyl -1,2,3,4- tetrahydropyridine (5-11)
By 3- hydroxyl -3- to benzyloxy-phenyl -1- benzyl piepridine (3-24,11.0g, 29.4mmol), glacial acetic acid (50mL, 0.84mol), chloroacetic chloride (50mL, 0.70mol) is added in reaction flask, heating, and TLC detection raw material is anti-after back flow reaction 90min Should reaction be stopped, acetic acid is evaporated under reduced pressure completely, 20% sodium hydrate aqueous solution is then added to residue, adjusts (20mL × 3) are then extracted with ethyl acetate in pH value of solution=8-9, and collected organic layer is dried with anhydrous sodium sulfate, filtering, Solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (mixture of compound (4-11) and compound (5-11)) 8.6g, yield 81.9%, MS-ESI (m/z): 356.5 (M+H)+。
Embodiment 87:1- (2,4- dimethoxy-benzyl) -5- to benzyloxy-phenyl -1,2,3,6- tetrahydropyridine (4-12) and Synthesis of 1- (2,4- the dimethoxy-benzyl) -5- to benzyloxy-phenyl -1,2,3,4- tetrahydropyridine (5-12)
By 3- hydroxyl -3- to benzyloxy-phenyl -1- (2,4- dimethoxy-benzyl)-piperidines (3-26,12.8g, 29.5mmol), glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, and reflux is anti- It answers TLC after 90min to detect raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, be then added 20% to residue Sodium hydrate aqueous solution, adjust pH value of solution=8-9, be then extracted with ethyl acetate (20mL × 3), collected organic layer, with nothing Aqueous sodium persulfate is dried, filtering, solvent is spin-dried for obtain crude product, crude product silica gel column chromatography obtains (compound (4-12) and change Close the mixture of object (5-12)) 10.1g, yield 82.7%.MS-ESI (m/z): 416.5 (M+H)+。
Embodiment 88:5- to benzyloxy-phenyl -1,2,3,6- tetrahydropyridine (4-13) and 5- to benzyloxy-phenyl -1,2,3, The synthesis of 4- tetrahydropyridine (5-13)
By 3- hydroxyl -3- to benzyloxy-phenyl -1- t-Butyldimethylsilyl-piperidines (3-27,11.0g, 27.7mmol), Glacial acetic acid (60mL, 1.00mol), chloroacetic chloride (60mL, 0.84mol) are added in reaction flask, heating, after back flow reaction 90min TLC detects raw material fully reacting, stops reaction, acetic acid is evaporated under reduced pressure, and 20% hydroxide is then added to residue Sodium water solution adjusts pH value of solution=8-9, (20mL × 3) is then extracted with ethyl acetate, collected organic layer uses anhydrous sodium sulfate It is dried, filters, solvent is spin-dried for obtaining crude product, crude product silica gel column chromatography obtains product (compound (4-13) and compound The mixture of (5-13)) 5.9g, yield 79.8%, MS-ESI (m/z): 266.4 (M+H)+。
The synthesis of embodiment 89:3- p-methoxyphenyl piperidines (1-2)
By the mixture (8.0g, 28.6mmol) of compound (4-2) and compound (5-2), palladium carbon (1.6g, 20%), nothing Water methanol (40mL), glacial acetic acid (1.6mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 16h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, and uses second Acetoacetic ester is extracted (50mL × 3), and collected organic layer is dried, filtered with anhydrous sodium sulfate, and solvent is spin-dried for, crude product silicon Plastic column chromatography, obtains product 3- p-methoxyphenyl piperidines (1-2) 4.9g, yield 89.5%, and MS-ESI (m/z): 192.3 (M+ H)+。
The synthesis of embodiment 90:3- p-methoxyphenyl piperidines (1-2)
By the mixture (7.5g, 39.6mmol) of compound (4-3) and compound (5-3), palladium carbon (0.38g, 5%), nothing Water methanol (40mL) is added in autoclave, and is passed through hydrogen, and vacuum displacement three times, is heated to 40 DEG C, reacts 6h, TLC detection Raw material fully reacting stops reaction, palladium carbon is filtered, solvent is spin-dried for, crude product silica gel column chromatography obtains product 3- to methoxy Base Phenylpiperidine (1-2) 7.3g, yield 96.2%, MS-ESI (m/z): 192.3 (M+H)+。
The synthesis of embodiment 91:3- p-methoxyphenyl piperidines (1-2)
By the mixture (10.0g, 29.5mmol) of compound (4-4) and compound (5-4), palladium carbon (1.0g, 10%), nothing Water methanol (60mL), glacial acetic acid (3.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 10h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and after solvent is spin-dried for, is added water (50mL), is used in combination Ethyl acetate is extracted (50mL × 3), and collected organic layer is dried, filtered with anhydrous sodium sulfate, crude product silica gel column chromatography, Obtain product 3- p-methoxyphenyl piperidines (1-2) 5.2g, yield 92.4%, MS-ESI (m/z): 192.3 (M+H)+。
The synthesis of embodiment 92:N- tert-butyl -3- p-methoxyphenyl piperidines (6-3)
By the mixture (7.9g, 32.2mmol) of compound (4-5) and compound (5-5), palladium carbon (0.40g, 5%), nothing Water methanol (40mL) is added in autoclave, and is passed through hydrogen, and vacuum displacement three times, is heated to 40 DEG C, reacts 6h, TLC detection Raw material fully reacting stops reaction, palladium carbon is filtered, solvent is spin-dried for, crude product silica gel column chromatography, obtains product N- tert-butyl- 3- p-methoxyphenyl piperidines (6-3) 7.9g, yield 99.2%, MS-ESI (m/z): 248.4 (M+H)+。
The synthesis of embodiment 93:3- p-methoxyphenyl piperidines (1-2)
N- tert-butyl -3- p-methoxyphenyl piperidines (6-3) (7.6g, 30.7mmol) is added in 100mL glass flask, Add concentrated hydrochloric acid (40mL).Under stirring, it is heated to reflux 24 hours.Detection raw material has reacted, and stops reaction.Into reaction solution NaOH solution is added, adjusts pH value to 8-10, ethyl acetate extracts (50mLX3), merges organic layer, and it is dry that anhydrous sodium sulfate is added Dry, filtering is spin-dried for solvent, crude product silica gel column chromatography obtains product 3- p-methoxyphenyl piperidines (1-2) 4.2g, yield 71.5%, MS-ESI (m/z): 192.3 (M+H)+。
Synthesis of the embodiment 94:3- to ethoxybenzene phenylpiperidines (1-3)
By the mixture (8.6g, 29.3mmol) of compound (4-6) and compound (5-6), palladium carbon (1.7g, 20%), nothing Water methanol (40mL), glacial acetic acid (2.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 16h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, and uses second Acetoacetic ester is extracted (50mL × 3), and collected organic layer is dried, filtered with anhydrous sodium sulfate, and solvent is spin-dried for, crude product silicon Plastic column chromatography, obtains product 3- to ethoxybenzene phenylpiperidines (1-3) 5.3g, yield 88.1%, and MS-ESI (m/z): 206.3 (M+ H)+。
Synthesis of the embodiment 95:3- to ethoxybenzene phenylpiperidines (1-3)
By the mixture (10.0g, 28.3mmol) of compound (4-7) and compound (5-7), palladium carbon (1.0g, 10%), nothing Water methanol (60mL), glacial acetic acid (3.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 10h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and after solvent is spin-dried for, is added water (50mL), is used in combination Ethyl acetate is extracted (50mL × 3), and collected organic layer is dried, filtered with anhydrous sodium sulfate, is spin-dried for, crude product silicagel column Chromatography, obtains product 3- to ethoxybenzene phenylpiperidines (1-3) 5.4g, yield 93.1%, and MS-ESI (m/z): 206.3 (M+H)+。
The synthesis of embodiment 96:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (6.9g, 26.0mmol) of compound (4-8) and compound (5-8), palladium carbon (1.4g, 20%), nothing Water methanol (40mL), glacial acetic acid (2.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 16h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, adjusts pH It is worth to 5-6, and is extracted (50mL × 3) with ethyl acetate, collected organic layer is dried, filtered with anhydrous sodium sulfate, it is spin-dried for, Crude product silica gel column chromatography, obtains product 3- para hydroxybenzene phenylpiperidines (1-4) 4.1g, yield 88.9%, MS-ESI (m/z): 178.3(M+H)+。
The synthesis of embodiment 97:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (9.5g, 29.2mmol) of compound (4-9) and compound (5-9), palladium carbon (1.0g, 10%), nothing Water methanol (60mL), glacial acetic acid (3.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 10h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and after solvent is spin-dried for, is added water (50mL), adjusts PH value is extracted (50mL × 3) with ethyl acetate to 5-6, and collected organic layer is dried, filtered with anhydrous sodium sulfate, rotation Dry, crude product silica gel column chromatography obtains product 3- para hydroxybenzene phenylpiperidines (1-4) 4.9g, yield 94.7%, MS-ESI (m/z): 178.3(M+H)+。
The synthesis of embodiment 98:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (6.8g, 38.8mmol) of compound (4-10) and compound (5-10), palladium carbon (0.3g, 5%), nothing Water methanol (40mL) is added in autoclave, and is passed through hydrogen, and vacuum displacement three times, is heated to 40 DEG C, reacts 6h, TLC detection Raw material fully reacting stops reaction, palladium carbon is filtered, is spin-dried for, crude product silica gel column chromatography obtains product 3- p-hydroxybenzene piperazine Pyridine (1-4) 6.8g, yield 98.9%, MS-ESI (m/z): 178.3 (M+H)+。
The synthesis of embodiment 99:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (10.8g, 30.4mmol) of compound (4-11) and compound (5-11), palladium carbon (2.2g, 20%), Anhydrous methanol (60mL), glacial acetic acid (3.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 16h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, adjusts PH value is saved to 5-6, and is extracted (50mL × 3) with ethyl acetate, collected organic layer is dried, filtered with anhydrous sodium sulfate, rotation Dry, crude product silica gel column chromatography obtains product 3- para hydroxybenzene phenylpiperidines (1-4) 4.6g, yield 85.6%, MS-ESI (m/z): 178.3(M+H)+。
The synthesis of embodiment 100:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (12.6g, 30.3mmol) of compound (4-12) and compound (5-12), palladium carbon (1.3g, 10%), Anhydrous methanol (60mL), glacial acetic acid (3.0mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 60 DEG C, 10h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, adjusts PH value is saved to 5-6, and is extracted (50mL × 3) with ethyl acetate, collected organic layer is dried, filtered with anhydrous sodium sulfate, rotation Dry, crude product silica gel column chromatography obtains product 3- para hydroxybenzene phenylpiperidines (1-4) 5.1g, yield 94.9%, MS-ESI (m/z): 178.3(M+H)+。
The synthesis of embodiment 101:3- para hydroxybenzene phenylpiperidines (1-4)
By the mixture (8.2g, 30.9mmol) of compound (4-13) and compound (5-13), palladium carbon (0.8g, 10%), Anhydrous methanol (40mL), glacial acetic acid (1.6mL) are added in autoclave, and are passed through hydrogen, and vacuum displacement three times, is heated to 40 DEG C, 10h is reacted, TLC detects raw material fully reacting, stops reaction, palladium carbon is filtered, and water (50mL) is added after being spin-dried in solvent, adjusts PH value is saved to 5-6, and is extracted (50mL × 3) with ethyl acetate, collected organic layer is dried, filtered with anhydrous sodium sulfate, rotation Dry, crude product silica gel column chromatography obtains product 3- para hydroxybenzene phenylpiperidines (1-4) 5.1g, yield 93.2%, MS-ESI (m/z): 178.3(M+H)+。
Embodiment 102:(S) -3- p-methoxyphenyl piperidines ((S) -1-2) preparation
3- p-methoxyphenyl piperidines (1-2,20.2g, 105.6mmol) is dissolved in isopropanol (30mL), it will be dissolved with L- wine Isopropanol (40mL) solution of stone acid (15.91g, 106.0mmol) is added drop-wise to the isopropyl of racemic 3- p-methoxyphenyl piperidines In alcoholic solution, 2h is stirred, filtering obtains tartrate；Then, methanol (2L) is added to the tartrate, is heated to completely molten Xie Hou stops stirring；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains crude white solid, and 1N hydroxide is added Sodium water solution (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, slightly Product silica gel column chromatography obtains product 5.8g, i.e. (S) -3- p-methoxyphenyl piperidines, yield 28.8%, MS-ESI (m/z): 192.3(M+H)+；Ee=94.86%.
Embodiment 103:(S) the preparation of -3- to ethoxybenzene phenylpiperidines ((S) -1-3)
3- is dissolved in isopropanol (30mL) to ethoxybenzene phenylpiperidines (1-3,22.5g, 109.6mmol), it will be dissolved with L- wine Isopropanol (40mL) solution of stone acid (17.3g, 115.0mmol) is added drop-wise to racemic 3- to the isopropanol of ethoxybenzene phenylpiperidines In solution, 2h is stirred, filtering obtains tartrate；Then, methanol (2L) is added to the tartrate, is heated to being completely dissolved Afterwards, stop stirring；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains crude white solid, and 1N sodium hydroxide is added Aqueous solution (50mL), is extracted with ethyl acetate (25mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, crude product With silica gel column chromatography, product 5.6g is obtained, i.e. (S) -3- is to ethoxybenzene phenylpiperidines, yield 24.9%, MS-ESI (m/z): 206.3(M+H)+；Ee=96.73%.
Embodiment 104:(S) -3- para hydroxybenzene phenylpiperidines ((S) -1-4) preparation
3- para hydroxybenzene phenylpiperidines (1-4,26.8g, 151.2mmol) are dissolved in isopropanol (40mL), it will be dissolved with L- winestone Isopropanol (50mL) solution of sour (23.8g, 158.8mmol) is added drop-wise to the aqueous isopropanol of racemic 3- para hydroxybenzene phenylpiperidines In, 2h is stirred, filtering obtains tartrate；Then, methanol (2.5L) is added to the tartrate, is heated to after being completely dissolved, Stop stirring；Be slow cooling to room temperature, -20 DEG C crystallization 7 days, filtering obtains crude white solid, and it is water-soluble that sodium hydroxide is added Liquid, adjusting pH value to 6-7, is extracted with ethyl acetate (25mL, 4), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, Crude product silica gel column chromatography, obtained crude product use silica gel purification again, obtain product 9.0g, i.e. (S) -3- para hydroxybenzene phenylpiperidines, Yield 33.6%, ESI (m/z): 178.3 (M+H)+；Ee=96.52%.
Embodiment 105:(S) -3- p-methoxyphenyl-N- acetyl group-piperidines ((S) -8-3) preparation
(S) -3- p-methoxyphenyl piperidines ((S) -1-2,5.3g, 27.7mmol) is dissolved in methylene chloride (30mL), It adds triethylamine (5.6g, 55.4mmol), under ice-water bath, acetic anhydride (3.4g, 33.3mmol) slowly is added dropwise.It is added dropwise Afterwards, it is slowly warmed to room temperature, continues stirring 5 hours.Reaction solution is washed with water to neutrality, then is washed with saturated salt solution (10mL), After anhydrous sodium sulfate is dry, filtering is spin-dried for solvent, crude product silica gel column chromatography obtains (S) -3- p-methoxyphenyl-N- acetyl Base-piperidines ((S) -8-3) 6.4g, yield 99.1%, ESI (m/z): 234.3 (M+H)+。
Embodiment 106:(S) the preparation of -3- to ethoxyl phenenyl-N- acetyl group-piperidines ((S) -8-4)
(S) -3- is dissolved in methylene chloride (30mL) ethoxybenzene phenylpiperidines ((S) -1-3,5.2g, 25.3mmol), It adds triethylamine (5.1g, 50.7mmol), under ice-water bath, acetic anhydride (3.1g, 30.4mmol) slowly is added dropwise.It is added dropwise Afterwards, it is slowly warmed to room temperature, continues stirring 5 hours.Reaction solution is washed with water to neutrality, then is washed with saturated salt solution (10mL), After anhydrous sodium sulfate is dry, filtering is spin-dried for solvent, crude product silica gel column chromatography obtains (S) -3- to ethoxyl phenenyl-N- acetyl Base-piperidines ((S) -8-4) 6.1g, yield 97.5%, ESI (m/z): 248.3 (M+H)+。
Embodiment 107:(S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1) preparation
(S) -3- para hydroxybenzene phenylpiperidines ((S) -1-4,4.7g, 26.5mmol) are dissolved in methylene chloride (30mL), then It is added triethylamine (8.5g, 79.6mmol), under ice-water bath, acetic anhydride (6.8g, 66.3mmol) slowly is added dropwise.After being added dropwise, It is slowly warmed to room temperature, continues stirring 5 hours.First reaction solution is washed with water to neutrality, after being spin-dried for solvent, gained crude product methanol The dissolution of (20mL) and water (20mL), then NaOH solution (2.0mol/L, 20mL) is added into solution, after stirring 1 hour, decompression is steamed Dry organic solvent, then hydrochloric acid is added into remaining water phase, pH value is adjusted to 3-5, and ethyl acetate (20mL*2) extraction merges organic Layer, saturated salt solution (20mL) washing, anhydrous sodium sulfate dry, filter, and solvent evaporated, crude product silica gel column chromatography obtains (S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1) 5.7g, yield 98.0%, ESI (m/z): 220.3 (M+H)+。
Embodiment 108:(S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1) preparation
(S) -3- p-methoxyphenyl-N- acetyl group-piperidines ((S) -8-3,5.3g, 22.7mmol) is dissolved in dry two In chloromethanes (20mL), under ice-water bath, cooling reaction solution is to 5 DEG C hereinafter, BCl is slowly added dropwise3(5.3g, 45.4mmol) is dissolved in dry The solution of dry methylene chloride (10mL).After being added dropwise, room temperature continues stirring 3 hours, and detection raw material disappears.Add into reaction solution Water quenching, and washed with saturated salt solution (20mLX2), anhydrous sodium sulfate dries, filters, and solvent under reduced pressure is evaporated, crude product silica gel Column chromatography, obtains product 3.8g, yield 75.9%, and ESI (m/z): 220.3 (M+H)+。
Embodiment 109:(S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1) preparation
(S) -3- is dissolved in dry two to ethoxyl phenenyl-N- acetyl group-piperidines ((S) -8-4,5.1g, 20.6mmol) In chloromethanes (20mL), under ice-water bath, cooling reaction solution is to 5 DEG C hereinafter, BCl is slowly added dropwise3(4.8g, 41.2mmol) is dissolved in dry The solution of dry methylene chloride (10mL).After being added dropwise, room temperature continues stirring 3 hours, and detection raw material disappears.Add into reaction solution Water quenching, and washed with saturated salt solution (20mLX2), anhydrous sodium sulfate dries, filters, and solvent under reduced pressure is evaporated, crude product silica gel Column chromatography, obtains product 3.4g, yield 75.2%, and ESI (m/z): 220.3 (M+H)+。
Embodiment 110:(S) -3- p-hydroxybenzene-N- t-butoxycarbonyl-piperidin ((S) -9'-2) preparation
(S) -3- para hydroxybenzene phenylpiperidines ((S) -1-4,4.9g, 27.6mmol) are dissolved in methylene chloride (50mL), then It is added sodium hydroxide solution (2.0mmol/L, 30mL), under stirring, Boc acid anhydrides (7.6g, 33.2mmol) slowly is added dropwise.It drips Bi Hou is slowly warmed to room temperature, and continues stirring 1 hour, and detection reaction terminates.First by reaction solution liquid separation, water layer is removed, water is used (20mLX3) is washed till neutrality, then is washed with saturated ammonium chloride solution (20mL), and anhydrous sodium sulfate dries, filters, and is spin-dried for solvent, slightly Product silica gel column chromatography obtains (S) -3- p-hydroxybenzene-N- t-butoxycarbonyl-piperidin ((S) -9'-2) 7.6g, yield 99.2%, ESI (m/z): 278.4 (M+H)+。
Embodiment 111:(S) the preparation of -3- to methanesulfonyloxyphenyl-N- acetyl group-piperidines ((S) -10'-1)
(S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1,5.9g, 26.9mmol) is dissolved in dry two It in chloromethanes (30mL), adds triethylamine (5.45g, 53.8mmol), 5 DEG C is cooled in ice-water bath hereinafter, first is slowly added dropwise Sulfonic acid chloride (3.7g, 32.2mmol).It after being added dropwise, is slowly warmed to room temperature, continues stirring 3 hours, detect fully reacting.It will be anti- It answers liquid water (10mLX3) to be washed till neutrality, then is washed with saturated salt solution (15mL), anhydrous sodium sulfate dries, filters, and solvent is spin-dried for, Crude product silica gel column chromatography, obtains product (S) -3- to methanesulfonyloxyphenyl-N- acetyl group-piperidines ((S) -10'-1,7.4g), Yield 92.5%, ESI (m/z): 298.4 (M+H)+。
Embodiment 112:(S) -4- (1- Acetylpiperidin -3- base) -1- tolysulfonyl oxygroup benzene ((S) -10'-2) system It is standby
(S) -3- p-hydroxybenzene-N- acetyl group-piperidines ((S) -9'-1,6.3g, 28.7mmol) is dissolved in dry two It in chloromethanes (30mL), adds triethylamine (5.82g, 57.46mmol), 5 DEG C is cooled in ice-water bath hereinafter, being slowly added into pair Toluene sulfochloride (6.57g, 34.5mmol).It after being added dropwise, is slowly warmed to room temperature, continues stirring 3 hours, detection has been reacted Entirely.Reaction solution water (10mLX3) is washed till neutrality, then is washed with saturated salt solution (15mL), anhydrous sodium sulfate dries, filters, molten Agent is spin-dried for, crude product silica gel column chromatography, obtains product (S) -4- (1- Acetylpiperidin -3- base) -1- tolysulfonyl oxygroup benzene ((S) -10'-2,10.1g), yield 94.2%, ESI (m/z): 374.5 (M+H)+。
Embodiment 113:(S) the preparation of -3- to methanesulfonyloxyphenyl-N- t-butoxycarbonyl-piperidin ((S) -10'-3)
(S) -3- p-hydroxybenzene-N- t-butoxycarbonyl-piperidin ((S) -9'-2,6.1g, 22.0mmol) is dissolved in drying Methylene chloride (30mL) in, add triethylamine (4.45g, 44.0mmol), 5 DEG C be cooled in ice-water bath hereinafter, slowly dripping Add mesyl chloride (3.02g, 26.39mmol).It after being added dropwise, is slowly warmed to room temperature, continues stirring 3 hours, detection has been reacted Entirely.Reaction solution water (10mLX3) is washed till neutrality, then is washed with saturated salt solution (15mL), anhydrous sodium sulfate dries, filters, molten Agent is spin-dried for, crude product silica gel column chromatography, obtains product (S) -3- to methanesulfonyloxyphenyl-N- t-butoxycarbonyl-piperidin ((S) - 10'-3,7.5g), yield 95.9%, ESI (m/z): 356.4 (M+H)+。
Embodiment 114:(S) -4- (1- t-butoxycarbonylpiperidin -3- base) -1- tolysulfonyl oxygroup benzene ((S) -10'-4) Preparation
(S) -3- p-hydroxybenzene-N- t-butoxycarbonyl-piperidin ((S) -9'-2,6.6g, 23.8mmol) is dissolved in drying Methylene chloride (30mL) in, add triethylamine (4.82g, 47.59mmol), be cooled in ice-water bath 5 DEG C hereinafter, slowly plus Enter paratoluensulfonyl chloride (5.44g, 28.56mmol).It after being added dropwise, is slowly warmed to room temperature, continues stirring 3 hours, detection is anti- It should be complete.Reaction solution water (10mLX3) is washed till neutrality, then is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, mistake Filter, solvent are spin-dried for, and crude product silica gel column chromatography obtains product (S) -4- (1- t-butoxycarbonylpiperidin -3- base) -1- tolysulfonyl Oxygroup benzene ((S) -10'-4,9.8g), yield 95.4%, ESI (m/z): 432.6 (M+H)+。
Embodiment 115:(S) -3- p-bromophenyl piperidines ((S) -10) preparation
Triphenylphosphine (9.06g, 34.53mmol) is dissolved in acetonitrile (10mL), ice-water bath is cooled to 0 DEG C, is vigorously stirred Under, bromine (5.52g, 34.53mmol) slowly is added dropwise.After being added dropwise, reaction solution is slowly warmed to room temperature stirring.By -3- pairs of (S) After hydroxy phenyl piperidines ((S) -1-4,5.1g, 28.77mmol) is added in reaction solution, it is heated to 70 DEG C and reacts 30 minutes, it will be molten Agent is evaporated, and residue continues to be heated to 250 DEG C, is reacted 1 hour.After being cooled to room temperature, residue is dissolved with q. s. methylene chloride, And through silica gel column chromatography, product (S) -3- p-bromophenyl piperidines ((S) -10,5.20g, yield 75.2%) is obtained, ESI (m/z): 242.1,240.1 (M+H)+。
Embodiment 116:(S) preparation of -3- p-bromophenyl-N- acetyl group-piperidines (9-1)
(S) -3- p-bromophenyl piperidines ((S) -10,5.0g, 20.8mmol) is dissolved in methylene chloride (30mL), is added Under ice-water bath, acetic anhydride (2.55g, 25.0mmol) slowly is added dropwise in triethylamine (4.2g, 41.64mmol).After being added dropwise, slowly Slowly it is warmed to room temperature, continues stirring 5 hours.Reaction solution is washed with water to neutrality, then is washed with saturated salt solution (10mL), anhydrous sulphur After sour sodium is dry, filtering is spin-dried for solvent, crude product silica gel column chromatography obtains (S) -3- p-bromophenyl-N- acetyl group-piperidines (9- 1) product 5.7g, yield 97.0%, ESI (m/z): 284.2,282.2 (M+H)+。
Embodiment 117:(S) -3- p-bromophenyl-N- t-butoxycarbonyl-piperidin (9-3) preparation
(S) -3- p-bromophenyl piperidines ((S) -10,5.5g, 22.9mmol) is dissolved in methylene chloride (50mL), is added Under stirring, Boc acid anhydrides (6.27g, 27.5mmol) slowly is added dropwise in sodium hydroxide solution (2.0mmol/L, 30mL).It is added dropwise Afterwards, it is slowly warmed to room temperature, continues stirring 1 hour, detection reaction terminates.First by reaction solution liquid separation, water layer is removed, water is used (20mLX3) is washed till neutrality, and anhydrous sodium sulfate dries, filters, and after being spin-dried for solvent, crude product silica gel column chromatography is obtained -3- pairs of (S) 7.2 grams of product of bromophenyl-N- t-butoxycarbonyl-piperidin (9-3), yield 92.6%, ESI (m/z): 342.3,340.3 (M+H)+。
Embodiment 118:(S) -2- (4- (1- Acetylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide The synthesis of (24')
(S) -3- is dissolved in methanesulfonyloxyphenyl-N- acetyl group-piperidines ((S) -10'-1,3.9g, 13.1mmol) In DMA (20mL), then by potassium carbonate (5.44g, 39.3mmol) and N- tert-butyl -1H- indazole -7- formamide (22,3.13g, 14.43mmol) it is added in reaction flask.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 hour.To again (1R, 2R)-(-)-N, N'- dimethyl -1,2- cyclohexanediamine (0.19g, 1.31mmol) and CuBr (0.09g, 0.66mmol) are added anti- It answers in bottle, continues nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C and reacts 24 hours.Stop reaction, By the near room temperature of reaction solution, reaction solution is filtered with diatomite, appropriate DMA washing.Water (50mL) is added into filtrate, then uses dichloro Methane (50mLX2) extraction, merges organic layer, washes (20mLX3), and saturated salt solution (20mL) is washed, and anhydrous sodium sulfate is dry, mistake Filter, filtrate are spin-dried for obtaining crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (1- Acetylpiperidin -3- base) benzene Base)-N- tert-butyl -2H- indazole -7- formamide (24', 4.5g, yield 81.9%), ESI (m/z): 419.6 (M+H)+。
Embodiment 119:(S) -2- (4- (1- Acetylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide The synthesis of (24')
By (S) -4- (1- Acetylpiperidin -3- base) -1- tolysulfonyl oxygroup benzene ((S) -10'-2,5.9g, It 15.8mmol) is dissolved in DMA (25mL), then by potassium carbonate (6.55g, 47.39mmol) and N- tert-butyl -1H- indazole -7- formyl Amine (22,3.78g, 17.38mmol) is added in reaction flask.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 is small When.Again by (1R, 2R)-(-)-N, N'- dimethyl -1,2- cyclohexanediamine (0.22g, 1.58mmol) and CuBr (0.11g, It 0.79mmol) is added in reaction flask, continues nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C of reactions 24 Hour.Stop reaction, by the near room temperature of reaction solution, reaction solution is filtered with diatomite, appropriate DMA washing.Water is added into filtrate (50mL), then extracted with methylene chloride (50mLX2), merge organic layer, wash (20mLX3), saturated salt solution (20mL) is washed, nothing Aqueous sodium persulfate dries, filters, and filtrate is spin-dried for obtaining crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (1- acetyl Phenylpiperidines -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide (24', 4.88g, yield 73.8%), ESI (m/z): 419.6(M+H)+。
Embodiment 120:(S) -2- (4- (1- t-butoxycarbonylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- first The synthesis of amide (24)
(S) -3- is molten to methanesulfonyloxyphenyl-N- t-butoxycarbonyl-piperidin ((S) -10'-3,6.4g, 18.0mmol) In DMA (25mL), then by potassium carbonate (7.47g, 54.02mmol) and N- tert-butyl -1H- indazole -7- formamide (22, 4.30g, 19.81mmol) it is added in reaction flask.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 hour.Again will (1R, 2R)-(-)-N, N'- dimethyl -1,2- cyclohexanediamine (0.26g, 1.80mmol) and CuBr (0.13g, 0.90mmol) add Enter in reaction flask, continues nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C and reacts 24 hours.Stop anti- It answers, by the near room temperature of reaction solution, reaction solution is filtered with diatomite, appropriate DMA washing.Water (50mL) is added into filtrate, then uses Methylene chloride (50mLX2) extraction, merges organic layer, washes (20mLX3), and saturated salt solution (20mL) is washed, and anhydrous sodium sulfate is dry Dry, filtering, filtrate is spin-dried for obtaining crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (1- t-butoxycarbonylpiperidin -3- Base) phenyl)-N- tert-butyl -2H- indazole -7- formamide (24,7.19g, yield 83.8%), ESI (m/z): 477.6 (M+H)+。
Embodiment 121:(S) -2- (4- (1- t-butoxycarbonylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- first The synthesis of amide (24)
By (S) -4- (1- t-butoxycarbonylpiperidin -3- base) -1- tolysulfonyl oxygroup benzene ((S) -10'-4,5.8g, It 13.44mmol) is dissolved in DMA (25mL), then by potassium carbonate (5.57g, 40.32mmol) and N- tert-butyl -1H- indazole -7- first Amide (22,3.21g, 14.78mmol) is added in reaction flask.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 Hour.Again by (1R, 2R)-(-)-N, N'- dimethyl -1,2- cyclohexanediamine (0.19g, 1.34mmol) and CuBr (0.10g, It 0.67mmol) is added in reaction flask, continues nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C of reactions 24 Hour.Stop reaction, reaction solution is down to room temperature, reaction solution is filtered with diatomite, appropriate DMA washing.Water is added into filtrate (50mL), then extracted with methylene chloride (50mLX2), merge organic layer, wash (20mLX3), saturated salt solution (20mL) is washed, nothing Aqueous sodium persulfate dries, filters, and filtrate is spin-dried for obtaining crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (tertiary fourth of 1- Oxygen carbonyl piperidines -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide (24,4.92g, yield 76.8%), ESI (m/ z):477.6(M+H)+。
Embodiment 122:(S) -2- (4- (1- Acetylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide The synthesis of (24')
(S) -3- p-bromophenyl-N- acetyl group-piperidines (9-1,5.7g, 20.2mmol) is dissolved in DMA (25mL), then will Reaction is added in potassium carbonate (8.38g, 60.6mmol) and N- tert-butyl -1H- indazole -7- formamide (22,4.83g, 22.22mmol) In bottle.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 hour.Again by (1R, 2R)-(-)-N, N'- dimethyl- 1,2- cyclohexanediamine (0.29g, 2.02mmol) and CuBr (0.14g, 1.01mmol) are added in reaction flask, continue nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C and reacts 24 hours.Stop reaction, by the near room temperature of reaction solution, reaction Liquid is filtered with diatomite, appropriate DMA washing.Water (50mL) is added into filtrate, then is extracted with methylene chloride (50mLX2), merges Organic layer is washed (20mLX3), and saturated salt solution (20mL) is washed, and anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for obtaining crude product.Institute Crude product silica gel column purification is obtained, product (S) -2- (4- (1- Acetylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole-is obtained 7- formamide (24', 7.49g, yield 88.6%), ESI (m/z): 419.6 (M+H)+。
Embodiment 123:(S) -2- (4- (1- t-butoxycarbonylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- first The synthesis of amide (24)
(S) -3- p-bromophenyl-N- t-butoxycarbonyl-piperidin (9-3,6.4g, 18.81mmol) is dissolved in DMA (25mL) In, then by potassium carbonate (7.80g, 56.43mmol) and N- tert-butyl -1H- indazole -7- formamide (22,4.50g, 20.69mmol) It is added in reaction flask.Under stirring, it will blow under nitrogen tube intercalation reaction liquid level, deoxidation 1 hour.Again by (1R, 2R)-(-)-N, N'- dimethyl -1,2- cyclohexanediamine (0.27g, 1.88mmol) and CuBr (0.13g, 0.94mmol) are added in reaction flask, continue Nitrogen blowing deoxidation 30 minutes.Under nitrogen protection, reaction solution is heated to 110 DEG C and reacts 24 hours.Stop reaction, reaction solution is near Room temperature, reaction solution are filtered with diatomite, appropriate DMA washing.Water (50mL) is added into filtrate, then with methylene chloride (50mLX2) Extraction merges organic layer, washes (20mLX3), and saturated salt solution (20mL) is washed, and anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for Obtain crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (1- t-butoxycarbonylpiperidin -3- base) phenyl)-N- uncle Butyl -2H- indazole -7- formamide (24,8.01g, yield 89.4%), ESI (m/z): 477.6 (M+H)+。
Embodiment 124:(S) -2- (4- (piperidines -3- base) phenyl) -2H- indazole -7- formamide (11) synthesis
By (S) -2- (4- (1- Acetylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide (24', 12.60g, 30.1mmol) be added ortho-xylene (15mL) in, then into muddy reaction solution be added methanesulfonic acid (39mL, 602mmol).Reaction solution is heated to 40 DEG C and reacts 3 hours, detects raw material fully reacting.Water is added into reaction solution (150mL), toluene extract (40mLX2), merge organic layer, are washed with water (20mLX2), then washed with saturated salt solution (20mL), Anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for, and obtains crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (piperazine Pyridine -3- base) phenyl) -2H- indazole -7- formamide (11) 8.88g, yield 92.1%, ESI (m/z): 321.4 (M+H)+。
Embodiment 125:(S) -2- (4- (piperidines -3- base) phenyl) -2H- indazole -7- formamide (11) synthesis
By (S) -2- (4- (1- t-butoxycarbonylpiperidin -3- base) phenyl)-N- tert-butyl -2H- indazole -7- formamide (24, 16.7g, 35.04mmol) be added ortho-xylene (20mL) in, then into muddy reaction solution be added methanesulfonic acid (45mL, 700mmol).Reaction solution is heated to 40 DEG C and reacts 3 hours, detects raw material fully reacting.Water is added into reaction solution (150mL), toluene extract (40mLX2), merge organic layer, are washed with water (20mLX2), then washed with saturated salt solution (20mL), Anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for, and obtains crude product.Gained crude product silica gel column purification obtains product (S) -2- (4- (piperazine Pyridine -3- base) phenyl) -2H- indazole -7- formamide (11) 10.00g, yield 89.1%, ESI (m/z): 321.4 (M+H)+。
Specific embodiments of the present invention are described in detail above, but it is merely an example, the present invention is simultaneously unlimited It is formed on particular embodiments described above.To those skilled in the art, any couple of present invention carries out equivalent modifications and Substitution is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and Modification, all should be contained within the scope of the invention.

Claims (19)

1. the synthetic method of a kind of (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine, which is characterized in that including synthesizing as follows Route:
Wherein, step (a) are as follows: the 3- piperidones (2) and contraposition R of N protection2Grignard reaction occurs for substituted phenyl-magnesiumhalide, generates 3- hydroxyl -3- Phenylpiperidine (3)；
Wherein, step (b) are as follows: alcoholic extract hydroxyl group elimination reaction occurs for 3- hydroxyl -3- Phenylpiperidine (3), generates compound (4) and chemical combination The mixture of object (5)；
Wherein, step (c) are as follows: under transition-metal catalyst catalysis, the mixture and hydrogen source of compound (4) and compound (5) Hydrogenation reduction occurs, generates the 3- Phenylpiperidine (6) of N protection；
Wherein, step (d) are as follows: 3- Phenylpiperidine (6) deprotection base R of N protection1, generate racemic 3- Phenylpiperidine (1)；
Wherein, step (e) are as follows: in chemical resolution solvent, racemic 3- Phenylpiperidine (1) is torn open using acid resolving agent Point, obtain (R) -3- Phenylpiperidine ((R) -1) or/and (S) -3- Phenylpiperidine ((S) -1).
2. synthetic method according to claim 1, which is characterized in that R1Selected from following any: trityl, benzyl are right Methoxy-benzyl, 2,4- dimethoxy-benzyls, tert-butyl, trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl Dimethyl silicon substrate, tert-butyl diphenyl silicon substrate.
3. synthetic method according to claim 1, which is characterized in that R2Selected from following any: H, methoxyl group, ethyoxyl, Isopropoxy, positive propoxy, allyl oxygroup, normal-butyl oxygroup, isobutyl group oxygroup, tert-butoxy, methoxymethoxy, ethoxy Ylmethoxy, methoxy ethoxy, 2- tetrahydro-pyran oxy, trimethyl silicane base oxethyl methoxyl group, t-Butyldimethylsilyl Ethoxymethyl) epoxide, trimethylsiloxy group, triethyl group siloxy, tri isopropyl siloxany, tertiary butyl dimethyl Si base, tertiary fourth Base diphenyl siloxy, benzyloxy, to methoxybenzyl oxygroup, 2,4- dimethoxybenzyloxycarbonyl bases.
4. synthetic method according to claim 1, which is characterized in that described transition metal-catalyzed in the step (c) Agent is selected from following any: Raney's nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
5. synthetic method according to claim 1, which is characterized in that in the step (e), the chemical resolution solvent Selected from following any one or more combination: methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, tetrahydrofuran, ethyl acetate, Methylene chloride.
6. synthetic method according to claim 1, which is characterized in that in the step (e), the acidity resolving agent choosing From following any: tartaric acid, dibenzoyl tartaric acid, two pairs of toluyl tartaric acid, malic acid, camphorsulfonic acid, camphor tree Olic acid, mandelic acid, quininic acid.
7. the synthetic method of a kind of (R) -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine, which is characterized in that including synthesizing as follows Route:
Wherein, step (a) are as follows: the 3- piperidones (2) and contraposition R of N protection2Grignard reaction occurs for substituted phenyl-magnesiumhalide, generates 3- hydroxyl -3- Phenylpiperidine (3)；
Wherein, step (f) are as follows: 3- hydroxyl -3- Phenylpiperidine (3) and (CnH2n+1)3SiH reaction, directly generates the 3- benzene of N protection Phenylpiperidines (6)；Wherein, the integer that n is 1~4；
Wherein, step (d) are as follows: 3- Phenylpiperidine (6) deprotection base R of N protection1, generate racemic 3- Phenylpiperidine (1)；
Wherein, step (e) are as follows: in chemical resolution solvent, racemic 3- Phenylpiperidine (1) is torn open using acid resolving agent Point, obtain (R) -3- Phenylpiperidine ((R) -1) or/and (S) -3- Phenylpiperidine ((S) -1).
8. synthetic method according to claim 7, which is characterized in that in the step (f), (CnH2n+1)3SiH Selected from following any: triethylsilane, three n-propyl silane, tri isopropyl silane.
9. synthetic method according to claim 7, which is characterized in that in the step (f), the chemical resolution solvent Selected from following any one or more combination: methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, tetrahydrofuran, ethyl acetate, Methylene chloride.
10. synthetic method according to claim 7, which is characterized in that in the step (f), the acidity resolving agent Selected from following any: tartaric acid, dibenzoyl tartaric acid, two pairs of toluyl tartaric acid, malic acid, camphorsulfonic acid, Camphoric acid, mandelic acid, quininic acid.
11. the synthetic method of the chiral intermediate α of Ni Lapani a kind of, which comprises the following steps:
S1: according to claim 1 or synthetic method as claimed in claim 7 prepares (S) -3- Phenylpiperidine ((S) -1), wherein R2 For H；
S2: nitration reaction is occurred into for (S) -3- Phenylpiperidine ((S) -1) and nitrating agent, generates (S) -3- p-nitrophenyl phenylpiperidines；
S3: carrying out nitro-reduction reaction for (S) -3- p-nitrophenyl phenylpiperidines and reduction system, generates (S) -3- to aminocarbonyl phenyl Piperidines, i.e. the chiral intermediate α of Ni Lapani.
12. the synthetic method of the chiral intermediate α of Ni Lapani according to claim 11, which is characterized in that the nitre Agent is selected from following any: nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, chloro-nitric acid, Butylnitrate ester, methyl nitrate, NO2BF4, NO2PF6。
13. the synthetic method of the chiral intermediate α of Ni Lapani according to claim 11, which is characterized in that described to go back Substance system is selected from following any: ferric trichloride/hydrazine hydrate, Fe/HCl, Zn/HCl, LiAlH4, transition-metal catalyst/hydrogen Gas, sodium dithionite；Wherein, the transition-metal catalyst is selected from following any: Raney's nickel, palladium carbon, palladium dioxide, platinum It is black, platinum dioxide.
14. the synthetic method of the chiral intermediate β of Ni Lapani a kind of, which comprises the following steps:
P1: according to claim 1 or synthetic method as claimed in claim 7 prepares (S) -3- Phenylpiperidine ((S) -1), wherein R2 For H；
P2: (S) -3- Phenylpiperidine ((S) -1) and N protection reagent are reacted, (S) -3- Phenylpiperidine of N-protected is generated；
P3: bromo-reaction is occurred into for (the S) -3- Phenylpiperidine of N-protected and brominated reagent, generates (S) -3- of N-protected to bromine Phenylpiperidine；
P4: (S) -3- p-bromophenyl piperidines of N-protected is subjected to deprotection reaction, generates (S) -3- p-bromophenyl piperidines, i.e. Buddhist nun The chiral intermediate β of La Pani.
15. the synthetic method of the chiral intermediate β of Ni Lapani according to claim 14, which is characterized in that the N is protected Reagent is protected selected from following any: chloroacetic chloride, propionyl chloride, butyl chloride, benzene sulfonyl chloride, BOC acid anhydrides.
16. the synthetic method of the chiral intermediate β of Ni Lapani according to claim 14, which is characterized in that the bromine It is selected from for reagent following any: NBS, Br2, HBr, excessively pyridinium bromide hydrobromide, C5H6Br2N2O2,2,4,4,6- tetrabromobisphenols, 5- cyclohexadienone.
17. the synthetic method of the chiral intermediate γ of Ni Lapani a kind of, which comprises the following steps:
P'1: according to claim 1 or synthetic method as claimed in claim 7 prepares (S) -3- Phenylpiperidine ((S) -1), wherein R2Selected from following any: methoxyl group, ethyoxyl, isopropoxy, positive propoxy, allyl oxygroup, normal-butyl oxygroup, isobutyl group Oxygroup, tert-butoxy, methoxymethoxy, ethoxymethyl) epoxide, methoxy ethoxy, 2- tetrahydro-pyran oxy, trimethyl silicane Base oxethyl methoxyl group, t-Butyldimethylsilyl ethoxymethyl) epoxide, trimethylsiloxy group, triethyl group siloxy, three isopropyls Base siloxy, tertiary butyl dimethyl Si base, tert-butyl diphenyl siloxy, benzyloxy, to methoxybenzyl oxygroup, 2,4- diformazans Oxygroup benzyloxy；
P'2: (S) -3- Phenylpiperidine ((S) -1) and N protection reagent are reacted, (S) -3- phenyl piperazine of N-protected is generated Pyridine；
P'3: by (S) -3- Phenylpiperidine eliminating hydroxide protecting group of N-protected, (S) -3- (4- hydroxy benzenes of N-protected is generated Base)-piperidines；
P'4: it by (S) -3- (4- hydroxy phenyl)-piperidines of N-protected and activated sulfonyl chlorine or active sulfonic acid anhydride reactant, generates and lives Property ester, i.e. the chiral intermediate γ of Ni Lapani.
18. the synthetic method of the chiral intermediate γ of Ni Lapani according to claim 17, which is characterized in that the N Reagent is protected to be selected from following any: chloroacetic chloride, propionyl chloride, butyl chloride, benzene sulfonyl chloride, BOC acid anhydrides.
19. the synthetic method of the chiral intermediate γ of Ni Lapani according to claim 17, which is characterized in that the work Property sulfonic acid chloride be selected from it is following any: mesyl chloride, paratoluensulfonyl chloride, benzene sulfonyl chloride；The activity sulphonic acid anhydride is fluoroform Sulphonic acid anhydride.
CN201910134281.2A 2018-03-02 2019-02-22 (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani Pending CN109810047A (en)

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