Study On The Synthesis Of Palibociclib And Apraclonidine Hydrochloride

Breast cancer is one of the most common malignant tumor in women and it has the incidence of 7%-10%among all kinds of malignant tumors.Palbociclib,developed by Pfizer,was approved for the treatment of breast cancer by US FDA on February 3,2015.Palbociclib is a kind of oral CDK 4/6 inhibitor drugs and it prevent the synthesis of DNA by blocking the cell cycle transition from G1 phase to S phase,inhibiting the CDK 4/6 selectively.Adjusting the CDK 4/6 to recover the normal cell cycle and further blocking the tumor cell proliferation.In this thesis,the advance on the treatment of breast cancer and related drugs was reviewed at first,and then have summarized the synthetic methods of Palbociclib.Based on the above research,Palbociclib was prepared by a prefect route and its crystal structure was determined.Meantime,the glaucoma treatment drug Apraclonidine Hydrochloride was researched in this thesis,achieved gratifying results as well.The main work is as follows:（1）The synthesis of Palbociclib:The 4-（6-nitropyridin-3-yl）piperazine-1-carboxylic acid tert-butyl ester was prepared with the yield of 78%from 5-bromo-2-nitropyridine through reacting with piperazine and di-tert-butyl dicarbonate in two steps.And then the 4-（6-amino-pyridin-3-yl）-piperazine-1-carboxylic acid tert-butyl ester was obtained by the reduction of nitro group with Fe and acetic acid,the yield of this step is up to 89%.The 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one was obtained by 5-bromo-2,4-dichloro-pyrimidine through reacting with cyclopentylamine,trans-crotonic acid and NBS in four steps,the yield of the four steps is 49%.The 4-[6-[6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino]pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared at last as the yield of 86%from connecting 4-（6-aminopyridin-3-yl）piperazine-1-carboxylic acid tert-butyl ester and 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one under the catalytic of Na H.And then the product reacted with butyl vinyl ether to get4-[6-（1-butoxyl-vinyl）-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyramidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester with the yield of 76%.Palbociclib was obtained after11 steps with the total yield of 21%by the hydrolysis of methanesulfonic acid and the arreagment.The product structure was confirmed by IR,¹H NMR,¹³C NMR and HRMS.（2）The crystal research of Palbociclib:The crystal of Palbociclib was characterized by X-ray power diffraction（PXRD）,thermogravimetric analysis（TGA）,and differential scanning calorimetry（DSC）.The analysis results suggest that Palbociclib is anhydrous form and its crystal structure is the same to WO 2016030439.（3）The synthesis of Apraclonidine Hydrochloride:The 2-（2’,6’-dichloro-4’-nitrophenyl-amino）-2-imidazoline was prepared from 2,6-dichloro-4-nitroaniline through reacting with formic acid solution of acetic anhydride,SO₂Cl₂ and ethylenediamine in three steps,the yield of this three steps was 40%.And then the compound of 2,6-dichloro-N’-（4,5-dihydro-1H-imidazol-2-yl）-1,4-benzenediamine was obtained with 78%yield by the reduction of nitro group with Pd/C in the solution of hydrazine hydrate.Apraclonidine Hydrochloride was obtained by reacting with HCl at last and did some improvements about its procedure.The total synthesis of Apraclonidine Hydrochloride inclouding 5 steps and the total synthesis yield was 27%.The product structure was confirmed by IR,¹H NMR,¹³C NMR and HRMS.Its crystal structure was determined through x-ray diffraction.The result indicated that the compound collected is Apraclonidine Hydrochloride.