CN110407841A - A kind of synthetic method of anti-tumor drug Rui Boxini - Google Patents
A kind of synthetic method of anti-tumor drug Rui Boxini Download PDFInfo
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Abstract
The present invention relates to the synthetic methods of anti-tumor drug Rui Boxini a kind of.This method is specifically included that 4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate and the chloro- 7- cyclopenta-N of 2-, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide reacts under the action of catalyst, extraction, boil off solvent, recrystallization, by obtained 4- [6- [[7- cyclopenta -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine -2-base] -3- pyridyl group] -1- piperazinyl t-butyl formate is stirred to react in hydrochloric acid solution, Rui Boxini is made.The preparation method is easy to operate, and high income, reaction route is short, and the three wastes are few, easy to industrialized production.
Description
Technical field
The invention belongs to the synthesis field of anti-tumor drug, in particular to a kind of synthesis side of anti-tumor drug Rui Boxini
Method.
Background technique
Rui Boxini (Ribociclib, I), chemical name are as follows: 7- cyclopenta-N, N- dimethyl -2- [[5- (1- piperazine) -2-
(pyridyl group) amino] -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (7-cyclopentyl-N, N-dimethyl-2- [[5-
(1-piperazinyl)-2-pyridinyl]amino]-7H-Pyrrolo[2,3-d]pyrimidine-6-
Carboxamide), molecular formula: C23H30N8O, CAS registration number: 1211441-98-3.This product is a kind of novel targeted small molecule medicine
Object, alternative inhibit cell cycle protein dependent kinase 4/6 (CDK4/6) activity, reduce breast cancer cell line proliferation and
Play antitumor action.Clinical research confirmation, compared with being applied alone Letrozole to treat, Rui Boxini can prolong with Letrozole drug combination
Long patient's progression free survival phase.Therefore, which obtains the breakthrough drug identification of FDA and lists in approval on March 13rd, 2017,
Trade name Kisqali, oral dose is 600mg (3, every 200mg) once a day, is discontinued 1 week after treatment 3 weeks.It removes
Outside independent oral medication breast cancer, Rui Boxini can also be shared with endocrine therapeutic agents such as Letrozole etc., it is shown that collaboration
Therapeutic effect.Ribociclib can swash with Aromatase Inhibitor Combination as initial endocrine class therapeutic scheme for post menopausal
In plain receptor positive, human epidermal growth factor acceptor -2 negative advanced stage or metastatic breast cancer female patient, have preferable
Application prospect.
In view of the beneficial therapeutic effect in Rui Boxini clinic for breast cancer, therefore synthesis technology is carried out to it and is ground
Study carefully, reduces production cost and be of great significance.
Anti- synthesis analysis is carried out according to the structure feature of Rui Boxini and to it, the study found that Rui Boxini is segmented into
Chloro- 7- cyclopenta -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (II) of N, N- dimethyl -2- and 5- piperazinyl -2- amino pyrrole
Pyridine (III) two parts (structural formula is as follows) (Poratti, M.;Marzaro,G.Third-generation CDK
inhibitors:A review on the synthesis and binding modes of Palbociclib,
Ribociclib and Abemaciclib,European Journal of Medicinal Chemistry,2019,172,
143-153;Deng Yuxiao, Ren Yeming Sun Jinrui Duan Chonggang woods control the secret Li Danfeng light tinkling of pieces of jade, Ribociclib succinate synthetic route
Diagram, Chinese Journal of New Drugs, 2019,28 (6): 677-682).The chloro- 7- cyclopenta -7H- pyrrolo- of wherein N, N- dimethyl -2-
[2,3] pyrimidine -6- formamide (II) is the key intermediate for synthesizing Rui Boxini.
Current N reported in the literature, chloro- 7- cyclopenta -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of N- dimethyl -2-
(II) there are mainly four types of synthetic methods:
Method one: 2, the chloro- 5- Bromopyrimidine (1) of 4- bis- are reacted with cyclopentamine (2), generate the chloro- 4- of the bromo- 2- of N- cyclopenta -5-
Aminopyrimidine (3) then coupling reaction occurs with propilolic alcohol (4) under the action of triphenylphosphine palladium and obtains compound
(5), cyclization obtains compound (6) under the action of tetrabutyl ammonium fluoride, most generates afterwards through Cymag and manganese dioxide effect are lower
Cyanalcohol (7) finally reacts to obtain chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- of 2- with dimethylamine
Formamide (II), yield 23%, reaction equation is as follows.(Brain,C.T.;Cho,Y.S.;Giralde,J.W..;Lagu,
B.;Levell,J.;Luzzio,M.;Perez,L.B.;Wang,Y.;Yang,F.Pyrrolopyrimidine compounds
As inhibitors at CDK4/6, WO2011101409,2011)
The chloro- 4- aminopyrimidine (3) of two: the N- bromo- 2- of cyclopenta -5- of method and 3,3- dimethoxy propine (8) are in triphenyl
The lower coupling of phosphine dichloride palladium effect obtains compound (9), and cyclization obtains compound (10) under tetrabutyl ammonium fluoride effect, hydrochloric acid
Hydrolysis of acetals obtains compound (11).It is aoxidized through Oxone and chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine -6- formic acid (12) of 2-, In is made
It reacts to obtain chloro- 7- the cyclopenta-N, N- bis- of 2- with dimethylamine (13) under the action of condensing agent HBTU, diisopropyl ethyl amine
Methyl -7H- pyrrolo- [2,3] pyrimidine -6- formamide (II), yield 20%.(Besong,G.;Brain,C.T.;Brook,
C.A.;Congreve,M.S.;Dagostin,C.;He,C.;Hou,Y.;Howard,S.;Li,Y.;Lu,Y.;Mortenson,
P.;Smith,T.;Sung,M.;Woodhead,S.;Wrona,W.Pyrrolopyrimidine compounds as CDK
inhibitors,WO2010020675,2010;) 2017 years Wang etc. also report it is phonetic by the chloro- 7H- pyrrolo- [2,3-d] of 2-
Pyridine -6- formic acid (12) is reacted with thionyl chloride first generates acyl chlorides, and the amide preparation chloro- 7- ring penta of 2- is then reacted into dimethylamine
Base-N, N- dimethyl -7H- pyrrolo- [2,3] pyrimidine -6- formamide (II).(Wang,L.;Zheng,L.;Kong,X.;
Concise synthesis of pyrrolo[2,3-d]pyri-midine derivatives vis the Cu-
catalyzed coupling reaction Green Chemistry Letters and Reviews,2017,10(1):
42-47.)
Method three: Chinese patent CN106478641 discloses the novel synthesis of Rui Boxini intermediate, this method packet
Include: the chloro- 4- aminopyrimidine (3) of the bromo- 2- of N- cyclopenta -5- and N, N- dimethyl propylene alkynyl amide (14) are in triphenylphosphine palladium
Under the action of occur coupled reaction obtain compound (15), in the presence of stannous chloride and DBU occur cyclization be made the chloro- 7- ring of 2-
Amyl-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (II), two-step reaction yield 65%, reaction equation
It is as follows.
In above-mentioned synthetic method, method one and two reaction step of method are longer, starting material propilolic alcohol and 3,3- diformazan
Oxygroup propine price is more expensive, and three reaction step of method is shorter, but N is not provided in document, the preparation of N- dimethyl propylene alkynyl amide
Method, and N, N- dimethyl propylene alkynyl amide does not have a large amount of supply of commodities, and the triphenylphosphine two more expensive using price yet
Palladium chloride, high production cost.Therefore, synthetic method easy to operate, production cost is low is found, to reduction production cost and industry
Metaplasia production is of great significance.
About the synthesis of Rui Boxini, Chinese patent CN105384741 discloses chloro- by intermediate (19) and intermediate 2-
7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide (II) is acted in palladium acetate and ligand BINAP
Lower to be coupled, Rui Boxini, two step yields are made in the Boc protecting group that compound (20) is then sloughed in hydrochloric acid toluene solution
50%.
Patent WO2017211245 is disclosed under acetic acid palladium chtalyst with CsCO3Deng for alkali, change under organophosphite ligand effect
It closes object (19) and compound (II) coupling and obtains compound (20).
Chinese patent CN109553621 is disclosed in LiHMDS (Me2Si)2NHLi acts on lower compound (19) and compound
(II) coupling synthesis compound (20), yield 54% in toluene.
In the above-mentioned synthetic method for preparing Rui Boxini, prepare compound (20) is needed using the transition such as palladium acetate gold
Belong to, and palladium is heavy metal, is more toxic, and highly basic LiHMDS price is costly, needs stringent waterless operation, studies its conjunction
It is of great significance at method.
Summary of the invention
Technical problem to be solved by the invention is to provide the synthetic methods of anti-tumor drug Rui Boxini a kind of, to overcome
Transition metal palladium, step complexity, defect at high cost are used in the synthesis of prior art China and Sweden Bo Xini.
In Chinese patent CN106478641 (see synthetic method three), Sonogashi is coupled cyclization reaction and needs two steps
It carries out, it is cumbersome.In view of propine amide terminal alkynes can with mantoquita act on generate alkynes copper, and ligand tetramethylethylenediamine and
Contain 2 N atoms in the structures such as N, N- diphenyloxalic acid diamide, stabilization, N, N- can be played to alkynes copper with cupric coordination
Dimethyl propylene alkynyl amide occurs to react similar to Sonogashi with the chloro- 4- aminopyrimidine of the bromo- 2- of N- cyclopenta -5-, then alkynyl
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2- is obtained with direct one step of cyclization of amino
(II), reaction step is shortened, experimental implementation is simplified.By chloro- 7- cyclopenta-N, the N- dimethyl -7H- pyrrolo- [2,3-d] of 2-
The mistake of coupling reaction occurs for pyrimidine -6- formamide (II) and 4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate (19)
Cheng Zhong, it is contemplated that sodium iodide etc. in chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
Chlorine atom, which reacts, generates iodo- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-, increases
The reactivity of chlorine then (mainly uses Cu under CuCl catalysis+Catalysis) obtained-[6- [[7- ring penta is reacted in DMSO
Base -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine -2-base] -3- pyridyl group] -1- piperazinyl t-butyl formate
(20), it avoids using reagents such as expensive palladium acetates, reduces production cost, it is easy to industrialized production.
The present invention provides the synthetic method of anti-tumor drug Rui Boxini a kind of, comprising the following steps:
(1) N,N-DMAA and bromine are added in solvent with molar ratio for 1:1.0~1.5, electrophilic addition
Reaction, washing, evaporates solvent, obtains N, N- dimethyl -2,3- dibromo propionamide;
(2) by N in step (1), N- dimethyl -2,3- dibromo propionamide and alkali are dissolved in solvent with molar ratio 1:1.0~1.5
Middle reaction, extraction, evaporates solvent, purifies, obtains N, N- dimethyl propylene alkynyl amide;
(3) by N in step (2), N- dimethyl propylene alkynyl amide is being catalyzed with the chloro- 4- aminopyrimidine of the bromo- 2- of N- cyclopenta -5-
It is reacted under agent, additive, alkali and solvent condition, extracts, evaporate solvent, purified, obtain chloro- 7- cyclopenta-N, the N- dimethyl-of 2-
7H- pyrrolo- [2,3-d] pyrimidine -6- formamide, wherein N, the chloro- 4- ammonia of N- dimethyl propylene alkynyl amide, the bromo- 2- of N- cyclopenta -5-
Yl pyrimidines, catalyst, additive and alkali molar ratio be 1:0.5~2.0:0.2~1.0:0.2~1.0:1.0~2.0, N, N-
The ratio of dimethyl propylene alkynyl amide and solvent is 1g:2~20mL, and additive is tetramethylethylenediamine or N, N- diphenyl oxalic acid two
Amide;
(4) by chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine-the 6- formamide of 2- in step (3),
4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate, catalyst, additive and alkali is with molar ratio for 1.0~1.5:
1.0:0.2~1.0:0.2~1.0:1.0~1.2 are reacted in a solvent, and extraction evaporates solvent, are recrystallized, are obtained 4- [6- [[7-
Cyclopenta -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine -2-base] -3- pyridyl group] the tertiary fourth of -1- piperazinyl formic acid
Ester, wherein the ratio of 4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate and solvent is 1g:2~20mL;
(5) 4- will be obtained in step (4), and [[[7- cyclopenta -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] is phonetic by 6-
Pyridine -2- base] -3- pyridyl group] -1- piperazinyl t-butyl formate is stirred to react in hydrochloric acid solution, adjusts pH to 8~9, it is precipitated,
Obtain Rui Boxini.
Solvent includes toluene or chloroform in the step (1).
Electrophilic addition reaction in the step (1) are as follows: be stirred to react 2~4h at room temperature.
Alkali is potassium tert-butoxide, sodium tert-butoxide or Sodamide in the step (2);Solvent is tetrahydrofuran or toluene.
Reaction in the step (2) are as follows: reacted 1~10 hour under room temperature~solvent for use reflux temperature.
The step (1), (2), (3) middle purifying are using recrystallization, and step (2) is using petroleum ether recrystallization, step
It (3) is using ethyl alcohol recrystallization.
Catalyst includes stannous chloride, cuprous bromide, cuprous iodide or nickel chloride in the step (3).
Alkali is potassium carbonate in the step (3);Solvent is dimethyl sulfoxide or N,N-dimethylformamide.
The step (3), reaction in (4) are as follows: react 12 at 80~100 DEG C~for 24 hours.
Catalyst is stannous chloride, cuprous bromide or cuprous iodide in the step (4);Solvent is that ethyl alcohol or dimethyl are sub-
Sulfone.
The step (4) is recrystallized using isopropyl ether.
The solvent of hydrochloric acid solution is ethyl alcohol or acetone in the step (5).
It is stirred to react in the step (5) are as follows: 3~8h of reaction is stirred at room temperature.
The synthesis equation of anti-tumor drug Rui Boxini is as follows in the present invention:
The structural formula of China and Sweden Bo Xini of the present invention are as follows:
Fusing point: 194-196 DEG C;Character: faint yellow solid.
The hydrogen nuclear magnetic resonance modal data of anti-tumor drug Rui Boxini is as follows in the present invention:
1H NMR(400MHz,CDCl3): δ 8.75 (s, 1H), 8.37 (d, J=9.1Hz, 1H), 8.07 (t, J=4.6Hz,
1H), 7.34 (dd, J=9.1,3.0Hz, 1H), 6.45 (s, 1H), 4.84-4.77 (m, 1H), 3.17 (s, 6H), 3.13 (t, J=
4.5Hz, 4H), 3.08 (d, J=5.0Hz, 4H), 2.65-2.57 (m, 2H), 2.07 (dq, J=16.0,8.7,7.9Hz, 4H),
1.72 (q, J=5.8Hz, 2H)
The carbon-13 nmr spectra data of anti-tumor drug Rui Boxini are as follows in the present invention:
13C NMR(101MHz,CDCl3):δ164.13,154.71,151.97,151.92,146.95,143.00,
136.90,131.83,126.58,112.49,112.43,101.06,57.89,51.24,46.08,30.13,24.70,
18.47.
Beneficial effect
The present invention uses N, and N- dimethylacrylamide is that raw material is passed through with bromine generation electrophilic addition, in potassium tert-butoxide effect
N is made in lower eliminate, N- dimethyl propylene alkynyl amide, then the stannous chloride and tetramethylethylenediamine the effects of under with N- cyclopenta-
The chloro- 4- aminopyrimidine of the bromo- 2- of 5- through coupling cyclization one-step method preparation chloro- 7- cyclopenta-N, N- dimethyl-the 7H- pyrrolo- of 2- [2,
3-d] pyrimidine -6- formamide, three-step reaction total recovery 45%, yield is higher.Reaction is shortened compared with patent CN106478641
Step simplifies experimental implementation.By chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
With 4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate under CuCl catalysis, sodium iodide is added,-[6- [[7- is made
Cyclopenta -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine -2-base] -3- pyridyl group] the tertiary fourth of -1- piperazinyl formic acid
Ester avoids the use of expensive palladium acetate, and this method equally reduces production cost, is easy to three-protection design and industrialization
Production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of compound Rui Boxini in the present invention.
Fig. 2 is the carbon-13 nmr spectra of compound Rui Boxini in the present invention.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
N, N- dimethylacrylamide, bromine and N, N- diphenyloxalic acid diamide (also known as oxanilide) etc. are purchased from Aladdin
Reagent (Shanghai) Co., Ltd.;Potassium tert-butoxide, sodium tert-butoxide, stannous chloride, cuprous bromide, cuprous iodide, nickel chloride, tetramethyl
Ethylenediamine etc. is purchased from Sinopharm Chemical Reagent Co., Ltd..The chloro- 4- aminopyrimidine of the bromo- 2- of N- cyclopenta -5-, 4- (6- amino -
3- pyridyl group) -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester etc. is purchased from smooth Science and Technology Ltd. of upper Haitai etc..
The nuclear-magnetism of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2- in the present invention
The hydrogen modal data that resonates is as follows:
1H NMR(400MHz,CDCl3): δ 8.81 (d, J=4.3Hz, 1H), 6.54 (d, J=3.0Hz, 1H), 4.90 (s,
1H), 3.18 (d, J=8.2Hz, 3H), 3.10 (d, J=5.1Hz, 3H), 2.43-2.32 (m, 2H), 2.11 (d, J=5.7Hz,
4H), 1.71 (d, J=8.3Hz, 2H)
The nuclear-magnetism of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2- in the present invention
The carbon modal data that resonates is as follows:
13C NMR(101MHz,CDCl3):δ163.33,153.60,152.09,151.81,135.42,117.09,
99.73,77.29,77.08,76.87,57.88,39.22,35.13,31.01,24.76.
Embodiment 1
The synthesis of N, N- dimethyl -2,3- dibromo propionamide
N,N-DMAA (30.0g, 0.30mol) is dissolved in 200 milliliters of toluene, bromine is added dropwise at room temperature
(50.4g, 0.30mol) is dripped off for 30 minutes, and room temperature continues to be stirred to react 2h, and toluene layer is with water (100mL × 2) after reaction
It washes, anhydrous sodium sulfate is dry, and decompression boils off toluene and obtains white solid 73.5g, yield: 95%.
Embodiment 2
The synthesis of N, N- dimethyl -2,3- dibromo propionamide
N,N-DMAA (45.0g, 0.45mol) is dissolved in 250 milliliters of chloroform, bromine is added dropwise at room temperature
(108.0g, 0.68mol) is dripped off for 30 minutes, and room temperature continues to be stirred to react 2h, and toluene layer is with water (100mL × 2) after reaction
It washes, anhydrous sodium sulfate is dry, and decompression boils off chloroform and obtains white solid 106.0g, yield: 92%.
Embodiment 3
The synthesis of N, N- dimethyl propylene alkynyl amide
The N that will be prepared in embodiment 1, N- dimethyl -2,3- dibromo propionamide (40.0g, 0.16mol) are dissolved in 200mL tetra-
In hydrogen furans, ice bath is cooled to 0 DEG C, and potassium tert-butoxide (18.0g, 0.16mol) is added portionwise, and adds within 30 minutes, be warmed to room temperature after
Continuous to be stirred to react 2h, reaction is finished, and decompression boils off tetrahydrofuran, is added 100 milliliters and 100 milliliters of water of methylene chloride, is stirred 5min,
Organic layer is separated, anhydrous sodium sulfate is dry, and decompression steaming vibrating dichloromethane obtains white solid 10.6g, yield: 68%, mp:67~70
℃。
Embodiment 4
The synthesis of N, N- dimethyl propylene alkynyl amide
The N that will be prepared in embodiment 1, N- dimethyl -2,3- dibromo propionamide (51.4g, 0.20mol) are dissolved in 200mL tetra-
In hydrogen furans, ice bath is cooled to 0 DEG C, and sodium tert-butoxide (19.2g, 0.20mol) is added portionwise, and adds within 30 minutes, be warmed to room temperature after
Continuous to be stirred to react 2h, reaction is finished, and decompression boils off tetrahydrofuran, is added 100 milliliters and 100 milliliters of water of methylene chloride, is stirred 5min,
Organic layer is separated, anhydrous sodium sulfate is dry, and decompression steaming vibrating dichloromethane obtains white solid 14.2g, yield: 73%, mp:69~71
℃。
Embodiment 5
The synthesis of N, N- dimethyl propylene alkynyl amide
The N that will be prepared in embodiment 2, N- dimethyl -2,3- dibromo propionamide (51.4g, 0.20mol) are dissolved in 200mL first
In benzene, ice bath is cooled to 0 DEG C, and potassium tert-butoxide (26.9g, 0.24mol) is added portionwise, and adds within 30 minutes, is warmed to room temperature and continues to stir
Reaction 2h is mixed, reaction is finished, and decompression boils off toluene, is added 100 milliliters and 200 milliliters of water of methylene chloride, is stirred 5min, separate organic
Layer, anhydrous sodium sulfate is dry, and decompression steaming vibrating dichloromethane obtains white solid 14.2g, yield: 73%, mp:69~71 DEG C.
Embodiment 6
The synthesis of N, N- dimethyl propylene alkynyl amide
The middle N that will be prepared in embodiment 2, N- dimethyl -2,3- dibromo propionamide (51.4g, 0.20mol) are dissolved in 200mL
In toluene, ice bath is cooled to 0 DEG C, and Sodamide (11.7g, 0.30mol) is added portionwise, and adds within 30 minutes, is warmed to room temperature and continues to stir
Reaction 10h is mixed, reaction is finished, and decompression boils off toluene, is added 100 milliliters and 200 milliliters of water of methylene chloride, is stirred 5min, separated
Machine layer, anhydrous sodium sulfate is dry, and decompression steaming vibrating dichloromethane obtains white solid 10.9g, yield: 56%, mp:69~71 DEG C.
Embodiment 7
The synthesis of N, N- dimethyl propylene alkynyl amide
The N that will be prepared in embodiment 2, N- dimethyl -2,3- dibromo propionamide (77.1g, 0.30mol) are dissolved in 500mL first
In benzene, ice bath is cooled to 0 DEG C, and potassium tert-butoxide (50.4g, 0.45mol) is added portionwise, and adds within 40 minutes, is warmed to room temperature and continues to stir
Reaction 3h is mixed, reaction is finished, and decompression boils off toluene, is added 250 milliliters and 200 milliliters of water of methylene chloride, is stirred 5min, separate organic
Layer, anhydrous sodium sulfate is dry, and decompression steaming vibrating dichloromethane obtains white solid 18.1g, yield: 62%, mp:69~71 DEG C.
Embodiment 8
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 3, N- dimethyl propylene alkynyl amide (9.7g, 0.1mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (27.5g, 0.1mol), stannous chloride (1.98g, 0.02mol), tetramethylethylenediamine (2.32g, 0.02mol)
It is added in 250mL eggplant type bottle with potassium carbonate (13.8g, 0.1mol), DMSO (150mL) is added and is stirred to react at 90~100 DEG C
12h, reaction are finished, and 200 milliliters of water are added.Reaction solution is extracted with ethyl acetate (150mL × 3), ethyl acetate layer saturated common salt
Water (150mL × 2) washing, ethyl acetate layer decompression boil off solvent and obtain oily liquids, and dehydrated alcohol recrystallizes to obtain white solid
20.7g, yield 71%, mp:103~105 DEG C.
Embodiment 9
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 4, N- dimethyl propylene alkynyl amide (9.7g, 0.1mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (27.5g, 0.05mol), stannous chloride (1.98g, 0.02mol), N, N- diphenyloxalic acid diamide (4.8g,
It 0.02mol) is added in 250mL eggplant type bottle with potassium carbonate (27.6g, 0.2mol), DMSO (100mL) is added at 90~100 DEG C
It is stirred to react 12h, reaction is finished, and 200 milliliters of water are added.Reaction solution is extracted with ethyl acetate (100mL × 3), and ethyl acetate layer is used
Saturated salt solution (100mL × 2) washing, ethyl acetate layer decompression boil off solvent and obtain oily liquids, and dehydrated alcohol recrystallizes white
Color solid 17.2g, yield 59%, mp:103~105 DEG C.
Embodiment 10
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 5, N- dimethyl propylene alkynyl amide (19.4g, 0.2mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (110.0g, 0.4mol), cuprous iodide (1.90g, 0.1mol), tetramethylethylenediamine (4.5g, 0.4mol) and
Potassium carbonate (27.6g, 0.2mol) is added DMSO (200mL) and is stirred to react at 90~100 DEG C for 24 hours, and reaction is finished, and 200 millis are added
Rise water.Reaction solution is extracted with ethyl acetate (200mL × 3), and ethyl acetate layer is washed with saturated salt solution (150mL × 2), is depressurized
It boils off solvent and obtains oily liquids, dehydrated alcohol recrystallizes to obtain white solid 30.9g, yield 53%, mp:103~105 DEG C.
Embodiment 11
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 6, N- dimethyl propylene alkynyl amide (9.7g, 0.1mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (27.5g, 0.05mol), stannous chloride (1.98g, 0.02mol), N, N- diphenyloxalic acid diamide (4.8g,
0.02mol) DMSO (100mL) is added and is stirred to react 12h at 90~100 DEG C with potassium carbonate (13.8g, 0.1mol), reaction is finished,
200 milliliters of water are added.Reaction solution is extracted with ethyl acetate (100mL × 3), and ethyl acetate layer is with saturated salt solution (100mL × 2)
Washing, ethyl acetate layer decompression boil off solvent and obtain oily liquids, dehydrated alcohol recrystallize white solid 17.2g, yield are
59%, mp:103~105 DEG C.
Embodiment 12
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 7, N- dimethyl propylene alkynyl amide (19.4g, 0.2mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (70.1g, 0.24mol), cuprous bromide (28.6g, 0.2mol), N, N- diphenyloxalic acid diamide (9.6g,
0.04mol) DMSO (100mL) is added and is stirred to react 12h at 90~100 DEG C with potassium carbonate (27.4g, 0.2mol), reaction is finished,
200 milliliters of water are added.Reaction solution is extracted with ethyl acetate (100mL × 3), and ethyl acetate layer is with saturated salt solution (100mL × 2)
Washing, ethyl acetate layer decompression boil off solvent and obtain oily liquids, dehydrated alcohol recrystallize white solid 34.5g, yield are
59%, mp:103~105 DEG C.
Embodiment 13
The synthesis of chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of 2-
The N that will be prepared in embodiment 7, N- dimethyl propylene alkynyl amide (19.4g, 0.2mol), the bromo- 2- of N- cyclopenta -5- are chloro-
4- aminopyrimidine (70.1g, 0.24mol), nickel chloride (5.16g, 0.04mol), tetramethylethylenediamine (2.23g, 0.2mol) and
Potassium carbonate (27.4g, 0.2mol) is added DMSO (100mL) and is stirred to react 12h at 90~100 DEG C, and reaction is finished, and 200 millis are added
Rise water.Reaction solution is extracted with ethyl acetate (100mL × 3), and ethyl acetate layer is washed with saturated salt solution (100mL × 2), acetic acid
Methacrylate layer decompression boils off solvent and obtains oily liquids, and dehydrated alcohol recrystallizes to obtain white solid 29.8g, yield 51%, mp:103
~105 DEG C.
Embodiment 14
4- [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3] pyrimidine -2-base] amino] -3-
Pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester synthesis
By 4- (6- amino -3- pyridyl group) -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (13.9g, 0.05mol) is implemented
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of the 2- prepared in example 8 (14.6g,
0.05mol), cuprous iodide (1.90g, 0.01mol), sodium iodide (7.5g, 0.05mol) and potassium carbonate (7.9g, 0.05mol) add
Enter ethyl alcohol (100mL) and be stirred at reflux reaction 12h, reaction is finished, filtered while hot, and filtrate is cooling, obtains faint yellow solid, dehydrated alcohol weight
Crystallize to obtain white solid 22.1g, yield 83%, mp:215~217 DEG C.
Embodiment 15
4- [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3] pyrimidine -2-base] amino] -3-
Pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester synthesis
4- (6- amino -3- pyridyl group) -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (22.3g, 0.08mol), embodiment 9
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of the 2- of middle preparation (23.4g,
0.08mol), stannous chloride (1.98g, 0.02mol), sodium iodide (5.1g, 0.034mol) and potassium carbonate (11.1g, 0.08mol)
Ethyl alcohol (300mL) is added and is stirred at reflux reaction 12h, reaction is finished, filtered while hot, and filtrate is cooling, obtains faint yellow solid, dehydrated alcohol
Recrystallize to obtain white solid 23.9g, yield 56%, mp:215~217 DEG C.
Embodiment 16
4- [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3] pyrimidine -2-base] amino] -3-
Pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester synthesis
4- (6- amino -3- pyridyl group) -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (13.9g, 0.05mol), embodiment
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of the 2- prepared in 10 (14.6g,
0.05mol), cuprous bromide (1.43g, 0.01mol), sodium iodide (1.50g, 0.01mol) and potassium carbonate (8.3g, 0.06mol)
Ethyl alcohol (200mL) is added and is stirred at reflux reaction 12h, reaction is finished, filtered while hot, and filtrate is cooling, obtains faint yellow solid, dehydrated alcohol
Recrystallize to obtain white solid 19.3g, yield 72%, mp:214~216 DEG C.
Embodiment 17
4- [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3] pyrimidine -2-base] amino] -3-
Pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester synthesis
4- (6- amino -3- pyridyl group) -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (27.8g, 0.10mol), embodiment
Chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine -6- formamide of the 2- prepared in 12 (43.8g,
0.15mol), stannous chloride (9.9g, 0.10mol), sodium iodide (15.0g, 0.10mol) and potassium carbonate (13.8g, 0.10mol)
Dimethyl sulfoxide (250mL) is added and stirs 100 DEG C of reaction 12h, reaction is finished, and 200 milliliters of water are added.Reaction solution ethyl acetate
(100mL × 3) extraction, ethyl acetate layer are washed with saturated salt solution (100mL × 2), and ethyl acetate layer decompression boils off solvent and obtains
Faint yellow solid, dehydrated alcohol recrystallize to obtain white solid 21.8g, yield 61%, mp:215~217 DEG C.
Embodiment 18
The synthesis of Rui Boxini
By the 4- prepared in embodiment 15 [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3]
Pyrimidine -2-base] amino] -3- pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (10.7g, 0.02mol) be dissolved in 200 milli
It rises in ethyl alcohol, is added 10 milliliters of 3N hydrochloric acid, reaction 4h is stirred at room temperature.Reaction is finished, and the reaction of 10% sodium hydrate aqueous solution tune is added dropwise
Liquid pH to 8~9, decompression boil off ethyl alcohol, filter to obtain faint yellow solid, acetone recrystallization obtains white solid 7.0g, yield: 81%.
Embodiment 19
The synthesis of Rui Boxini
By the 4- prepared in embodiment 16 [6- [(7- cyclopenta) -6- [(dimethylamino) carbonyl] -7H- pyrrolo- [2,3]
Pyrimidine -2-base] amino] -3- pyridyl group] -1- piperazinecarboxylic acid 1,1- dimethyl ethyl ester (8.0g, 0.015mol) is dissolved in 120mL
In acetone, 5 milliliters of 3N hydrochloric acid are added, reaction 6h is stirred at room temperature.Reaction is finished, and decompression boils off acetone, adds water 100mL, with 10% hydrogen
Aqueous solution of sodium oxide tune reaction solution pH to 8~9 filters to obtain faint yellow solid, and acetone recrystallization obtains white solid 4.7g, yield:
72%.
Claims (9)
1. a kind of synthetic method of anti-tumor drug Rui Boxini, comprising the following steps:
(1) N,N-DMAA and bromine are added in solvent with molar ratio for 1:1.0~1.5, electrophilic addition occurs
Reaction, washing, evaporates solvent, obtains N, N- dimethyl -2,3- dibromo propionamide;
(2) N in step (1), N- dimethyl -2,3- dibromo propionamide and alkali are dissolved in solvent with molar ratio 1:1.0~1.5 and are stirred
Reaction is mixed, extracts, evaporates solvent, purifies, obtains N, N- dimethyl propylene alkynyl amide;
(3) by N in step (2), N- dimethyl propylene alkynyl amide and the chloro- 4- aminopyrimidine of the bromo- 2- of N- cyclopenta -5- catalyst,
It is reacted under additive, alkali and solvent condition, extracts, evaporate solvent, purified, obtain chloro- 7- cyclopenta-N, the N- dimethyl -7H- of 2-
Pyrrolo- [2,3-d] pyrimidine -6- formamide, wherein N, the chloro- 4- amino of N- dimethyl propylene alkynyl amide, the bromo- 2- of N- cyclopenta -5- are phonetic
Pyridine, catalyst, additive and alkali molar ratio be 1:0.5~2.0:0.2~1.0:0.2~1.0:1.0~2.0, N, N- diformazan
The ratio of base propine amide and solvent is 1g:2~20mL, and additive is tetramethylethylenediamine or N, two acyl of N- diphenyl oxalic acid
Amine;
(4) by chloro- 7- cyclopenta-N, N- dimethyl -7H- pyrrolo- [2,3-d] pyrimidine-the 6- formamide of 2- in step (3), 4-
(6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate, catalyst, sodium iodide and alkali is with molar ratio for 1.0~1.5:1.0:
0.2~1.0:0.2~1.0:1.0~1.2 are reacted in a solvent, and extraction evaporates solvent, are recrystallized, are obtained 4- [6- [[7- ring penta
Base -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine -2-base] -3- pyridyl group] -1- piperazinyl t-butyl formate,
Wherein the ratio of 4- (6- amino -3- pyridyl group) -1- piperazinyl t-butyl formate and solvent is 1g:2~20mL;
(5) 4- [6- [[7- cyclopenta -6- [(dimethyl) carbonyl] -7H- pyrrolo- [2,3-d] pyrimidine-will be obtained in step (4)
2- yl] -3- pyridyl group] -1- piperazinyl t-butyl formate is stirred to react in hydrochloric acid solution, adjusts pH to 8~9, and it is precipitated, obtains
Rui Boxini.
2. method according to claim 1, which is characterized in that solvent includes toluene or chloroform in the step (1);It is electrophilic
Addition reaction are as follows: be stirred to react 2~4h at room temperature.
3. method according to claim 1, which is characterized in that alkali is potassium tert-butoxide, sodium tert-butoxide or ammonia in the step (2)
Base sodium;Solvent is tetrahydrofuran or toluene.
4. method according to claim 1, which is characterized in that reaction in the step (2) are as follows: room temperature~solvent for use returns
It is reacted 1~10 hour at a temperature of stream.
5. method according to claim 1, which is characterized in that catalyst includes stannous chloride, protobromide in the step (3)
Copper, cuprous iodide or nickel chloride;Alkali is potassium carbonate;Solvent is dimethyl sulfoxide or N,N-dimethylformamide.
6. method according to claim 1, which is characterized in that reaction in the step (3) are as follows: react 12 at 80~100 DEG C
~for 24 hours.
7. method according to claim 1, which is characterized in that catalyst is stannous chloride, cuprous bromide in the step (4)
Or cuprous iodide;Solvent is ethyl alcohol or dimethyl sulfoxide.
8. method according to claim 1, which is characterized in that in the step (5) solvent of hydrochloric acid solution be ethyl alcohol or
Acetone.
9. method according to claim 1, which is characterized in that be stirred to react in the step (5) are as follows: reaction 3 is stirred at room temperature
~8h.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115850285A (en) * | 2022-11-24 | 2023-03-28 | 贵州大学 | Endoperoxide compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application |
CN117069663A (en) * | 2023-08-31 | 2023-11-17 | 四川维亚本苑生物科技有限公司 | Synthesis method of rebaudinib intermediate V and synthesis method of rebaudinib |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0519427B1 (en) * | 1991-06-20 | 1995-04-26 | Takeda Chemical Industries, Ltd. | N-substituted-3-iodopropiolamide, production and use thereof |
CN103980086A (en) * | 2014-05-16 | 2014-08-13 | 盐城师范学院 | Preparation method of 1,3-diacetylene catalytic system |
CN104478820A (en) * | 2014-12-22 | 2015-04-01 | 杭州瀚康生物医药科技有限公司 | Preparation method of rivaroxabanintermediate |
CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | The novel synthesis of Rui Boxini intermediate |
CN107936029A (en) * | 2018-01-08 | 2018-04-20 | 南京奇可药业有限公司 | A kind of method of synthesis Rui Boxini |
WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of ribociclib and its salts |
-
2019
- 2019-08-20 CN CN201910768772.2A patent/CN110407841A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0519427B1 (en) * | 1991-06-20 | 1995-04-26 | Takeda Chemical Industries, Ltd. | N-substituted-3-iodopropiolamide, production and use thereof |
CN103980086A (en) * | 2014-05-16 | 2014-08-13 | 盐城师范学院 | Preparation method of 1,3-diacetylene catalytic system |
CN104478820A (en) * | 2014-12-22 | 2015-04-01 | 杭州瀚康生物医药科技有限公司 | Preparation method of rivaroxabanintermediate |
CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | The novel synthesis of Rui Boxini intermediate |
WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of ribociclib and its salts |
CN107936029A (en) * | 2018-01-08 | 2018-04-20 | 南京奇可药业有限公司 | A kind of method of synthesis Rui Boxini |
Non-Patent Citations (2)
Title |
---|
白东虎等: "炔烃偶联反应研究的新进展", 《有机化学》 * |
薛永强: "《现代有机合成方法与技术》", 31 December 2003 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115850285A (en) * | 2022-11-24 | 2023-03-28 | 贵州大学 | Endoperoxide compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application |
CN117069663A (en) * | 2023-08-31 | 2023-11-17 | 四川维亚本苑生物科技有限公司 | Synthesis method of rebaudinib intermediate V and synthesis method of rebaudinib |
CN117069663B (en) * | 2023-08-31 | 2023-12-26 | 四川维亚本苑生物科技有限公司 | Synthesis method of rebaudinib intermediate V and synthesis method of rebaudinib |
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