CN107827869A - A kind of preparation method of 4 (base of 6 aminopyridine 3) piperidinyl-1 t-butyl formates - Google Patents
A kind of preparation method of 4 (base of 6 aminopyridine 3) piperidinyl-1 t-butyl formates Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of 4 (base of 6 aminopyridine 3) piperidinyl-1 t-butyl formates.With the dimethylpropionamides of N (5 bromopyridine 2) 2,2, the piperidones of N tertbutyloxycarbonyls 4, Raney's nickel etc. for raw material, purpose product 4 (base of 6 aminopyridine 3) piperidinyl-1 t-butyl formate is obtained by three-step reaction.Present invention process stabilization easy to operate, often step product can be easily separated, yield it is high, it is environment-friendly, comprehensive yield is more than 82%, compared with the yield of existing process 42%, have and be obviously improved, and raw material is cheap and easy to get, existing biology, medicine, the production cost of chemical intermediate are significantly reduced, is advantageous to industrial-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of 4- (6- aminopyridine -3- bases) piperidines -1- formic acid
The preparation method of the tert-butyl ester.
Background technology
4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, English name：tert-Butyl-4-(6-
AMinopyridin-3-yl) piperidine-1-carboxylate, molecular formula are C15H23N3O2.White powdery solid, it is
A kind of biology well, medicine, chemical intermediate.
The synthesis open source literature report of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates is few, existing synthesis
Technique, it can substantially be divided into two classes：
Method one, using 2- nitro -5- bromopyridines and 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) -
5,6- dihydropyridine -1 (2- hydrogen)-t-butyl formates are coupled under catalyzing by metal palladium, then using palladium carbon hydrogenation double bond
Meanwhile nitro is reduced simultaneously.Synthetic route is as follows：
Method two, using 2- nitro -5- bromopyridines and 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) -
5,6- dihydropyridine -1 (2- hydrogen)-t-butyl formates are coupled under catalyzing by metal palladium, then using palladium carbon hydrogenation double bond
Meanwhile nitro is reduced simultaneously.Synthetic route is as follows：
Raw materials used expensive in both the above method, catalyst amount is up to 0.1 equivalent, and yield is low after reaction, very
Connection boron ester is relevant with pyridine amine moiety complexing caused by big degree and coupling, causes reaction impurities a lot, and post processing needed
Silicagel column could purify, and content of beary metal is difficult to effectively control to pharmaceutical intermediate requirement level in product.Therefore, it is overall
On see that existing synthesis technique yield is low, hardly possible purifying, economic benefit is all bad.
The content of the invention
For the above-mentioned deficiency of prior art, the present invention provides a kind of stabilization easy to operate, each step product can be easily separated, receive
Rate is high, environment-friendly, production cost is low, is adapted to 4- (6- aminopyridine -3- bases) piperidines -1- formic acid uncles of industrial-scale production
The preparation method of butyl ester.
The present invention provides a kind of preparation method of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, reactional equation
Formula is as follows：
Set out from N- (the bromo- pyridine -2- of 5-) -2,2- dimethylpropionamides, by addition reaction, reduction reaction, deprotection
4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates are obtained after the three-step reactions such as reaction, are specifically comprised the following steps：
The first step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin
Under ultralow temperature, n-BuLi is added in N- (the bromo- pyridine -2- of 5-) -2,2- dimethylpropionamide solution, then
N- tertbutyloxycarbonyl -4- piperdinones are added, 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxyls are obtained after reaction
Base-N- t-butoxycarbonylpiperidins.
In this step, the solution of N- (the bromo- pyridine -2- of 5-) -2,2- dimethylpropionamides is ether, tetrahydrofuran, 2- first
The solution that any combination of base tetrahydrofuran, n-hexane or above-mentioned solvent obtains；The solution of N- tertbutyloxycarbonyl -4- piperidones is
The solution that ether, tetrahydrofuran, 2- methyltetrahydrofurans, any combination of n-hexane or above-mentioned solvent obtain.N- (the bromo- pyrroles of 5-
Pyridine -2-) -2,2- dimethylpropionamides, n-BuLi and N- tertbutyloxycarbonyl -4- piperidones molar feed ratio example be 1：2.5-
3.5：1-1.2.Preferable organic solvent is tetrahydrofuran or 2- methyltetrahydrofurans.
Second step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins
It is molten that 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidins and Raney's nickel add alcohol
In agent, reaction solution back flow reaction obtains 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins.
In this step, alcoholic solvent is selected from any combination of ethanol, methanol, isopropanol or above-mentioned solvent.4- (6- trimethyl second
Acylamino- -3- pyridine radicals) the molar ratio example of -4- hydroxy-ns-t-butoxycarbonylpiperidin and Raney's nickel is 1:1-1.5.It is preferred that
Solvent is ethanol.
3rd step：The synthesis of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins are added into alkali lye and organic solvent
In mixed solution, after reaction Heating selectivity deprotection, 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates are obtained.
In this step, the alkali lye is sodium hydrate aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution or above-mentioned
Any combination of reagent；Organic solvent is methanol, ethanol, isopropanol etc..4- (6- amino -3- pyridine radicals)-N- tertbutyloxycarbonyls
Piperidines, the molar ratio of alkali lye are 1：5-10.Preferred solvent is methanol.
Invention beneficial effect：
Compared with conventional synthetic method, the present invention has the advantages that：
1) comprehensive yield of the invention is more than 82%, more existing 42% yield, has and is obviously improved, be greatly reduced
4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formate production costs.
2) present invention has selected cheap raw material to replace expensive borane reagent and palladium reagent, optimizes preparation technology,
While reducing environmental pollution, production cost is greatly reduced.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.These embodiments are interpreted as being merely to illustrate this hair
It is bright rather than limit the scope of the invention.After the content of the invention recorded has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalence changes and modification equally fall into the model that the claims in the present invention are limited
Enclose.
The experimental method of unreceipted actual conditions in following examples of the present invention, is generally carried out according to normal condition.
Raw material used or reagent are commercially available in addition to special instruction in following examples of the present invention.
20-35 DEG C of room temperature average described in following examples of the present invention.Unless otherwise indicated, described reagent is not special
Explanation is not purified directly use.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and
And just it can be used without processing.Reaction is analyzed by TLC or analyzed by HPLC, judges to react by the consumption of parent material
Termination.The thin-layer chromatography (TLC) of analysis is glass plate (the EMD chemicals in pre-coated silica gel 60F2540.25 millimeter plates
Company (EMDChemicals)) on carry out, imaged with the iodine on UV light (254nm) or silica gel, or TLC product dyed therebies such as alcohol phosphorus
Molybdic acid, ninhydrin solution, liquor potassic permanganate or cerous sulfate solution heat together.
Embodiment 1
The first step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin
At -70 DEG C, n-BuLi (37.2mL, 93mmol) hexane solution (2.5N) is slowly added into N- (the bromo- pyrroles of 5-
Pyridine -2-) -2,2- dimethylpropionamides (7.94g, 31mmol) ether (80mL) in, reactant mixture stirs at this temperature
Mix 1 hour.The ether (60mL) of N- tertbutyloxycarbonyl -4- piperidones (6.15g, 31mmol) is added in reaction solution at -70 DEG C,
And stir 2 hours.After the completion of TLC monitoring reactions, reaction, ethyl acetate extraction is quenched in aqueous ammonium chloride solution, and organic layer is spin-dried for simultaneously
Cross quick silicagel column and purify to obtain solid 11.01g, yield 94.42%.
Through Mass Spectrometer Method, ESI/MS：M/z=322.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin.
Second step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins
4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidins (5g, 13.25mmol) and
Raney's nickel (1g, 17.04mmol) is added in ethanol (180mL), and reaction solution back flow reaction is cooled to room temperature after 5 hours.Filter thunder
Buddhist nun's nickel, solution are spin-dried for obtaining solid 4.54g, yield 94.78%.
Through Mass Spectrometer Method, ESI/MS：M/z=306.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals)-N- t-butoxycarbonylpiperidins.
3rd step：The synthesis of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins (4g, 11.07mmol) are added into 5N
In the mixed solution of sodium hydrate aqueous solution (11.07mL, 55.33mmol) and methanol (11mL), reaction return stirring 20 minutes,
Solution is extracted with ethyl acetate after being cooled to room temperature, and organic layer merges, dries, filters, being spin-dried for and to obtain white solid 2.85g, HPLC:
99.2%, yield 92.84%.
HNMR(400MHz,MeOD):7.76 (d, J=2.3Hz, 1H), 7.38 (dd, J=8.6,2.3Hz, 1H), 6.56
(d, J=8.6Hz, 1H), 4.21-4.18 (m, 2H), 2.84 (brs, 2H), 2.60 (m, 1H), 1.78-1.75 (m, 2H), 1.58-
1.57(m,2H),1.48(s,9H)；MSm/z278.2[MH]+.
The total recovery of three-step reaction：83%.
Embodiment 2
The first step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin
At -65 DEG C, n-BuLi (1.94L, 4.85mol) hexane solution (2.5N) is slowly added into N- (the bromo- pyrroles of 5-
Pyridine -2-) -2,2- dimethylpropionamides (500g, 1.94mol) tetrahydrofuran (1L) in, reactant mixture maintain -65 DEG C to -
Stirred 1 hour at 70 DEG C.The tetrahydrofuran (2L) of N- tertbutyloxycarbonyl -4- piperidones (465g, 2.33mol) adds at -65 DEG C
Enter in reaction solution, and stir 2 hours.After the completion of TLC monitoring reactions, reaction is quenched in aqueous ammonium chloride solution, ethyl acetate extraction, has
Machine layer is spin-dried for and excessively quick silicagel column purifies to obtain solid 704.6g, yield 96.0%.
Through Mass Spectrometer Method, ESI/MS：M/z=322.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin.
Second step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins
4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin
(700.0g, 1.85mol) and Raney's nickel (163.3g, 2.78mol) are added in methanol (3.5L), and reaction solution backflow is anti-
Room temperature is cooled to after answering 5 hours.Raney's nickel is filtered, solution is spin-dried for obtaining solid 643g, yield 95.9%.
Through Mass Spectrometer Method, ESI/MS：M/z=306.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals)-N- t-butoxycarbonylpiperidins.
3rd step：The synthesis of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins (600g, 1.66mol) are added into 5N
In the mixed solution of potassium hydroxide aqueous solution (3.32L, 16.60mol) and ethanol (3.3L), reaction return stirring 20 minutes, drop
Warm to room temperature rear solution to be extracted with ethyl acetate, organic layer merges, dries, filters, being spin-dried for and to obtain white solid 432g, HPLC:
99.4%, yield 93.83%；
The total recovery of three-step reaction：86%.
Embodiment 3
The first step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin
At -78 DEG C, n-BuLi (46.6L, 116.67mol) hexane solution (2.5N) is slowly added into N-, and (5- is bromo-
Pyridine -2-) -2,2- dimethylpropionamides (10kg, 38.89mol) tetrahydrofuran (20L) in, reactant mixture is at -78 DEG C
Stirred 1 hour to -70 DEG C.The tetrahydrofuran (12L) of N- tertbutyloxycarbonyl -4- piperidones (7.75kg, 38.89mol) is at -78 DEG C
In lower addition reaction solution, and stir 2 hours.After the completion of TLC monitoring reactions, reaction, ethyl acetate extraction is quenched in aqueous ammonium chloride solution
Take, organic layer is spin-dried for and excessively quick silicagel column purifies to obtain solid 13.79kg, yield 93.9%.
Through Mass Spectrometer Method, ESI/MS：M/z=322.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin.
Second step：The synthesis of 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins
4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin (12kg, 31.79mmol)
Added with Raney's nickel (1.87kg, 31.79mmol) in isopropanol (60L), reaction solution back flow reaction is cooled to room temperature after 5 hours.
Raney's nickel is filtered, solution is spin-dried for obtaining solid 10.91kg, yield 94.95%.
Through Mass Spectrometer Method, ESI/MS：M/z=306.3 [MH]+, it is 4- (6- trimethyl-acetyls -3- to determine the solid
Pyridine radicals)-N- t-butoxycarbonylpiperidins.
3rd step：The synthesis of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins (10kg, 27.66mol) are added into 5N
In the mixed solution of lithium hydroxide aqueous solution (38.73L, 193.65mol) and isopropanol (38.73mL), return stirring 20 is reacted
Minute, solution is extracted with ethyl acetate after being cooled to room temperature, and organic layer merges, dries, filters, being spin-dried for and to obtain white solid
7.06kg,HPLC:99.3%, yield 92.05%.
The total recovery of three-step reaction：82%.
Comparative example 1 (literature examples)
The synthetic route reported in document WO201324078A1 is as follows：
The first step, prepare 6- nitros -3', 6'- dihydro -2'- hydrogen-[3,4'] bipyridyl -1'- t-butyl carbonates
By the bromo- 2- nitropyridines (6.56g, 32.3mmol, Eq=1) of 5- and 4- (4,4,5,5- tetramethyl -1,3,2- dioxies
Miscellaneous borine -2- bases) (2- the hydrogen)-t-butyl formate of -5,6- dihydropyridines -1 (10g, 32.3mmol, Eq=1) is added to equipped with two
In the flask of the ring of oxygen six (160mL), a yellow solution is formed.By cesium carbonate (21.1g, 64.7mmol, Eq=2) and water
(6mL) is added in the solution and is added two (triphenylphosphine) palladium chlorides (2.27g, 3.23mmol, Eq=0.1) after the displacement of argon gas.
Reactant mixture is heated to 80 DEG C and stirred 15 hours.Reaction solution is poured into 500mL water and is extracted with ethyl acetate, and organic layer is used
Salt water washing, magnesium sulfate are dried, and filtering, are spin-dried for, excessively quick silicagel column obtains pink solid after purification.The solid is beaten with ether
Slurry, obtains 2.2g products after filtering.
Second step, prepare 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
By 6- nitros -3', 6'- dihydro -2'- hydrogen-[3,4'] bipyridyl -1'- t-butyl carbonates (4.9g, 16.0mmol,
Eq=1.00) add in ethanol (300mL) and ethyl acetate (75mL), then add palladium carbon (1.32g, 1.24mmol, Eq=
0.0773).Reactant mixture is replaced 2 times with hydrogen, is reacted overnight under hydrogen.LC/MS confirms that reaction is completed the protection of nitrogen and descended
Filter and wash filter cake with ethyl acetate.Filtrate is spin-dried for obtaining product.
Comparative example 2 (literature examples)
Reported in document JournalofMedicinalChemistry, 2010, vol.53, #22p.7938-7957
Synthetic route is as follows：
The first step：Prepare 6- amino -3', 6'- dihydro -2'- hydrogen-[3,4'] bipyridyl -1'- t-butyl carbonates
The bromo- PAs of 5- (26,0.67g, 3.9mmol) and 4- (4,4,5,5- tetramethyl -1,3,2- dioxa boron
Alkane -2- bases) (2- the hydrogen)-t-butyl formate of -5,6- dihydropyridines -1 (27,1.20g, 3.9mmol) mixture in add four (three
Phenylphosphine) palladium (0.45g, 0.39mmol) and potassium fluoride/alchlor (3.6g)；Reactant mixture deaerates 0.5 hour and heated
Reacted 2 hours to 100 DEG C.Reactant mixture is diluted with ethyl acetate, and filtering, filter cake is washed with ethyl acetate.Filtrate sulfuric acid
Sodium is dried, and filtering is spin-dried for, and excessively quick silicagel column obtains brown solid 6- amino -3', 6'- dihydro -2'- hydrogen-[3,4'] bipyridyls -
1'- t-butyl carbonates (0.75g, 70%).
Second step, prepare 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates
10% palladium carbon (0.2g) is added into 6- amino -3', 6'- dihydro -2'- hydrogen-[3,4'] bipyridyl -1'- carbonic acid uncles
In ethanol (20mL) solution of butyl ester (0.75g, 2.7mmol), reaction solution hydrogenation 16 hours, reaction under hydrogen balloon effect
Mixture is filtered, and filter cake is eluted with ethanol (2-10mL).Filtrate is spin-dried for and excessively quick silicagel column obtain solid 4- (6- aminopyridines-
3- yls) piperidines -1- t-butyl formates (0.45g, 60%).
Claims (9)
- A kind of 1. preparation method of 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, it is characterised in that：From N- (5- Bromo- pyridine -2-) -2,2- dimethylpropionamides set out, successively by addition reaction, reduction reaction, deprotection reaction three-step reaction After obtain 4- (6- aminopyridine -3- bases) piperidines -1- t-butyl formates；Reaction equation is as follows：
- 2. according to the preparation method of a kind of 4- of claim 1 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：First step addition reaction, operation are as follows：Under ultralow temperature, n-BuLi is added into N- (the bromo- pyridine -2- of 5-) -2, In 2- dimethylpropionamide solution, N- tertbutyloxycarbonyl -4- piperdinones are then added, 4- (6- front threes are obtained after reaction Base acetylaminohydroxyphenylarsonic acid 3- pyridine radicals) -4- hydroxy-ns-t-butoxycarbonylpiperidin.
- 3. according to the preparation method of a kind of 4- of claim 2 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：In first step addition reaction, N- (the bromo- pyridine -2- of 5-) -2,2- dimethylpropionamides, n-BuLi and N- tertiary butyloxycarbonyls The molar feed ratio example of base -4- piperidones is 1：2.5-3.5：1-1.2.
- 4. according to the preparation method of a kind of 4- of claim 2 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：In first step addition reaction, reaction solution is selected from diethyl ether solution, tetrahydrofuran solution, 2- methyltetrahydrofurans solution, just Any combination of hexane solution or above-mentioned solution.
- 5. according to the preparation method of a kind of 4- of claim 1 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：Second step reduction reaction, operation are as follows：4- (6- trimethyl-acetyl -3- pyridine radicals) -4- hydroxy-ns-tertiary fourth Oxygen carbonyl piperidines and Raney's nickel are added in alcoholic solvent, reaction solution back flow reaction obtain 4- (6- trimethyl-acetyl -3- pyridine radicals) - N- t-butoxycarbonylpiperidins.
- 6. according to the preparation method of a kind of 4- of claim 5 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：In second step reduction reaction, alcoholic solvent is selected from any combination of ethanol, methanol, isopropanol or above-mentioned solvent；4- (6- tri- Methylacetamido -3- pyridine radicals) molar ratio of -4- hydroxy-ns-t-butoxycarbonylpiperidin and Raney's nickel is 1:1-1.5.
- 7. according to the preparation method of a kind of 4- of claim 1 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：3rd step deprotection reaction, operation are as follows：By 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- tertiary butyloxycarbonyls Phenylpiperidines are added in alkali lye and organic solvent, Heating selectivity deprotection reaction, obtain 4- (6- aminopyridine -3- bases) piperidines - 1- t-butyl formate products.
- 8. according to the preparation method of a kind of 4- of claim 7 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, its feature It is：In 3rd step deprotection reaction, the alkali lye is that sodium hydrate aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide are water-soluble Any combination of liquid or above-mentioned aqueous alkali；Organic solvent is selected from methanol, ethanol or isopropanol.
- 9. according to the preparation method of a kind of 4- of claim 7 or 8 (6- aminopyridine -3- bases) piperidines -1- t-butyl formates, it is special Sign is：In 3rd step deprotection reaction, 4- (6- trimethyl-acetyl -3- pyridine radicals)-N- t-butoxycarbonylpiperidins, alkali lye Molar ratio be 1：5-10；Reaction dissolvent is methanol.
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| WO2020253865A1 (en) * | 2019-06-21 | 2020-12-24 | 甘李药业股份有限公司 | Methods for preparing cdk4/6 inhibitor and salt and intermediate thereof |
| CN112608299A (en) * | 2020-12-24 | 2021-04-06 | 山东铂源药业有限公司 | Synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate |
| CN114364668B (en) * | 2019-06-21 | 2024-07-16 | 甘李药业股份有限公司 | CDK4/6 inhibitors, and salts and intermediates thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020253865A1 (en) * | 2019-06-21 | 2020-12-24 | 甘李药业股份有限公司 | Methods for preparing cdk4/6 inhibitor and salt and intermediate thereof |
| CN114364668A (en) * | 2019-06-21 | 2022-04-15 | 甘李药业股份有限公司 | CDK4/6 inhibitors, salts and intermediates thereof |
| CN114364668B (en) * | 2019-06-21 | 2024-07-16 | 甘李药业股份有限公司 | CDK4/6 inhibitors, and salts and intermediates thereof |
| CN110540535A (en) * | 2019-10-23 | 2019-12-06 | 上海再启生物技术有限公司 | process suitable for preparing 4- (6-aminopyridin-3-yl) substituted piperidine in amplification way |
| CN112608299A (en) * | 2020-12-24 | 2021-04-06 | 山东铂源药业有限公司 | Synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate |
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