CN107488175A - A kind of pa wins the preparation method of XiLin key intermediate - Google Patents

Abstract

The invention discloses the preparation method that a kind of pa wins the picoline of XiLin key intermediate 6 bromine, 2 methylsulfinyl 8 cyclopenta 5 simultaneously (2,3 d) pyrimidine 7 (8H) ketone.This method is using deracil as initiation material; through methylating; chloro; bromo synthesizes the methylthiopyrimidine of 5 bromine, 4 chlorine 2, is then alkylated with cyclopentamine, is reacted with 2 butenoic acids through heck; then the picoline of intramolecular acylation reaction synthesis 2 methyl mercapto 8 cyclopenta 5 simultaneously (2; 3 d) pyrimidine 7 (8H) ketone, finally reacted with NBS and prepare the picoline of 6 bromine, 2 methylsulfinyl, 8 cyclopenta 5 simultaneously (2,3 d) pyrimidine 7 (8H) ketone.The step of preparation process of the present invention is short, and not using dangerous technique, simple to operate, cost of material is low, meets the use demand of people.

Description

A kind of pa wins the preparation method of XiLin key intermediate

Technical field

The present invention relates to field of medicine preparation, specifically a kind of pa wins the preparation method of XiLin key intermediate.

Background technology

Pa wins XiLin, Palbociclib (PD0332991), the entitled 6- acetyl group -8- cyclopenta -5- methyl -2- of chemistry (5- piperazines -1- bases-pyridine -2- bases amino) -8H- pyridos ［ 2,3-d ］ pyrimidin-7-ones, are that Pfizer Inc. develops Cell cycle protein dependent kinase 4/6 (CDK4/6) inhibitor, trade name Ibrance.2 months 2015, FDA accelerated approval Palbociclib is used to treat the ER positives/HER2 feminine gender post menopausal metastatics with Letrozole (Letrozole) drug combination Patient with breast cancer, make the inhibitor medicaments of the CDK4 of first FDA approval/6 and be approved to list in the U.S..

The bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines of 6- simultaneously as pa win by (2,3-d) pyrimidine -7 (8H) -one The key intermediate in XiLin, its synthetic method is mainly using the chloro- 2- methylthiopyrimidines -5- Ethyl formates of 4- as initiation material, warp Alkylation, reduce, oxidation, with form reagent reacting, oxidation, with phosphorus ylide reagent reacting, bromo, oxidation is made.Such as CN2016105622638, PCT Int. Appl., 2012068381, PCT Int. Appl., 2010039997. is specific Route is as follows：

The synthetic schemes route is longer, and initiation material is expensive, uses the dangerous technique such as Lithium aluminum hydride reduction in course of reaction, this is just Inconvenience is brought for manufacturer.

The content of the invention

It is an object of the invention to provide the preparation method that a kind of pa wins XiLin key intermediate, to solve above-mentioned background skill The problem of being proposed in art.

To achieve the above object, the present invention provides following technical scheme：

A kind of pa wins the preparation method of XiLin key intermediate, comprises the following steps that：

Step 1, the preparation of 2- methyl mercapto -4- pyrimidones：Deracil is dissolved in dimethyl carbonate, in potassium carbonate and four fourths Under the catalysis of base ammonium bromide, 2- methyl mercapto -4- pyrimidones are prepared, reaction equation is as follows：

；

Step 2, the preparation of the bromo- 2- methyl mercaptos -4- pyrimidones of 5-：2- methyl mercapto -4- pyrimidones and NBS are dissolved in dichloromethane In, back flow reaction prepares the bromo- 2- methyl mercaptos -4- pyrimidones of 5-, and reaction equation is as follows：

；

Step 3, the preparation of the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-：The bromo- 2- methyl mercaptos -4- pyrimidones of 5- are dissolved in pyridine, POCl3 is added dropwise under 80-90 degrees Celsius and prepares the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-, reaction equation is as follows：

；

Step 4, the preparation of the bromo- 4- cyclopentamines base -2- methylthiopyrimidines of 5-：The chloro- 2- methylthiopyrimidines of the bromo- 4- of 5- are dissolved in second In alcohol, cyclopentamine reaction is added dropwise below 10 degrees Celsius and prepares the bromo- 4- cyclopentamines base -2- methylthiopyrimidines of 5-, reaction equation is as follows：

；

Step 5, the preparation of 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines simultaneously (2,3-d) pyrimidine -7 (8H) -one：By the bromo- 4- of 5- Cyclopentamine base -2- methylthiopyrimidines carry out Heck reactions with crotonic acid, then prepare 8- cyclopenta -5- first with acetic anhydride Simultaneously (2,3-d) pyrimidine -7 (8H) -one, reaction equation are as follows for base -2- methylsulfanyl pyridines：

；

Step 6, the system of the bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines of 6- simultaneously (2,3-d) pyrimidine -7 (8H) -one It is standby：By 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines, simultaneously (2,3-d) pyrimidine -7 (8H) -one, NBS and water reaction prepare 6- Simultaneously (2,3-d) pyrimidine -7 (8H) -one, reaction equation are as follows for bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines：

。

Compared with prior art, the beneficial effects of the invention are as follows：The step of preparation process of the present invention is short, not using danger Technique, simple to operate, cost of material is low, meets the use demand of people.

Embodiment

The technical scheme of this patent is described in more detail with reference to embodiment.

Embodiment 1

A kind of pa wins the preparation method of XiLin key intermediate, comprises the following steps that：

Step 1, the preparation of 2- methyl mercapto -4- pyrimidones：Take deracil 128g, dimethyl carbonate 500g, potassium carbonate 300g, TBAB 1g, 120 ° of reaction 8h are warming up to, after reaction terminates, room temperature is cooled to, filters, filtrate decompression is returned The complete dimethyl carbonate of unreacted is received, residue adds 300 milliliters of water, 300 milliliters of ethyl acetate extractions, dried, filtering, filtrate Add 100 milliliters of petroleum ethers and recrystallize to obtain white powder 132g, yield 93%；

Step 2, the preparation of the bromo- 2- methyl mercaptos -4- pyrimidones of 5-：2- methyl mercapto -4- pyrimidone 142g are taken, are dissolved in 500 milliliters In dichloromethane, NBS 190g, back flow reaction 6h are added, after reaction terminates, is cooled to room temperature, is filtered, filtrate washing is organic Mutually dry, light yellow solid 190g, yield 87% are recrystallized to give under ice bath；

Step 3, the preparation of the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-：The bromo- 2- methyl mercaptos -4- pyrimidone 110g of 5- are taken, are dissolved in In 400g pyridines, system is warming up to 80 °, and POCl3 100g is added dropwise, and after being added dropwise, continues to react 5h, after reaction terminates, It is cooled to room temperature, under ice bath, adjusts pH to 8-9,500 milliliters of ethyl acetate extractions with saturated sodium bicarbonate, anhydrous magnesium sulfate is done It is dry, filtering, filtrate decompression recycling design, residue petroleum ether：Ethyl acetate=1:3 recrystallize to obtain faint yellow solid powder 98g, Yield 83%.

Step 4, the preparation of the bromo- 4- cyclopentamines base -2- methylthiopyrimidines of 5-：Take the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5- 238g, is dissolved in 300 milliliters of THF, adds 130g triethylamines, under ice bath, 90g cyclopentamines is added dropwise, drips off within 30 minutes, continues to react 2h, after reaction terminates, 400g water is added into system, separates out solid, dries, obtains light yellow solid 255g, yield 89%；

Step 5, the preparation of 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines simultaneously (2,3-d) pyrimidine -7 (8H) -one：Take 287g 5- Bromo- 4- cyclopentamines base -2- methylthiopyrimidines, 800 milliliters of 1-METHYLPYRROLIDONEs are added, lead to nitrogen 30min, add 200 milligrams Lead acetate, nitrogen bubble ventilation 30min, 95g crotonic acids, 220g triethylamines are added, nitrogen bubble ventilation 30min, is heated to 65 ° Stirring reaction, 200 milligrams of lead acetates were added after 2 hours, are added three times altogether, then be spaced and add within 2 hours 100 milligrams of acetic acid Button, coreaction 8h, after reaction terminates, it is wet that reaction is cooled to room, and 200 milliliters of acetic anhydride is added dropwise, and it is small to then heat to 50 ° of reactions 1 When, after reaction terminates, room temperature is cooled to, water 1L is added, whisks one hour, is filtered, 500 milliliters of water washings of filter cake, solid is again Use isopropanol:Water=1:1 800 milliliters of mashing of mixed solvent, are filtered, and 45 ° of filter cake is dried in vacuo to obtain white powder solid 236g, Yield 86%；

Step 6, the system of the bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines of 6- simultaneously (2,3-d) pyrimidine -7 (8H) -one It is standby：Take 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines simultaneously (2,3-d) pyrimidine -7 (8H) -one 275g, NBS 400g, acetonitrile 800 milliliters, water 20g and glacial acetic acid 5g, system react 2h, react after terminating, and add water 1L to reaction system, stirring separates out admittedly Body, filter, wash to obtain white solid, dry, obtain white solid 321g, yield 87%.

The synthetic route of the present invention is as follows：

This method is using deracil as initiation material, through methylating, chloro, and the bromo synthesis chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-, Then it is alkylated with cyclopentamine, is reacted with 2- butenoic acids through heck, then intramolecular acylation reaction synthesis 2- methyl mercapto -8- ring penta Base -5- picolines simultaneously (2,3-d) pyrimidine -7 (8H) -one, finally reacted with NBS and prepare the bromo- 2- methylsulfinyls -8- rings of 6- Amyl group -5- picolines simultaneously (2,3-d) pyrimidine -7 (8H) -one, production cost is low, easy to operate, and does not use dangerous technique, Meets the needs of producer.

It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling Change is included in the present invention.Any mark in claim should not be considered as to the involved claim of limitation.

Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art It is appreciated that other embodiment.

Claims (1)

1. a kind of pa wins the preparation method of XiLin key intermediate, it is characterised in that comprises the following steps that：

Step 1, the preparation of 2- methyl mercapto -4- pyrimidones：Deracil is dissolved in dimethyl carbonate, in potassium carbonate and four fourths Under the catalysis of base ammonium bromide, 2- methyl mercapto -4- pyrimidones are prepared, reaction equation is as follows：

；

Step 2, the preparation of the bromo- 2- methyl mercaptos -4- pyrimidones of 5-：2- methyl mercapto -4- pyrimidones and NBS are dissolved in dichloromethane In, back flow reaction prepares the bromo- 2- methyl mercaptos -4- pyrimidones of 5-, and reaction equation is as follows：

；

Step 3, the preparation of the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-：The bromo- 2- methyl mercaptos -4- pyrimidones of 5- are dissolved in pyridine, POCl3 is added dropwise under 80-90 degrees Celsius and prepares the chloro- 2- methylthiopyrimidines of the bromo- 4- of 5-, reaction equation is as follows：

；

Step 4, the preparation of the bromo- 4- cyclopentamines base -2- methylthiopyrimidines of 5-：The chloro- 2- methylthiopyrimidines of the bromo- 4- of 5- are dissolved in second In alcohol, cyclopentamine reaction is added dropwise below 10 degrees Celsius and prepares the bromo- 4- cyclopentamines base -2- methylthiopyrimidines of 5-, reaction equation is as follows：

；

Step 5, the preparation of 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines simultaneously (2,3-d) pyrimidine -7 (8H) -one：By the bromo- 4- of 5- Cyclopentamine base -2- methylthiopyrimidines carry out Heck reactions with crotonic acid, then prepare 8- cyclopenta -5- first with acetic anhydride Simultaneously (2,3-d) pyrimidine -7 (8H) -one, reaction equation are as follows for base -2- methylsulfanyl pyridines：

；

Step 6, the system of the bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines of 6- simultaneously (2,3-d) pyrimidine -7 (8H) -one It is standby：By 8- cyclopenta -5- methyl -2- methylsulfanyl pyridines, simultaneously (2,3-d) pyrimidine -7 (8H) -one, NBS and water reaction prepare 6- Simultaneously (2,3-d) pyrimidine -7 (8H) -one, reaction equation are as follows for bromo- 2- methylsulfinyls -8- cyclopenta -5- picolines：

。