CN104447739A - Deuterated palbociclib derivative, and preparation method and application thereof - Google Patents

Deuterated palbociclib derivative, and preparation method and application thereof Download PDF

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CN104447739A
CN104447739A CN201410623485.XA CN201410623485A CN104447739A CN 104447739 A CN104447739 A CN 104447739A CN 201410623485 A CN201410623485 A CN 201410623485A CN 104447739 A CN104447739 A CN 104447739A
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deuterated
compound
palbociclib
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formula
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CN104447739B (en
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吴豫生
牛成山
邹大鹏
张森
郭瑞云
李敬亚
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Zhejiang homologous health medicine Limited by Share Ltd
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TETRANOV BIOPHARM Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a deuterated palbociclib derivative, and a preparation method and an application thereof. A structural formula of the deuterated palbociclib derivative is as shown in a formula (I), a formula (II), a formula (III) or a formula (IV). According to the deuterated palbociclib derivative disclosed by the invention, through selective deuteration of palbociclib, the pharmacokinetic property of the medicine is improved, thus the curative effect, the safety and the tolerance of the medicine are improved. According to the deuterated palbociclib salt disclosed by the invention, the solubility and the dissolution rate of the medicine are improved; a new compound is provided for synthesis of a novel anti-tumor medicine through synthesis of the deuterated palbociclib derivative; and the deuterated palbociclib derivative has similar biologic activity to the palbociclib, and has a good medicine application prospect.

Description

A kind of deuterated Palbociclib derivative, preparation method and application
Technical field
The invention belongs to pharmaceutical compound technical field, be specifically related to a kind of deuterated Palbociclib derivative, also relate to a kind of preparation method and application of deuterated Palbociclib derivative simultaneously.
Background technology
Mammary cancer is the malignant tumour occurring in mammary gland glandular epithelium tissue; In mammary cancer, 99% occurs in women, and the male sex only accounts for 1%.Mammary gland is not the vitals maintaining human life activity, and breast cancer in situ is not fatal; But because breast cancer cell loses Normocellular characteristic, connect loose between cell, easily come off; Cancer cells is once come off, and free cancer cells can send out whole body with blood or lymph liquid, forms transfer, threat to life.At present, mammary cancer has become the able-bodied kinds of tumor of threat women.
Palbociclib is the New Target tropism breast cancer treatment medicine developed by Pfizer company, and it can Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), recovers the cell cycle to control, and blocks tumor cell proliferation.II phase clinical study shows that Palbociclib can make the Progression free survival phase (PFS) of advanced breast cancer patient on average double.FDA authorizes the Palbociclib breakthrough therapy identification for the treatment of late period or transitivity ER+/HER2-mammary cancer in April, 2013.Therefore, study new there is higher curative effect, key that the compound and preparation method thereof of security and tolerance becomes development of new antitumor drug.
Summary of the invention
The object of this invention is to provide a kind of deuterated Palbociclib derivative, for synthesizing new antitumor drug provides new compound.
Second object of the present invention is to provide a kind of preparation method of deuterated Palbociclib derivative.
3rd object of the present invention is to provide the application of a kind of deuterated Palbociclib derivative in preparation treatment breast cancer medicines.
In order to realize above object, the technical solution adopted in the present invention is: a kind of deuterated Palbociclib derivative, and its structural formula is such as formula shown in (I), formula (II), formula (III) or formula (IV):
Wherein, R is acid; N is 1 or 2.Formula (III), with formula (IV), is salify relation between R and deuterated Palbociclib.Described salt can be a hydrochlorate and also can be multi-acid salt.
Described R be can with the organic acid of deuterated Palbociclib salify or mineral acid.
Described R is HCl (hydrochloric acid), H 2sO 4(sulfuric acid), H 3pO 4(phosphoric acid), HF (hydrofluoric acid), HBr (Hydrogen bromide), HI (hydroiodic acid HI), HOCH 2cH 2sO 3h (hydroxyethylsulfonic acid), CH 3sO 3h (methylsulfonic acid), CH 3cOOH (acetic acid) or citric acid.
A preparation method for above-mentioned deuterated Palbociclib derivative, comprises the following steps:
1) getting 2,4-bis-chloro-5-bromo pyrimi piperidine (compound 5a) adds in solvent with deuterated cyclopentamine (compound 5) or deuterated cyclopentamine salt, reacts, obtain compound 6 under alkali reagent effect;
2), under protection of inert gas, compound 6 and methyl crotonate are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 7;
3) compound 7 is added in solvent, under alkali reagent existence condition, carry out Intra-molecular condensation, obtain compound 8;
4) compound 8 and brominated reagent are added in solvent, carry out bromo-reaction, obtain compound 9;
5) getting 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester (compound 9a) adds in solvent with compound 9, carries out substitution reaction, obtain compound 10 under alkali reagent effect;
6), under protection of inert gas, compound 10 and vinyl n-butyl ether are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 11;
7) compound 11 is added in solvent, under acid effect, carry out ether bond rupture reaction, obtain compound 12;
8) compound 12 is added in solvent, Boc protecting group occurs under acid effect and removes reaction, obtain the deuterated Palbociclib shown in formula (I).
Wherein, described catalyzer comprises Primary Catalysts and part; Described Primary Catalysts is Palladous chloride or palladium, and described part is triphenylphosphine, 1,1 '-bis-(diphenylphosphine) ferrocene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
Step 1) in, described deuterated cyclopentamine is prepared by the method comprised the following steps:
A) get cyclopentanone (compound 1) and deuterated reductive agent to add in solvent and react, obtain compound 2;
B) compound 2 and hydroxy activated reagent are added in solvent, react under alkali reagent existence condition, obtain compound 3;
C) add in solvent by compound 3 and azido group donor, azide substitution reaction is carried out in heating, obtains compound 4;
D) under reductive agent effect, the nitrine in compound 4 is reduced into amine, obtains deuterated cyclopentamine (compound 5).
Described deuterated cyclopentamine salt is generated by deuterated cyclopentamine and acid-respons.Described deuterated cyclopentamine salt is deuterated cyclopentamine hydrochloride.Described deuterated cyclopentamine hydrochloride is reacted by deuterated cyclopentamine and concentrated hydrochloric acid and generates.
Step 1) in, described deuterated cyclopentamine salt generates deuterated cyclopentamine under the effect of alkali reagent, continues to participate in reaction.
Described alkali reagent is triethylamine, pyridine, DMAP, salt of wormwood, cesium carbonate, KOH, NaOH, butyllithium, lithium diisopropylamine, LHMDS, DIPEA, K 2cO 3, Na 2cO 3in any one or combination.
Described deuterated reductive agent is deuterated lithium aluminium hydride, deuterated sodium borohydride, deuterated acetic acid sodium borohydride or deuterated sodium cyanoborohydride; Described hydroxy activated reagent is Methanesulfonyl chloride or Tosyl chloride; Described azido group donor is sodiumazide or azido-Trimethoxy silane; Described reductive agent is triphenylphosphine.
Described solvent is benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, ether, dioxane, trichloromethane, dimethyl formamide (DMF), acetic acid, tetrahydrofuran (THF), propyl carbinol.
Preferred:
Step a) in, described deuterated reductive agent is deuterated lithium aluminium hydride (LiAlD 4), deuterated sodium borohydride (NaBD 4), deuterated acetic acid sodium borohydride (NaB (OAc) 3or deuterated sodium cyanoborohydride (NaBCND D) 3).The quality of described deuterated reductive agent and cyclopentanone is 1 ~ 4:1.Preferred further, deuterated reductive agent and the quality of cyclopentanone are 1.2:1.
Step a) in, described solvent is benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, ether, dioxane or trichloromethane.Step a) described in react and at room temperature carry out.
Step b) in, described hydroxy activated reagent is Methanesulfonyl chloride (MsCl) or Tosyl chloride (TsCl).The consumption of described hydroxy activated reagent is: compound 2 is 1:1 ~ 20 with the mol ratio of hydroxy activated reagent.
Step b) in, described alkali reagent is any one or combination in triethylamine, pyridine, DMAP (DMAP), sodium hydroxide.The consumption of described alkali reagent is: the mol ratio of alkali reagent and hydroxy activated reagent is 1:1 ~ 20.
Step b) in, described solvent is methylene dichloride, trichloromethane or ether.
Step c) in, described azido group donor is sodiumazide (NaN 3) or azido-Trimethoxy silane (TMSN 3).The mol ratio of described azido group donor and compound 3 is 1 ~ 2:1.
Step c) in, described solvent is dimethyl formamide (DMF), acetonitrile or dioxane.
Step c) in, the temperature of described azide substitution reaction is 70 ~ 110 DEG C.
Steps d) in, described reductive agent is triphenylphosphine (PPh 3).The mol ratio of described reductive agent and compound 4 is 1:1 ~ 3.
Step 1) in, the mol ratio of described 2,4-bis-chloro-5-bromo pyrimi piperidines and deuterated cyclopentamine or deuterated cyclopentamine salt is 1:0.3 ~ 3.
Step 1) in, described alkali reagent is triethylamine (Et 3n), pyridine or DMAP (DMAP).The consumption of described alkali reagent is: every deuterated cyclopentamine of 7g or deuterated cyclopentamine salt use alkali reagent 16ml.
Step 1) in, described solvent is methyl alcohol, ethanol or dioxane.
Step 2) in, described compound 6 is 1:1 ~ 1.5 with the mol ratio of methyl crotonate.
Step 2) in, described catalyzer comprises Primary Catalysts and part; Described Primary Catalysts is Palladous chloride or palladium, and described part is triphenylphosphine, 1,1 '-bis-(diphenylphosphine) ferrocene (dppf) or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO).The consumption of described catalyzer is: the mol ratio of Primary Catalysts, part and compound 6 is 0.05:0.10:1.
Step 2) in, described alkali reagent is salt of wormwood or cesium carbonate.The consumption of described alkali reagent is: the mol ratio of alkali reagent and compound 6 is 3:1.
Step 2) in, described solvent is dimethyl formamide (DMF) or dioxane.
Step 2) in, the temperature of described linked reaction is 70 ~ 110 DEG C.
Step 3) in, described alkali reagent is KOH or NaOH.The consumption of described alkali reagent is: the mol ratio of alkali reagent and compound 7 is 0.5 ~ 10:1.
Step 3) in, described solvent is dimethyl formamide (DMF) or dioxane.
Step 4) in, described brominated reagent is N-bromosuccinimide (NBS) or bromine.The mol ratio of described brominated reagent and compound 8 is 0.8 ~ 4:1.
Step 4) in, described solvent is acetic acid or acetonitrile.
Step 5) in, the mol ratio of 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester and compound 9 is 0.5 ~ 3:1.
Step 5) in, described alkali reagent is butyllithium, lithium diisopropylamine (LDA) or LHMDS (LiHMDS).The consumption of described alkali reagent is: the mol ratio of alkali reagent and compound 9 is 1.05 ~ 1.2:1.
Step 5) in, described solvent is toluene, dioxane or tetrahydrofuran (THF).
Step 5) in, the temperature of described substitution reaction is-10 ~ 25 DEG C.
Step 6) in, the mol ratio of described vinyl n-butyl ether and compound 10 is 1 ~ 10:1.
Step 6) in, described catalyzer comprises Primary Catalysts and part; Described Primary Catalysts is Palladous chloride or palladium, and described part is triphenylphosphine, 1,1 '-bis-(diphenylphosphine) ferrocene (dppf) or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO).The consumption of described catalyzer is: the mass ratio of Primary Catalysts, part and compound 10 is 0.05:0.10:1.
Step 6) in, described alkali reagent is triethylamine or DIPEA (DIPEA).The consumption of described alkali reagent is: the mass ratio of alkali reagent and compound 10 is 2 ~ 16:1 ~ 45.
Step 6) in, described solvent is dimethyl formamide (DMF), dioxane or propyl carbinol (n-BuOH).
Step 6) in, the temperature of described linked reaction is 70 ~ 110 DEG C.
Step 7) in, described acid is hydrochloric acid or sulfuric acid.The consumption of described acid is: every 300mg compound 11 uses acid 0.5 ~ 2ml.
Step 7) in, described solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF).
Step 8) in, described acid is trifluoroacetic acid or hydrochloric acid.The consumption of described acid is: every 250mg compound uses acid 0.5 ~ 2ml.
Step 8) in, described solvent is methylene dichloride or dioxane.
In the preparation method of described deuterated cyclopentamine, the chemical formula that synthetic route relates to is:
Step is a):
Step b):
Step c):
Steps d):
Wherein, steps d) in the deuterated cyclopentamine of gained can generate deuterated cyclopentamine salt with acid-respons, deuterated cyclopentamine salt is in step 1) under alkali reagent effect, generate deuterated cyclopentamine, continue to participate in reaction.
The preparation method of the deuterated Palbociclib shown in formula (I), the chemical formula that synthetic route relates to is:
Step 1):
Step 2):
Step 3):
Step 4):
Step 5):
Step 6):
Step 7):
Step 8):
A preparation method for above-mentioned deuterated Palbociclib derivative, comprises Palbociclib and heavy water (D 2o) add in solvent, hydrogen deuterium exchange reaction occurs under alkali reagent effect, obtain the deuterated Palbociclib shown in formula (II).
Wherein, heavy water (D 2o) consumption is: the Palbociclib of every 100mg adds heavy water 2 ~ 10ml.Described alkali reagent is K 2cO 3or Na 2cO 3.The consumption of described alkali reagent is: the mass ratio of alkali reagent and Palbociclib is 1 ~ 5:1.Described solvent is methylene dichloride, tetrahydrofuran (THF) or dioxane.
Described Palbociclib is prepared by the method comprised the following steps:
1) getting the chloro-5-bromo pyrimi piperidine of 2,4-bis-(compound 5a) adds in solvent with cyclopentamine (compound 5b), reacts, obtain compound 14 under alkali reagent effect;
2), under protection of inert gas, compound 14 and methyl crotonate are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 15;
3) compound 15 is added in solvent, under alkali reagent existence condition, carry out Intra-molecular condensation, obtain compound 16;
4) compound 16 and brominated reagent are added in solvent, carry out bromo-reaction, obtain compound 17;
5) get 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester and compound 17 adds in solvent, under alkali reagent effect, carry out substitution reaction, obtain compound 18;
6), under protection of inert gas, compound 18 and vinyl n-butyl ether are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 19;
7) compound 19 is added in solvent, under acid effect, carry out ether bond rupture reaction, obtain compound 20;
8) compound 20 is added in solvent, Boc protecting group occurs under acid effect and removes reaction, obtain described Palbociclib.
In the preparation method of Palbociclib, except raw material cyclopentamine, the control of the kind of all the other raw materials, add-on and technical parameter is with the preparation method of the deuterated Palbociclib shown in above-mentioned formula (I).The consumption of deuterated cyclopentamine or deuterated cyclopentamine salt in the preparation method of the deuterated Palbociclib shown in consumption cotype (I) of cyclopentamine.
A kind of preparation method of above-mentioned deuterated Palbociclib derivative, comprise and the deuterated Palbociclib shown in formula (I) is added in solvent, HCl gas is passed under room temperature, filter after reaction, obtain the deuterated Palbociclib salt shown in formula (III), wherein R is HCl, is deuterated Palbociclib hydrochloride.
Wherein, described solvent is methylene dichloride.
A kind of preparation method of above-mentioned deuterated Palbociclib derivative, comprise and the deuterated Palbociclib shown in formula (II) is added in solvent, add the hydroxyethylsulfonic acid aqueous solution again, filter after reaction, obtain the deuterated Palbociclib salt shown in formula (IV), wherein R is HOCH 2cH 2sO 3h, is deuterated Palbociclib isethionate.
Wherein, the mol ratio of the deuterated Palbociclib shown in hydroxyethylsulfonic acid and formula (II) is 1:1.Described solvent is the mixture of methyl alcohol and water.The temperature of described reaction is 35 ~ 55 DEG C.
A kind of above-mentioned application of deuterated Palbociclib derivative in the inhibitor medicaments for the preparation of T suppression cell Cyclin dependent kinase 4 and 6 (CDK4/6).
The application of a kind of above-mentioned deuterated Palbociclib derivative in preparation treatment breast cancer medicines.
Deuterated medicine refers to and the part hydrogen atom in drug molecule is replaced with deuterium, and because the shape of deuterium in drug molecule is substantially the same with hydrogen with volume, deuterated medicine generally also can retain original biological activity and selectivity.Simultaneously because carbon-deuterium key is at lower frequency vibration, be better than C-H, directly can affect the attributes such as the absorption of medicine, distribution, metabolism and excretion, thus the curative effect of raising medicine, security and tolerance.Deuterated medicine has that search time is short, cost is few, security and the advantage such as success ratio is high, subject is few, receives and pays close attention to widely.
Deuterated Palbociclib derivative of the present invention, by deuterated to the selectivity of Palbociclib, improves the medicine of medicine for character, and then improves the curative effect of medicine, security and tolerance; Deuterated Palbociclib salt of the present invention, improves solubleness and the dissolution rate of medicine; The synthesis of deuterated Palbociclib derivative, for synthesizing new antitumor drug provides new compound; Deuterated Palbociclib derivative and Palbociclib have similar biological activity, have good medicinal application prospect.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1
The synthetic route of deuterated cyclopentamine hydrochloride relates to chemical formula and is:
Deuterated cyclopentamine hydrochloride is prepared by the method comprised the following steps:
A) synthetic compound 2: the LiAlD getting 2.2g 4add the ether (Et of 100ml 2o), in, system is cooled to 0 DEG C; Under nitrogen protection, slowly drip the diethyl ether solution containing 8g cyclopentanone (compound 1), after dropwising, system is warming up to room temperature and continues reaction 1h; After reaction terminates, add saturated saturated NH 4the cancellation of Cl solution is reacted, and by extracted with diethyl ether three times, merges organic phase, dry, concentrated, obtains 8g colourless transparent liquid compound 2;
The nuclear magnetic resonance information of compound 2 is: 1h NMR (400MHz, CDCl 3): δ 1.78-1.74 (m, 4H), 1.58-1.55 (m, 4H);
B) synthetic compound 3: the compound 2 getting 5.2g is dissolved in the methylene dichloride (DCM) of 100ml, adds triethylamine (Et 3n) DMAP of 25ml and catalytic amount, system is cooled to 0 DEG C; Slowly drip the MsCl (mol ratio of compound 2, hydroxy activated reagent and alkali reagent is 1:3:3) of 15ml under nitrogen protection and react 2h; After reaction terminates, drip saturated NH to system 4the cancellation of Cl solution is reacted, separatory, and organic phase washed with water, saturated nacl aqueous solution wash, dry, concentrated, obtains 10g light reddish brown color fluid cpds 3;
The nuclear magnetic resonance information of compound 3 is: 1h NMR (400MHz, CDCl 3): δ 2.98 (m, 3H), 1.98-1.86 (m, 4H), 1.84-1.73 (m, 2H), 1.64-1.60 (m, 2H);
C) synthetic compound 4: under nitrogen protection, gets the NaN of 10g compound 3 and 1eq 3add (mol ratio of azido group donor and compound 3 is 1:1) in the DMF of 100ml, be warming up to 80 DEG C and react and spend the night; After reaction terminates, system is down to room temperature, adds H 2o, extracted with diethyl ether, merge organic phase, organic phase saturated nacl aqueous solution washs, dry, concentrated, obtains 11g compound 4 crude product;
D) synthetic compound 5: get the H that 11g compound 4 crude product adds THF and the 5ml of 150ml 2in the mixed solvent that O is mixed, add 25g triphenylphosphine (mol ratio of reductive agent and compound 4 is 1:1), room temperature reaction 3h, reacts complete, in system, drip concentrated hydrochloric acid, until reaction system is slightly acidic, concentrate system, adds H in batches 2o, extraction into ethyl acetate 3 times, concentrated aqueous phase, adds 20ml acetone, filters, obtains 4g compound as white solid 5c.
The nuclear magnetic resonance information of compound 5c is: 1h NMR (400MHz, CDCl 3): δ 1.91-1.87 (m, 2H), 1.61-1.58 (m, 2H), 1.48-1.43 (m, 2H).
Embodiment 2
The deuterated Palbociclib derivative of the present embodiment, structural formula is such as formula shown in (I):
The chemical formula that the synthetic route of the deuterated Palbociclib derivative of the present embodiment relates to is as follows:
The preparation method of the deuterated Palbociclib derivative of the present embodiment, comprises the following steps:
1) synthetic compound 6: get 7g embodiment 1 gained compound 5c (deuterated cyclopentamine hydrochloride generates deuterated cyclopentamine (compound 5) under alkali reagent effect) and be dissolved in 100ml dehydrated alcohol, add the Et of 16ml 3n, adds 2, the 4-bis-chloro-5-bromo pyrimi piperidines (compound 5a) (mol ratio of 2,4-bis-chloro-5-bromo pyrimi piperidine and deuterated cyclopentamine salt is 0.7:1) of 9g in system in batches under agitation condition, add rear continuation reaction 2h; After reaction terminates, filter, filtrate concentrates, and add water precipitation white solid, and solid adds a small amount of sherwood oil, stirs after 10 minutes and filters, obtain 8g compound as white solid 6;
The nuclear magnetic resonance information of compound 6 is: 1h NMR (400MHz, CDCl 3): δ 8.08 (s, 1H), 5.44 (s, 1H), 2.14-2.09 (m, 2H), 1.77-1.73 (m, 2H), 1.71-1.63 (m, 2H), 1.50-1.42 (m, 2H);
2) synthetic compound 7: the K getting 8g compound 6, the methyl crotonate of 1eq, the Pd (OAc) 2 of 5%eq, DABCO, 3eq of 10%eq 2cO 3to add in the DMF of 50ml that (compound 6 is 1:1 with the mol ratio of methyl crotonate, the mol ratio of Primary Catalysts, part and compound 6 is 0.05:0.10:1, the mol ratio of alkali reagent and compound 6 is 3:1), be heated to 85 DEG C under nitrogen protection and react 3h; After reaction terminates, filter, filtrate adds water and is extracted with ethyl acetate, organic phase saturated common salt water washing, dry, concentrated, and column chromatography is purified to obtain 1.8g compound as white solid 7;
The nuclear magnetic resonance information of compound 7 is: 1h NMR (400MHz, CDCl 3): δ 7.79 (s, 1H), 5.96-5.94 (d, 1H, J=1.36), 4.89 (s, 1H), 3.76 (s, 3H), (2.41-2.40 d, 3H, J=1.28), 2.11-2.06 (m, 2H), 1.74-1.61 (m, 4H), 1.42-1.35 (m, 2H);
3) synthetic compound 8: the KOH getting 140mg adds in the DMF of 20ml, system is cooled to 0 DEG C, the DMF solution 7ml (mol ratio of alkali reagent and compound 7 is 0.9:1) containing 800mg compound 7 is slowly dripped, reaction 15min under nitrogen protection; After reaction terminates, system being poured directly in frozen water and being extracted with ethyl acetate, organic phase saturated common salt water washing, dry, concentrated, column chromatography is purified to obtain 350mg compound as white solid 8;
The nuclear magnetic resonance information of compound 8 is: 1h NMR (400MHz, CDCl 3): δ 8.74 (s, 1H), 6.54-6.53 (d, 1H, J=1.12), 2.45-2.44 (d, 3H, J=1.16), 2.25-2.17 (m, 2H), 2.13-2.09 (m, 2H), 1.93-1.87 (m, 2H), 1.69-1.65 (m, 2H);
4) synthetic compound 9: get 220mg compound 8, the NaOAc of 270mg adds in 20ml acetic acid, add 270mg bromine (mol ratio of brominated reagent and compound 8 is 2:1) under nitrogen protection, system is warming up to 50 DEG C of reaction 35h; After reaction terminates, system is down to room temperature, adds Na 2sO 3solid cancellation is reacted, and system concentrates remove portion acetic acid, adds saturated NaHCO afterwards 3, extraction into ethyl acetate, organic phase saturated common salt water washing, dry, concentrated, obtain 300mg compound as white solid 9;
The nuclear magnetic resonance information of compound 9 is: 1h NMR (400MHz, CDCl 3): δ 8.86 (s, 1H), 2.67 (s, 3H), 2.22-2.11 (m, 4H), 1.95-1.91 (m, 2H), 1.70-1.66 (m, 2H);
5) synthetic compound 10: 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester getting 490mg adds in 15ml dry toluene, system is cooled to 0 DEG C, drip the LiHMDS of 1.05eq, after dropwising, rise to room temperature and continue reaction 30min; Reaction terminates rear system and is cooled to 0 DEG C, (mol ratio of 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester and compound 9 is 2:1 to drip the toluene solution 5ml containing 300mg compound 9, the mol ratio of alkali reagent and compound 9 is 1.05:1), after dropwising, rise to room temperature and react 40min; Reaction terminates rear system and is cooled to 0 DEG C, adds saturated NH 4the cancellation of Cl solution is reacted, separatory, after organic phase is concentrated, adds ethyl acetate, filters, obtain 450mg yellow solid compound 10;
The nuclear magnetic resonance information of compound 10 is: 1h NMR (400MHz, CDCl 3): δ 8.82 (s, 1H), 8.37 (s, 1H), 8.19-8.16 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.76), 7.35-7.32 (dd, 1H, J1=2.92, J2=9.12), (3.62-3.60 t, 4H, J=4.84), (3.13-3.11 t, 4H, J=4.72), 2.61 (s, 3H), 2.34-2.27 (m, 2H), 2.12-2.07 (m, 2H), 1.91-1.85 (m, 2H), 1.69-1.64 (m, 2H), 1.49 (s, 9H);
6) synthetic compound 11: under nitrogen protection, by the Pd (OAc) of 450mg compound 10,240mg vinyl n-butyl ether, 10mg 2, 50mg the DIEPA of dppf, 160mg add in the n-BuOH of 20ml that (mol ratio of vinyl n-butyl ether and compound 10 is 3:1, the mol ratio of Primary Catalysts, part and compound 10 is 0.05:0.10:1), system is warming up to 95 DEG C of reaction 20h; After reaction terminates, concentrate system, crosses post (DCM/EA:2/1), and column chromatography is purified to obtain 300mg dark yellow solid compound 11;
The nuclear magnetic resonance information of compound 11: 1h NMR (400MHz, CDCl 3): δ 8.77 (s, 1H), 8.25 (s, 1H), 8.22-8.20 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.6), 7.35-7.32 (dd, 1H, J1=2.92, J2=9.08), 4.53 (d, 1H, J=2.24), 4.18 (d, 1H, J=2.24), 3.88-3.84 (t, 2H, J=6.6), 3.63-3.60 (t, 4H, J=4.84), 3.13-3.10 (t, 4H, J=4.76), 2.42 (s, 3H), 2.38-2.30 (m, 2H), 2.14-2.03 (m, 2H), 1.87-1.81 (m, 2H), 1.76-1.70 (m, 2H), 1.69-1.64 (m, 2H), 1.49 (s, 9H), 1.47-1.39 (m, 2H), 0.96-0.92 (t, 3H, J=7.36),
7) synthetic compound 12: get 300mg compound 11 and add in 20ml methylene dichloride, drip about 0.5ml concentrated hydrochloric acid under room temperature, stir 1h, system separates out thick yellow solid, adds saturated NaHCO 3solution, the system of being adjusted to is weakly alkaline, system dichloromethane extraction, and organic phase is dry, concentrated, obtains 250mg dark yellow solid compound 12;
The nuclear magnetic resonance information of compound 12 is: 1h NMR (400MHz, CDCl 3): δ 8.84 (s, 1H), 8.38 (s, 1H), 8.17-8.14 (d, 1H, J=9.08), 8.06-8.05 (d, 1H, J=2.84), 7.35-7.31 (dd, 1H, J1=2.96, J2=9.08), 3.62-3.60 (t, 4H, J=4.84), 3.14-3.11 (t, 4H, J=4.76), 2.55 (s, 3H), 2.37 (s, 3H), 2.36-2.31 (m, 2H), 2.10-2.01 (m, 2H), 1.90-1.85 (m, 2H), 1.70-1.66 (m, 2H), 1.49 (s, 9H);
8) the deuterated Palbociclib shown in synthesis type (I): get 250mg compound 12 and add in 20ml methylene dichloride, drips 0.5ml trifluoroacetic acid, stirs 15h; After reaction terminates, add saturated NaHCO 3solution, is neutralized to weakly alkaline, system dichloromethane extraction, and organic phase is dry, and evaporating column Chromatographic purification obtains the deuterated Palbociclib of 180mg yellow solid, is designated as TRN-302;
The nuclear magnetic resonance information of the deuterated Palbociclib of gained is: 1h NMR (400MHz, CDCl 3): δ 8.82 (s, 1H), 8.23 (s, 1H), 8.17-8.15 (d, 1H, J=9.04), 8.06-8.05 (d, 1H, 2.84), 7.35-7.31 (dd, 1H, J1=2.96, J2=9.08), (3.17-3.15 t, 4H, J=4.24), (3.06-3.09 t, 4H, J=4.24), 2.55 (s, 3H), 2.37 (s, 3H), 2.34-2.31 (m, 2H), 2.08-2.01 (m, 2H), 1.90-1.85 (m, 2H), 1.71-1.67 (m, 2H).
Embodiment 3
The deuterated Palbociclib derivative of the present embodiment, structural formula is such as formula shown in (II):
The chemical formula that the synthetic route of the deuterated Palbociclib derivative of the present embodiment relates to is as follows:
The preparation method of the deuterated Palbociclib derivative of the present embodiment, comprises the following steps:
1) synthetic compound 14: get 7g cyclopentamine (compound 5b) and be dissolved in 100ml dehydrated alcohol, add the Et of 16ml 3n, adds 2, the 4-bis-chloro-5-bromo pyrimi piperidines (compound 5a) of 9g in system in batches under agitation condition, add rear continuation reaction 2h; After reaction terminates, filter, filtrate concentrates, and add water precipitation white solid, and solid adds a small amount of sherwood oil, stirs after 10 minutes and filters, obtain 8g compound as white solid 14;
The nuclear magnetic resonance information of compound 14 is: 1h NMR (CDCl 3, 400M): δ 8.08 (s, 1H), 5.44 (s, 1H), 4.45-4.36 (m, 1H), 2.15-2.10 (m, 2H), 1.75-1.65 (m, 4H), 1.50-1.42 (m, 2H);
2) synthetic compound 15: the Pd (OAc) getting 8g compound 14,1eq methyl crotonate, 5%eq 2, 10%eq the K of DABCO, 3eq 2cO 3, add in the DMF of 50ml; Be heated to 85 DEG C under nitrogen protection and react 3h; After reaction terminates, filter, filtrate adds water, and is extracted with ethyl acetate, organic phase saturated common salt water washing, dry, concentrated, and column chromatography is purified to obtain 1.9g compound as white solid 15;
The nuclear magnetic resonance information of compound 15 is: 1h NMR (400MHz, CDCl 3): δ 7.79 (s, 1H), 5.96-5.94 (d, 1H, J=1.36), 4.89 (s, 1H), 3.76 (s, 3H), 4.47-4.38 (m, 1H), (2.41-2.40 d, 3H, J=1.28), 2.13-2.07 (m, 2H), 1.74-1.64 (m, 4H), 1.44-1.36 (m, 2H);
3) synthetic compound 16: the KOH getting 140mg adds in the DMF of 20ml, and system is cooled to 0 DEG C, slowly drips the DMF solution 7ml containing 800mg compound 15, reaction 15min under nitrogen protection; After reaction terminates, system being poured directly in frozen water and being extracted with ethyl acetate, organic phase saturated common salt water washing, dry, concentrated, column chromatography is purified to obtain 360mg compound as white solid 16;
The nuclear magnetic resonance information of compound 16 is: 1h NMR (400MHz, CDCl 3): δ 8.74 (s, 1H), 6.54 (d, 1H, J=1.12), 5.89-5.80 (m, 1H), 2.45 (d, 3H, J=1.16), 2.25-2.17 (m, 2H), 2.13-2.09 (m, 2H), 1.93-1.87 (m, 2H), 1.69-1.65 (m, 2H);
4) synthetic compound 17: get 220mg compound 16, the NaOAc of 270mg adds in 20ml acetic acid, add 270mg bromine under nitrogen protection, system is warming up to 50 DEG C and reacts 35h; After reaction terminates, system is down to room temperature, adds Na 2sO 3solid cancellation is reacted, and system concentrates remove portion acetic acid, adds saturated NaHCO 3solution, is extracted with ethyl acetate afterwards, organic phase saturated common salt water washing, dry, concentrated, obtains 290mg compound as white solid 17;
The nuclear magnetic resonance information of compound 17 is: 1h NMR (400MHz, CDCl 3): δ 8.86 (s, 1H), 6.01-5.93 (m, 1H), 2.67 (s, 3H), 2.22-2.11 (m, 4H), 1.95-1.91 (m, 2H), 1.70-1.66 (m, 2H);
5) synthetic compound 18: 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester getting 490mg adds in 15ml dry toluene, system is cooled to 0 DEG C, drip the LiHMDS of 1.05eq, after dropwising, rise to room temperature and continue reaction 30min; After reaction terminates, system is cooled to 0 DEG C, and drips the toluene solution 5ml containing 300mg compound 17, after dropwising, rises to room temperature and reacts 40min; After reaction terminates, system is cooled to 0 DEG C, and adds saturated NH4Cl solution cancellation reaction, separatory, after organic phase is concentrated, adds ethyl acetate, filters, obtain 470mg yellow solid compound 18;
The nuclear magnetic resonance information of compound 18 is: 1h NMR (400MHz, CDCl 3): δ 8.82 (s, 1H), 8.37 (s, 1H), 8.19-8.16 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.76), 7.35-7.32 (dd, 1H, J1=2.92, J2=9.12), 5.96-5.79 (m, 1H), (3.62-3.60 t, 4H, J=4.84), (3.13-3.11 t, 4H, J=4.72), 2.61 (s, 3H), 2.34-2.27 (m, 2H), 2.12-2.07 (m, 2H), 1.91-1.88 (m, 2H), 1.69-1.64 (m, 2H), 1.49 (s, 9H);
6) synthetic compound 19: under nitrogen protection, gets the Pd (OAc) of 450mg compound 18,240mg vinyl n-butyl ether, 10mg 2, 50mg the DIEPA of dppf, 160mg, add in the n-BuOH of 20ml, system is warming up to 95 DEG C of reaction 20h; After reaction terminates, concentrate system, column chromatography is purified to obtain 290mg dark yellow solid compound 19;
The nuclear magnetic resonance information of compound 19 is: 1h NMR (400MHz, CDCl 3): δ 8.77 (s, 1H), 8.25 (s, 1H), 8.22-8.20 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.6), 7.35-7.32 (dd, 1H, J1=2.92, J2=9.08), 5.95-5.86 (m, 1H), 4.53 (d, 1H, J=2.24), 4.18 (d, 1H, J=2.24), 3.88-3.84 (t, 2H, J=6.6), 3.63-3.60 (t, 4H, J=4.84), 3.13-3.10 (t, 4H, J=4.76), 2.42 (s, 3H), 2.38-2.30 (m, 2H), 2.14-2.03 (m, 2H), 1.87-1.81 (m, 2H), 1.76-1.70 (m, 2H), 1.69-1.64 (m, 2H), 1.49 (s, 9H), 1.47-1.39 (m, 2H), 0.96-0.92 (t, 3H, J=7.36),
7) synthetic compound 20: get 300mg compound 19 and add in 20ml methylene dichloride, under room temperature, drip about 0.5ml concentrated hydrochloric acid, stir 1h, system separates out thick yellow solid, adds saturated NaHCO 3solution, the system of being adjusted to is weakly alkaline, system dichloromethane extraction, and organic phase is dry, concentrated, obtains 260mg dark yellow solid compound 20;
The nuclear magnetic resonance information of compound 20 is: 1h NMR (400MHz, CDCl 3): δ 8.84 (s, 1H), 8.38 (s, 1H), 8.17-8.14 (d, 1H, J=9.08), 8.06-8.05 (d, 1H, J=2.84), 7.35-7.31 (dd, 1H, J1=2.96, J2=9.08), 5.85-5.76 (m, 1H), 3.62-3.60 (t, 4H, J=4.84), 3.14-3.11 (t, 4H, J=4.76), 2.55 (s, 3H), 2.37 (s, 3H), 2.36-2.31 (m, 2H), 2.10-2.01 (m, 2H), 1.90-1.85 (m, 2H), 1.70-1.66 (m, 2H), 1.49 (s, 9H);
8) synthesize Palbociclib: get 250mg compound 20 and add in 20ml methylene dichloride, drip 0.5ml trifluoroacetic acid, stir 15h; After reaction terminates, add saturated NaHCO 3solution, system is neutralized to weakly alkaline, and with dichloromethane extraction, organic phase is dry, and evaporating column Chromatographic purification obtains 180mg yellow solid Palbociclib;
The nuclear magnetic resonance information of gained Palbociclib is: 1h NMR (400MHz, CDCl 3): δ 8.82 (s, 1H), 8.21 (s, 1H), 8.17-8.15 (d, 1H, J=9.04), 8.06-8.05 (d, 1H, 2.84), 7.35-7.31 (dd, 1H, J12=2.96, J13=9.08), 5.92-5.83 (m, 1H), (3.17-3.15 t, 4H, J=4.24), (3.06-3.09 t, 4H, J=4.24), 2.55 (s, 3H), 2.37 (s, 3H), 2.34-2.31 (m, 2H), 2.08-2.01 (m, 2H), 1.90-1.85 (m, 2H), 1.71-1.67 (m, 2H);
9) the deuterated Palbociclib shown in synthesis type (II): the K getting Palbociclib, 300mg of 100mg 2cO 3add the Isosorbide-5-Nitrae-dioxane (Dioxane) of 12ml and the D of 4ml 2in the mixed solvent that O is mixed, system is heated to 105 DEG C and stirs spend the night, and system concentrates, and adds dichloromethane extraction, organic phase saturated common salt water washing, dry, concentrated, obtains the deuterated Palbociclib of 100mg, is designated as TRN-303;
The nuclear magnetic resonance information of the deuterated Palbociclib of gained is: 1h NMR (400MHz, CDCl 3): δ 8.82 (s, 1H), 8.30 (s, 1H), 8.17-8.14 (d, 1H, J=9.04), 8.06-8.05 (d, 1H, J=2.8), 7.34-7.31 (dd, 1H, J1=2.92, J2=9.08), 5.92-5.83 (m, 1H), 3.16-3.14 (t, 4H, J=7.04), 3.08-3.05 (t, 4H, J=5.2), 2.38-2.31 (m, 2H), 2.06-2.05 (m, 2H), 1.90-1.87 (m, 2H), 1.72-1.68 (m, 2H);
Embodiment 4
The deuterated Palbociclib derivative (deuterated Palbociclib hydrochloride) of the present embodiment, structural formula is as shown in formula V:
The preparation method of the deuterated Palbociclib hydrochloride of the present embodiment, comprise: get the deuterated Palbociclib of 50mg embodiment 2 gained and add in 20ml dry methylene chloride, stirring at room temperature, pass into HCl gas, filter, get filter cake washed with dichloromethane, obtain deuterated Palbociclib hydrochloride as shown in formula V. 1H NMR(400MHz,DMSO-d 6)：δ9.16(s,2H),9.00(s,1H),8.09-8.08(d,,J＝2.60,1H),7.97-7.85(d,J＝9.30,1H),7.81-7.79(d,J＝9.20,1H),3.43-3.41(m,4H,),3.25-3.20(m,4H,),2.44(s,3H),2.34(s,3H),2.25-2.22(m,2H),1.92-1.89(m,2H),1.80-1.77(m,2H),1.61-1.59(m,2H)。
Embodiment 5
The deuterated Palbociclib derivative (deuterated Palbociclib isethionate) of the present embodiment, structural formula is such as formula shown in (VI):
The preparation method of the deuterated Palbociclib isethionate of the present embodiment, comprising: get the H that the deuterated Palbociclib of 45mg embodiment 3 gained adds 3ml methyl alcohol and 0.5ml 2o be mixed mixed solution in, under agitation condition, system is heated to 55 DEG C; Take hydroxyethylsulfonic acid aqueous solution 20mg (wherein, the mass percentage of hydroxyethylsulfonic acid is 80%, 1eq), add the H of 1ml 2o dilutes, diluent is slowly added dropwise to reaction system, to reaction system close to clarification, reduce system temperature to 35 DEG C, filter, methanol wash column filter cake, filtrate is concentrated into 2ml, hold over night at 4 DEG C, and solid is separated out, filter, obtain such as formula Palbociclib isethionate deuterated (VI) Suo Shi. 1H NMR(400M,D2O):δ8.92(s,1H),8.02-7.99(dd,J12＝2.52,J13＝8.96,1H),7.73(s,1H),7.40–7.38(d,J＝9.56,1H),5.76-5.67(m,1H),3.85-3.82(t,J＝6.64,2H),3.45-3.43(m,4H),3.39-3.37(m,4H),3.05-3.02(t,J＝6.60,2H),2.05-2.00(m,2H),1.9-1.83(m,4H),1.63-1.60(m,2H)。
Experimental example 1
The biological activity of this experimental example to the deuterated Palbociclib derivative of embodiment 2,3 gained detects.Sample message: comprise the deuterated Palbociclib shown in formula (I), deuterated Palbociclib, the Palbociclib shown in formula (II) totally 3 compounds.
Experiment content: the restraining effect testing deuterated Palbociclib, Palbociclib cell cycle protein dependent kinase 4 (CDK4) shown in the deuterated Palbociclib shown in formula (I), formula (II) and cell cycle protein dependent kinase 6 (CDK6) respectively.
Experimental result is as shown in table 1.
Table 1 biological activity test result
Experimental result shows, the deuterated Palbociclib shown in formula of the present invention (I), deuterated Palbociclib and the Palbociclib shown in formula (II) have similar biological activity.
Experimental example 2
This experimental example carries out drug metabolism experiment to the deuterated Palbociclib derivative of embodiment 2-3 gained.
These three kinds of compounds are carried out gastric infusion by the dosage of 5mg/kg to rat by the deuterated Palbociclib derivative of Example 2, embodiment 3 gained and Palbociclib respectively; Give three kinds of compounds with the dosage of 5mg/kg to rat intravenous injection respectively, the concentration of compound in rat plasma after mensuration administration, calculates relevant pharmacokinetic parameter.
Experimental result is:
1) the quiet note group AUC of Palbociclib 0-tbe 985.5 μ g/Lh, t 1/2=2.9h; Gavage group AUC 0-tbe 336.2 μ g/Lh, C maxbe 48.5 μ g/L, t 1/2=8.2h, absolute bioavailability is 34.1%;
2) the quiet note group AUC of embodiment 2 gained deuterated Palbociclib formula (I) 0-tbe 1498.8 μ g/Lh, t 1/2=3.5h; Gavage group AUC 0-tbe 511.1 μ g/Lh, C maxbe 89.5 μ g/L, t 1/2=6.6h, absolute bioavailability is 34.1%;
3) the quiet note group AUC of embodiment 3 gained deuterated Palbociclib formula (II) 0-tbe 1842.6 μ g/Lh, t 1/2=6.52; Gavage group AUC 0-tbe 645.5 μ g/Lh, C maxbe 99.2 μ g/L, t 1/2=12.4h, absolute bioavailability is 35.4%.
For result, medicine shows that the deuterated Palbociclib derivative that the present invention synthesizes has better medicine for character, especially deuterated Palbociclib formula (II) compound, has higher body internal stability, have good application prospect.

Claims (10)

1. a deuterated Palbociclib derivative, is characterized in that: its structural formula is such as formula shown in (I), formula (II), formula (III) or formula (IV):
Wherein, R is acid; N is 1 or 2.
2. deuterated Palbociclib derivative according to claim 1, is characterized in that: described R is HCl, H 2sO 4, H 3pO 4, HF, HBr, HI, HOCH 2cH 2sO 3h, CH 3sO 3h, CH 3cOOH or citric acid.
3. a preparation method for deuterated Palbociclib derivative as claimed in claim 1, is characterized in that: comprise the following steps:
1) getting 2,4-bis-chloro-5-bromo pyrimi piperidine and deuterated cyclopentamine or deuterated cyclopentamine salt adds in solvent, reacts, obtain compound 6 under alkali reagent effect;
2), under protection of inert gas, compound 6 and methyl crotonate are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 7;
3) compound 7 is added in solvent, under alkali reagent existence condition, carry out Intra-molecular condensation, obtain compound 8;
4) compound 8 and brominated reagent are added in solvent, carry out bromo-reaction, obtain compound 9;
5) get 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester and compound 9 adds in solvent, under alkali reagent effect, carry out substitution reaction, obtain compound 10;
6), under protection of inert gas, compound 10 and vinyl n-butyl ether are added in solvent, under catalyzer and alkali reagent existence condition, carries out linked reaction, obtain compound 11;
7) compound 11 is added in solvent, under acid effect, carry out ether bond rupture reaction, obtain compound 12;
8) compound 12 is added in solvent, Boc protecting group occurs under acid effect and removes reaction, obtain the deuterated Palbociclib shown in formula (I).
4. the preparation method of deuterated Palbociclib derivative according to claim 3, is characterized in that: described catalyzer comprises Primary Catalysts and part; Described Primary Catalysts is Palladous chloride or palladium, and described part is triphenylphosphine, 1,1 '-bis-(diphenylphosphine) ferrocene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
5. the preparation method of deuterated Palbociclib derivative according to claim 3, is characterized in that: step 1) in, described deuterated cyclopentamine is prepared by the method comprised the following steps:
A) get cyclopentanone and deuterated reductive agent to add in solvent and react, obtain compound 2;
B) compound 2 and hydroxy activated reagent are added in solvent, react under alkali reagent existence condition, obtain compound 3;
C) add in solvent by compound 3 and azido group donor, azide substitution reaction is carried out in heating, obtains compound 4;
D) under reductive agent effect, the nitrine in compound 4 is reduced into amine, obtains deuterated cyclopentamine.
6. the preparation method of the deuterated Palbociclib derivative according to claim 3,4 or 5, it is characterized in that: described alkali reagent is triethylamine, pyridine, DMAP, salt of wormwood, cesium carbonate, KOH, NaOH, butyllithium, lithium diisopropylamine, LHMDS, DIPEA, K 2cO 3, Na 2cO 3in any one or combination.
7. the preparation method of deuterated Palbociclib derivative according to claim 5, is characterized in that: described deuterated reductive agent is deuterated lithium aluminium hydride, deuterated sodium borohydride, deuterated acetic acid sodium borohydride or deuterated sodium cyanoborohydride; Described hydroxy activated reagent is Methanesulfonyl chloride or Tosyl chloride; Described azido group donor is sodiumazide or azido-Trimethoxy silane; Described reductive agent is triphenylphosphine.
8. the preparation method of a deuterated Palbociclib derivative as claimed in claim 1, it is characterized in that: comprise and Palbociclib and heavy water are added in solvent, under alkali reagent effect, there is hydrogen deuterium exchange reaction, obtain the deuterated Palbociclib shown in formula (II).
9. the application of a deuterated Palbociclib derivative as claimed in claim 1 in the inhibitor medicaments for the preparation of T suppression cell Cyclin dependent kinase 4 and 6.
10. the application of deuterated Palbociclib derivative as claimed in claim 1 in preparation treatment breast cancer medicines.
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CN110384702A (en) * 2019-07-30 2019-10-29 上海红蓝医药科技有限公司 A kind of novel anti-breast cancer medicines and preparation method thereof
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