CN108997214A - It is happy to cut down for Buddhist nun's intermediate and its preparation and the happy preparation cut down for Buddhist nun - Google Patents

It is happy to cut down for Buddhist nun's intermediate and its preparation and the happy preparation cut down for Buddhist nun Download PDF

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Publication number
CN108997214A
CN108997214A CN201810608772.1A CN201810608772A CN108997214A CN 108997214 A CN108997214 A CN 108997214A CN 201810608772 A CN201810608772 A CN 201810608772A CN 108997214 A CN108997214 A CN 108997214A
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chloro
cyclopropyl
formamide
water
buddhist nun
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何鹏
王学超
邓塔
何倩
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Chengdu Diao Pharmaceutical Group Co Ltd
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Chengdu Diao Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to pharmaceutical synthesis field, discloses a kind of pleasure and cut down for Buddhist nun's key intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea and its preparation and the happy preparation cut down for Buddhist nun.The pleasure is cut down for Buddhist nun's intermediate, its purity is greater than 99%, its preparation includes the following steps: (1) by cyclopropylamine and compound N, N'- carbonyl dimidazoles react in a solvent obtains N- cyclopropyl -1H- imidazoles -1- formamide, and (2) react N- cyclopropyl -1H- imidazoles -1- formamide with 4- amino -3- chlorophenol to obtain 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea.Intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea and the chloro- 7- methoxy quinoline -6- formamide of 4- are obtained final product pleasure and cut down for Buddhist nun by the present invention.The preparation method, it is easy to operate, raw material is cheap and easy to get, generate difficulty except property impurity it is less, directly adopt water and make solvent, without organic solvent, environmental pollution is small, product purity can be realized greater than 99% in simple post-process, and is a kind of method of environmentally protective economy, is suitble to large-scale industrial production.

Description

It is happy to cut down for Buddhist nun's intermediate and its preparation and the happy preparation cut down for Buddhist nun
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of pleasure is cut down for the water phase system of Buddhist nun's key intermediate It Preparation Method and its cuts down happy for the utilization in Buddhist nun's synthesis.
Background technique
Happy cut down for Buddhist nun (lenvatinib) is pressed down by a kind of oral polyceptor tyrosine kinase of Japanese Wei Cai company exploitation Preparation, has novel binding pattern, and targeting is raw in vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast The platelet-derived growth factor receptors (PDGFR) of growth factor receptor body (FGFR) 1-3, stem cell factor receptor β type. On 2 13rd, 2015 FDA ratify its listing for treating local recurrence or metastatic, keeping forging ahead, the differentiated that radioiodine is refractory Thyroid cancer；On May 13rd, 2016, FDA ratified happy cut down for Buddhist nun and everolimus combination treatment advanced metastatic clear-cell carcinoma again. In addition to this, Wei Cai company is also promoting happy cut down to treat a series of clinics that other cancers include liver cancer and cutaneum carcinoma etc. for Buddhist nun Therapy study.
The happy chemical name cut down for Buddhist nun are as follows: 4- [the chloro- 4- of 3- [[(cyclopropylamino) carbonyl] amino] phenoxy group] -7- methoxyl group - 6- quinoline formyl amine, structure are as follows:
It cuts down in the prior art there are many happy for Buddhist nun's intermediate and the happy synthetic route cut down for Buddhist nun, specific as follows:
Route one:
Patent CN100450998C, CN101337930B, WO2005044788, US7683172B2 (route one) etc. are introduced It is reacted with phenyl chloroformate (compound B) with 4- amino -3- chlorophenol (compound A) and generates midbody compound C, then again It reacts to obtain important intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) with cyclopropylamine (compound D), most It reacts to obtain happy cut down for Buddhist nun with the chloro- 7- methoxy quinoline -6- formamide (compound F) of 4- afterwards.
Route two:
Synthesis pleasure disclosed in patent CN106632033A (route two) is cut down extremely similar with route one for the method for Buddhist nun, only It is that the phenyl chloroformate (compound B) in route one is converted to chloromethane acid aryl ester (compound Ba) substituted on phenyl ring, Remaining step is identical.
Route three:
Patent CN101029022B, CN106660964A (route three) discloses 4- amino -3- chlorophenol (compound A) first It reacts to obtain midbody compound G with the chloro- 7- methoxy quinoline -6- formamide (compound F) of 4-, then (changes with phenyl chloroformate Close object B) and cyclopropylamine (compound D) reaction obtain find pleasure in cut down for Buddhist nun.
The above route one, route two and route three are intended to use price and the high phenyl chloroformate of toxicity, and chloro-carbonic acid Transformation is after phenyl ester participates in reaction in order to which the chemical substance phenol that toxicity is bigger, is difficult to remove, simultaneous reactions need to use a large amount of poles Property big organic solvent DMF and DMSO etc., be easy to cause very big environmental pollution, significantly limit its industrialized production and answer With.
Route four:
Patent CN105985289A (route four) discloses 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- first Amide (compound G), which reacts a step with compound I and obtains pleasure, to be cut down for Buddhist nun, but the synthesis difficulty of compound G is larger, without business Change, and compound I is not easy to reach in the market, property is unstable, needs now-making-now-using, these reasons all limit its industry and answer With.
Route five:
Patent CN104876864B (route five) is related to carrying out amino in advance to 4- amino -3- chlorophenol (compound A) Boc protects (tertiary butyl oxycarbonyl), then participates in remaining reaction, and the protection of amino can reduce the generation of side reaction, but thus institute Protection and deprotection increase reaction step and purification process in bring, reduce whole yield, affect industrialization efficiency.
Summary of the invention
For the deficiencies in the prior art and defect, seek that a kind of processing step is simple, environmental pollution is small, at low cost It is honest and clean, it is especially cut down without using the pleasure of organic solvent new for Buddhist nun's key intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea Aqueous phase preparation method, and applied to happy cut down in the preparation for Buddhist nun with very important realistic meaning, it will largely The upper problem of environmental pollution for reducing bulk pharmaceutical chemicals.
Carbonyl dimidazoles (CDI) are a kind of important medicine intermediates, are widely used as the adhesive of enzyme and protein, are applicable in It is wide, it especially can be used as the bonding agent of polypeptide compound, since it has different functional groups the selectivity of height, thus It has very important significance in biochemical synthesis, organic synthesis, the field of polymers, and the product that CDI is prepared as activator Convenient separation, process costs it is cheap (synthesising process research [J] application chemical industry of Qiu Fang benefit carbonyl dimidazoles, 2010 (10), 1478-1481).But CDI ingress of air is perishable, meets water and is easy to decompose, can make to produce having a small amount of water in reaction dissolvent Quality and yield are greatly affected, therefore generally forbid carrying out (Yang Fengling, Wen Jin under that condition of water in reaction process Plum carbonyl dimidazoles [J] finely and specialty chemicals, 2003 (1), 20).In the present invention, it finds, uses other than inventor CDI prepares carbamide compounds as activator in water phase, has received unexpected effect.
The object of the present invention is to provide a kind of pleasures to cut down for Buddhist nun's key intermediate synthetic method, preferably new aqueous synthesis method And is applied to pleasure and cut down in the synthesis for Buddhist nun.Specifically, the present invention provides the following technical scheme that
A kind of preparation method of 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea, which comprises the steps of:
(1) prepare N- cyclopropyl -1H- imidazoles -1- formamide: by cyclopropylamine and N, N'- carbonyl dimidazoles react to obtain N- cyclopropyl -1H- imidazoles -1- formamide；And
(2) 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is prepared: by N- cyclopropyl -1H- imidazoles -1-
Formamide reacts to obtain 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea with 4- amino -3- chlorophenol.
In addition, the present invention also provides a kind of 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl ureas, which is characterized in that the chemical combination Object is obtained by the preparation method of claim 1, wherein is cooled down to obtain to reaction system obtained in step (2) described 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea, the 1- contained (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea purity are greater than 98.5%, preferably greater than 99%.
The present invention also provides a kind of pleasures to cut down the preparation method for Buddhist nun, and the pleasure is cut down for Buddhist nun's structural formula such as following structural formula (Le) shown in:
It is characterized in that, this method comprises the following steps:
(1) N- cyclopropyl -1H- imidazoles -1- formamide is prepared: by cyclopropylamine and N, two miaow of N'- carbonyl
Azoles reacts to obtain N- cyclopropyl -1H- imidazoles -1- formamide；
(2) 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is prepared: by N- cyclopropyl -1H- imidazoles -1-
Formamide reacts to obtain intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea with 4- amino -3- chlorophenol； And
(3) preparation pleasure is cut down for Buddhist nun: by intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea and the chloro- 7- methoxyl group of 4- Quinoline -6- formamide obtains final product pleasure and cuts down for Buddhist nun.
Preferably for the above method, wherein in step (1), cyclopropylamine and N, the molar ratio of N'- carbonyl dimidazoles Example is 1:0.5-2, preferably 1:(0.9-1.8), is more preferably 1:(1.6-1.8).
More preferably, for the above method, wherein the reaction of step (1) carries out in a solvent, step (1) middle ring The usage ratio of propylamine and solvent is calculated as 10g:(20-150 with g/ml) ml, preferably 10g:(30-120) ml；
Further preferably solvent is water, and the usage ratio of cyclopropylamine and water is calculated as 10g:(30-100 with g/ml) ml, it is excellent Select 10g:(30-70) ml is further 10g:50ml.
More preferably, for the above method, wherein reaction temperature described in step (1) be 0 DEG C~60 DEG C, preferably 0 DEG C~ 30 DEG C, be further 0-25 DEG C.
More preferably, for the above method, wherein the reaction of step (1) carries out in a solvent, and the solvent is preferred Selected from one of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate or two kinds or more, more preferably water, Or the mixture of methylene chloride or water and methylene chloride, it is even more preferably water.
More preferably, for the above method, wherein N- cyclopropyl -1H- imidazoles -1- formamide and 4- amino-in step (2) The molar ratio of 3- chlorophenol is 1:(0.5-1.5), preferably 1:(0.59-1.0), further preferred 1:(0.59-0.85).
More preferably, for the above method, wherein the reaction temperature of step (2) be 0 DEG C~100 DEG C, preferably 60 DEG C~90 DEG C, further preferably 78 DEG C.
More preferably, for the above method, wherein the reaction of step (2) carries out in a solvent, and the solvent is preferably selected from One of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, propyl acetate or two kinds or more, more preferably For water or the mixture of ethyl acetate or tetrahydrofuran or water and ethyl acetate or water and tetrahydrofuran；Even more preferably For water.
More preferably, for the above method, wherein in step (3), 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea and The molar ratio of the chloro- 7- methoxy quinoline -6- amide of 4- is 1:(0.5-1.5)), preferably 1:(0.7-1).
The step (3) is reacted in the presence of alkali and solvent；It is preferred that the alkali is selected from potassium carbonate, cesium carbonate, hydroxide One of potassium, sodium hydroxide, potassium tert-butoxide or sodium tert-butoxide or two kinds or more, more preferably cesium carbonate, potassium hydroxide or uncle Butanol potassium.
In the step (3), the solvent is selected from methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, second One of propyl propionate, dimethyl sulfoxide or two kinds or more, preferably dimethyl sulfoxide or DMF or dimethyl sulfoxide and DMF Mixture.
More preferably, for the above method, in step (1), cyclopropylamine elder generation and compound N, the reaction of N'- carbonyl dimidazoles The reaction system containing N- cyclopropyl -1H- imidazoles -1- formamide is obtained without post-processing, then directly carries out step (2) reaction Obtain intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea.
Preparation method process route of the invention is succinct, reaction raw materials are cheap and easy to get, purity and high income.Further, Water can also be directlyed adopt and make solvent, be directly precipitated from water phase after reaction purity about 99% (such as 98.6%, 98.7%, 98.8%, 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea 99.0%, 99.1%, 99.5%, 99.6% etc.) avoids big The use for measuring organic solvent, can embody excellent environmentally protective effect.
Detailed description of the invention
Fig. 1 shows be embodiment 1 prepare pleasure cut down for Buddhist nun's intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea HPLC testing result (purity 99.3%).
What Fig. 2 was indicated is the happy HPLC testing result (purity 99.0%) cut down for Buddhist nun of final product prepared by embodiment 9.
Specific embodiment
The present invention provide it is a kind of prepare crucial pleasure and cut down for the method for Buddhist nun's intermediate, so as to brief, reaction raw materials at This low mode prepares purity and the pleasure of high income is cut down for Buddhist nun.
In the preferred embodiment of the present invention, happy intermediate 1- (the chloro- 4- hydroxyl of 2- cut down for Buddhist nun of preparation of the invention Base phenyl) -3- cyclopropyl urea (compound E) method, feature includes the following steps:
(1) N- cyclopropyl -1H- imidazoles -1- formamide (compound I) is prepared: by cyclopropylamine with compound CDI certain Temperature and solvent under reaction obtain N- cyclopropyl -1H- imidazoles -1- formamide；With
(2) 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) is prepared: by N- cyclopropyl -1H- imidazoles -1- Formamide (compound I) obtains intermediate 1- in certain temperature and solvent reaction with 4- amino -3- chlorophenol (compound A) (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea；
Preparation pleasure is cut down for Buddhist nun: by intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) and the chloro- 7- of 4- Methoxy quinoline -6- formamide (compound F) reacted under base reagent and solvent condition obtain final product pleasure cut down for Buddhist nun.
The method, it is characterised in that reaction temperature described in step (1) is 0 DEG C~60 DEG C, preferably 0 DEG C~25 DEG C； The solvent is selected from one of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate or a variety of, preferably Water and methylene chloride, more preferable water.
The method, it is characterised in that reaction temperature described in step (2) be 0 DEG C~100 DEG C, preferably 60 DEG C~90 ℃；The solvent is selected from one of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, propyl acetate Or a variety of, preferably water, tetrahydrofuran, ethyl acetate, the mixture of more preferable water and ethyl acetate, further preferably only water.
The method, it is characterised in that base reagent described in step (3) is selected from potassium carbonate, cesium carbonate, potassium hydroxide, hydrogen Sodium oxide molybdena, potassium tert-butoxide or sodium tert-butoxide；Solvent is selected from methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, second One of propyl propionate, dimethyl sulfoxide are a variety of, preferably dimethyl sulfoxide, DMF.
The method, it is characterised in that cyclopropylamine first reacts to obtain N- cyclopropyl -1H- imidazoles -1- with compound CDI Formamide (compound I) without post-processing, then directly reacts to obtain intermediate 1- with 4- amino -3- chlorophenol (compound A) (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) (is changed finally by with the chloro- 7- methoxy quinoline -6- formamide of 4- Close object F) it reacts to obtain finding pleasure in and cut down for Buddhist nun.
In a kind of most preferred embodiment of the invention, the present invention provide a kind of preparation of water phase it is happy cut down it is crucial intermediate for Buddhist nun Body 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) and happy cut down describe institute for the synthetic route of Buddhist nun for following process Show:
Compared with prior art, beneficial effect brought by the present invention is:
(1) it cuts down with existing preparation pleasure for Buddhist nun's intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) Reagent phenyl chloroformate used is compared, and reagent C DI (N, N'- carbonyl dimidazoles) used in the present invention is more environmentally-friendly and cheap easy ?.And solvent directly can also be made using water, the 1- (2- that purity is greater than 98.5% is directly precipitated from water phase after reaction Chloro-4-hydroxyl phenyl) -3- cyclopropyl urea, the use in reaction process with organic solvents a large amount of in last handling process is avoided, more Add environmentally protective.
(2) it is first reacted with compound CDI by cyclopropylamine and reacts to obtain key intermediate with 4- amino -3- chlorophenol again E, then be condensed with the chloro- 7- methoxy quinoline -6- formamide (compound F) of 4-, it can largely reduce due to 4- amino -3- chlorine Phenol bring side reaction with two active sites of amino and hydroxyl can obtain to be implemented without and carry out protection in advance To the satisfactory product of purity.
(3) respectively step reaction condition is mild, post-processing only need to be washed simply, can also simply wash that purity can be obtained is big In 99% product, and impurity caused by reacting is more easier to remove, and environmental pollution is small, this to the separation of bulk pharmaceutical chemicals, Purifying and mass production have important practical significance.
The present invention is further described by way of examples again below, provides implementation detail of the invention, but needs to refer to Out be that the embodiments described below is exemplary, for explaining only the invention, and be not considered as limiting the invention. Those skilled in the art are modified or substituted to it according to the prior art and are still fallen in protection scope of the present invention.
BrukerAscend400MHzNMR spectrometer is used in the following examples, compound is dissolved in appropriate deuterated In reagent, 1H-NMR analysis is carried out by internal standard of TMS under environment temperature.Nmr chemical be displaced (δ) as unit of ppm, and use with Lower abbreviation: s, it is unimodal；D, doublet；T, triplet；Q, quartet；M, multiplet；Brs, width unimodal.MS passes through WatersUPLC-VevoTMTQMS mass spectrograph (ESI) measurement.
React starting material, intermediate and embodiment compound can by precipitating, filtering, crystallization, evaporation, distillation with And the routine techniques such as chromatography (such as column chromatography, TLC isolates and purifies) carry out isolation and purification.
TLC uses Yantai Huanghai Sea HSGF254 tlc silica gel plate (0.2 ± 0.03mm), and TLC is isolated and purified using Yantai Huanghai Sea HSGF254 thin-layer chromatography thickness prepares plate (0.9~1mm), is purchased from Haiyang Chemical Plant, Qingdao.Column is chromatographed with the Yantai Huanghai Sea 300~400 mesh (Unite States Standard sieve) silica gel is carrier, is purchased from Haiyang Chemical Plant, Qingdao.
Product purity is detected using HPLC；For example, HPLC instrument model is Ultimate3000；Column temperature: 25 DEG C；Detect wave It is long: 252nm；Chromatographic column are as follows: phenomenex-C184.6 × 250mm column；Mobile phase: acetonitrile: water=20:80, additional 0.1% Formic acid；Flow velocity: 0.6ml/min
Commercialization solvent and reagent used in test unless otherwise specified, are not necessarily to be further purified or handle after purchase Directly use.In general, reaction process can be monitored by TLC, after selecting the suitable time to terminate reaction and carry out accordingly Reason.The purification condition of compound is it can also happen that variation, it is however generally that, the suitable conventional column chromatography of Rf value selection according to TLC Eluant, eluent, or respective compound is isolated and purified by preparing TLC.
The synthesis of embodiment 1:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (10g, 0.175mol), 50ml water makees solvent, is placed in item under ice bath Under part, CDI (51.08g, 0.315mol) is added in three batches, finishes, the reaction was continued at 0 DEG C 1h, TLC monitoring fully reacting, reaction Mixed liquor directly carries out next step reaction without any post-processing.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
Directly add into untreated N- cyclopropyl -1H- imidazoles -1- formamide (compound I) aqueous solution obtained by step 1 Enter raw material 4- amino -3- chlorophenol (compound A) (17.7g, 0.123mol), reaction mixture, which is placed in 78 DEG C of oil bath pans, to be added Heat, TLC monitors raw material A fully reacting after 4h.Reaction was completed, and reaction system is cooled to room temperature, and discovery has a large amount of white solids It is precipitated, filters, filter cake is washed with water, obtained solid is dry, obtain pale solid 1- (2- chloro-4-hydroxyl phenyl) -3- ring The total 24.6g of propyl urea (compound E), two-step reaction total recovery 88.0%, HPLC detect purity 99.9%, as shown in Figure 1.1δ=9.51 (s, 1H) HNMR (400MHz, DMSO), 7.71 (d, J=8.8Hz, 1H), 7.58 (s, 1H), 6.84 (d, J= 2.8Hz, 1H), 6.80 (d, J=2.4Hz, 1H), 6.68 (dd, J=8.8,2.8Hz, 1H), 2.57-2.52 (m, 1H), 0.70- 0.59(m,2H),0.45-0.34(m,2H).13CNMR (101MHz, DMSO) δ=156.48,153.59,128.53,124.33, (115.70,114.88,22.83,6.82.ESI-MS m/z)=248.98 [M+Na]+,227.02[M+H]+,225.01[M-H]-。
The synthesis of embodiment 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (10g, 0.175mol), 30ml water makees solvent, is placed in item under ice bath Under part, CDI (51.08g, 0.315mol) is added in three batches, finishes, the reaction was continued at 25 DEG C 1h, TLC monitor fully reacting, instead Mixed liquor is answered directly to carry out next step reaction without any post-processing.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
Directly add into untreated N- cyclopropyl -1H- imidazoles -1- formamide (compound I) aqueous solution obtained by step 1 Enter raw material 4- amino -3- chlorophenol (compound A) (17.7g, 0.123mol), reaction mixture, which is placed in 78 DEG C of oil bath pans, to be added Heat, TLC monitors raw material A fully reacting after 4h.Reaction was completed, and reaction system is cooled to room temperature, and discovery has a large amount of white solids It is precipitated, filters, filter cake is washed with water, obtained solid is dry, obtain pale solid 1- (2- chloro-4-hydroxyl phenyl) -3- ring The total 23.0g of propyl urea (compound E), two-step reaction total recovery 83%, product purity 99.0%.
The synthesis of embodiment 3:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (10g, 0.175mol), 100ml water makees solvent, is placed in item under ice bath Under part, CDI (42.57g, 0.2625mol) is added in three batches, finishes, the reaction was continued at 25 DEG C 1h, TLC monitor fully reacting, instead Mixed liquor is answered directly to carry out next step reaction without any post-processing.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
Directly add into untreated N- cyclopropyl -1H- imidazoles -1- formamide (compound I) aqueous solution obtained by step 1 Enter raw material 4- amino -3- chlorophenol (compound A) (17.7g, 0.123mol), reaction mixture, which is placed in 60 DEG C of oil bath pans, to be added Heat, TLC monitors raw material A fully reacting after 4h.Reaction was completed, and reaction system is cooled to room temperature, and ethyl acetate 100ml is added, With 6mol/L hydrochloric acid tune pH=2-3, liquid separation is stood, water phase is extracted 2 times with 50ml ethyl acetate, merges organic phase, anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and crude product is beaten with mixed solvent (petroleum ether: ethyl acetate=1:5-1:2), and it is solid that filtering obtains pink Body 1- (2- chloro-4-hydroxyl phenyl) total 15.0g of -3- cyclopropyl urea (compound E), two-step reaction total recovery 54%；Product purity 98.7%.
The synthesis of embodiment 4:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (20g, 0.35mol), 70ml water makees solvent, is placed in condition under ice bath Under, CDI (90.8g, 0.56mol) is added in three batches, finishes, the reaction was continued at room temperature 1h, TLC monitor fully reacting, and reaction is mixed It closes liquid and directly carries out next step reaction without any post-processing.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
Directly add into untreated N- cyclopropyl -1H- imidazoles -1- formamide (compound I) aqueous solution obtained by step 1 Enter raw material 4- amino -3- chlorophenol (compound A) (35.4g, 0.246mol), reaction mixture, which is placed in 78 DEG C of oil bath pans, to be added Heat, TLC monitoring raw material A has a small amount of residue after 4h, and reaction system is cooled to room temperature, and discovery has a large amount of white solids to be precipitated, and takes out Filter cake is washed with water in filter, filters and obtains the total 43.6g of solid 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E), and two Walk overall yield of reaction 78%, product purity 99.0%.
The synthesis of embodiment 5:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (20g, 0.35mol), 100ml water makees solvent, is placed in item under ice bath Under part, CDI (102.16g, 0.63mol) is added in three batches, finishes, the reaction was continued at room temperature 1h, TLC monitor fully reacting, instead Mixed liquor is answered directly to carry out next step reaction without any post-processing.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
Directly add into untreated N- cyclopropyl -1H- imidazoles -1- formamide (compound I) aqueous solution obtained by step 1 Enter raw material 4- amino -3- chlorophenol (compound A) (35.4g, 0.246mol), reaction mixture, which is placed in 90 DEG C of oil bath pans, to be added Heat, TLC monitoring raw material A is reacted completely after 4h, and reaction system is cooled to room temperature, and discovery has a large amount of white solids to be precipitated, and is filtered, Filter cake is washed with water, filtering obtains solid 1- (2- chloro-4-hydroxyl phenyl) total 47.6g of -3- cyclopropyl urea (compound E), two steps Overall yield of reaction 85%；Product purity 98.8%.
The synthesis of embodiment 6:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added CDI (28.8g, 0.178mol), 100ml methylene chloride makees solvent, then slowly It is added dropwise cyclopropylamine (8.45g, 0.148mol).It finishes, the reaction was continued at 0 DEG C 1h, TLC monitoring fully reacting.After reaction, dense Contracting reaction solution, without further purification, directly progress next step reaction.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
It takes 15.1g (0.105mol) 4- amino -3- chlorophenol (compound A) to be dissolved in 200mL ethyl acetate, step is added Rapid 1 resulting N- cyclopropyl -1H- imidazoles -1- formamide (compound I), is slowly heated to 78 DEG C and is stirred to react, and TLC is supervised after 5h Survey fully reacting.It is cooled to room temperature after reaction.After 200mL water is added, pH=1-2, stirring are adjusted using 6mol/L hydrochloric acid 10min, stratification, water phase are extracted with ethyl acetate 2 times, combined ethyl acetate organic phase, and anhydrous sodium sulfate is dry, depressurize dense Contracting obtains crude product.Using petroleum ether (v): the mashing of ethyl acetate (v)=1:5-1:2 mixed solvent obtains product 1- (2- Chloro-4-hydroxyl phenyl) the total 18.51g of -3- cyclopropyl urea (compound E), two step total recoverys are 78.0%, purity 96.8%.
The synthesis of embodiment 7:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (8.45g, 0.148mol), 100ml methylene chloride makees solvent, in batches Secondary addition CDI (28.8g, 0.178mol).It finishes, the reaction was continued at 0 DEG C 1h, TLC monitoring fully reacting.After reaction, dense Contracting reaction solution, without further purification, directly progress next step reaction.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
To 100ml water is added in the untreated resulting N- cyclopropyl -1H- imidazoles -1- formamide (compound I) of step 1, so After be directly added into raw material 4- amino -3- chlorophenol (compound A) (17.7g, 0.123mol), reaction mixture is placed in 78 DEG C of oil baths It is heated in pot, TLC monitors raw material A and reacts completely after 4h, and reaction system is cooled to room temperature, and discovery has a large amount of off-white powders to analyse Out, it filters, filter cake is washed with water, obtained solid is dry, obtain pale solid 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl The total 22.0g of base urea (compound E), two-step reaction total recovery 78.8%, product purity 97.1%.
The synthesis of embodiment 8:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
The synthesis of step 1:N- cyclopropyl -1H- imidazoles -1- formamide (compound I)
It in 250ml round-bottomed flask, is added cyclopropylamine (10g, 0.35mol), 50ml methylene chloride and water mixed liquid (v/v =1:1) solvent is made, under the conditions of being placed under ice bath, CDI (51.08g, 0.315mol) is added in three batches, finishes, continues at room temperature 1h is reacted, TLC monitors fully reacting.Reaction mixture stands liquid separation, and water phase is washed 2 times with 25ml methylene chloride, merges organic Phase, anhydrous sodium sulfate is dry, oily compound I is obtained after concentration, for reacting in next step.
The synthesis of step 2:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E)
To addition water and acetic acid second in resulting N- cyclopropyl -1H- imidazoles -1- formamide (compound I) handled by step 1 Ester mixed liquor 50ml (v/v=1:1), be then directly added into raw material 4- amino -3- chlorophenol (compound A) (17.7g, 0.123mol), reaction mixture is placed in 78 DEG C of oil bath pans and heats, and TLC monitors raw material A and reacts completely after 4h, by reaction system It is cooled to room temperature, ethyl acetate and each 25ml of water is added.With 6mol/L hydrochloric acid tune pH=2-3, liquid separation, water phase 50ml second are stood Acetoacetic ester extracts 2 times, merges organic phase, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, crude product mixed solvent (petroleum ether: acetic acid second Ester=1:5-1:2) mashing, it is total that filtering obtains pink solid 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (compound E) 22.6g, two-step reaction total recovery 80.9%, purity 95.9%.
Embodiment 9: the happy synthesis cut down for Buddhist nun
It weighs and (changes according to 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea of (1) the step of embodiment 1 and (2) preparation Close object E) 34.0g (150mmol), chloro- 7- methoxy quinoline -6- amide (compound F) 29.6g (125mmol) of 4-, cesium carbonate 600mLDMSO is added in 1.0L round-bottomed flask in 81.5g (250mmol), and 70 DEG C of heating reactions are placed under stirring, and TLC monitoring is anti- It answers.It is cooled to room temperature after reaction, the stirring of 1200mL water is added, gradually has solids generation, filter mixed liquor, water in system Filter wash cake obtains crude product.The crude product is beaten with aqueous acetone solution (6/18=acetone (v)/water (v)), drying can obtain after filtering Solid product pleasure is obtained to cut down for the total 46.0g of Buddhist nun, yield 86.2%, purity > 99%, HPLC testing result (purity 99.0%), (HPLC instrument model Ultimate3000 as shown in Figure 2；Column temperature: 25 DEG C；Detection wavelength: 252nm；Chromatographic column are as follows: Phenomenex-C184.6 × 250mm column；Mobile phase: acetonitrile: water=20:80, additional 0.1% formic acid；Flow velocity: 0.6ml/ min)。。1δ=8.68 (t, J=2.6Hz, 2H) HNMR (400MHz, DMSO), 8.29 (d, J=9.2Hz, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.51 (d, J=2.8Hz, 1H), 7.27 (dd, J=9.2, 2.8Hz, 1H), 7.21 (d, J=2.8Hz, 1H), 6.54 (d, J=5.2Hz, 1H), 4.05 (s, 3H), 2.63-2.56 (m, 1H), 0.74-0.63 (m, 2H), 0.51-0.39 (m, 2H) .ESI-MS (m/z)=449.02 [M+Na]+,427.04[M+H]+,424.96 [M-H]-。
Embodiment 10: the happy synthesis cut down for Buddhist nun
It weighs and (changes according to 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea of (1) the step of embodiment 1 and (2) preparation Close object E) 30.0g (132mmol), chloro- 7- methoxy quinoline -6- amide (compound F) 24.14g (102mmol) of 4-, the tert-butyl alcohol Potassium 14.81g (132mmol) is added 200mLDMSO, is placed in 70 DEG C under nitrogen protection and is stirred to react in 500ml round-bottomed flask, TLC monitoring reaction.It is cooled to room temperature after reaction, the stirring of 300mL water is added, gradually has solids generation in system, filters Mixed liquor, washing filter cake obtain crude product.The crude product is beaten with aqueous acetone solution (6/18=acetone (v)/water (v)), filtering Available solid product pleasure is dried afterwards to cut down for the total 35.0g of Buddhist nun, yield 80.4%, purity 99.0%.
Embodiment 11: the happy synthesis cut down for Buddhist nun
It weighs and (changes according to 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea of (1) the step of embodiment 1 and (2) preparation Close object E) 100.0g (442mmol), chloro- 7- methoxy quinoline -6- amide (compound F) 80.46g (340mmol) of 4-, the tert-butyl alcohol Potassium 49.6g (442mmol) is added 1000mLDMF, is placed in 70 DEG C under nitrogen protection and is stirred to react in 2.0L round-bottomed flask, TLC Monitoring reaction.It is cooled to room temperature after reaction, the stirring of 1500mL water is added, gradually there is solids generation in system, filtering is mixed Liquid is closed, washing filter cake obtains crude product.The crude product is beaten with aqueous acetone solution (6/18=acetone (v)/water (v)), after filtering Available solid product pleasure is dried to cut down for the total 118.6g of Buddhist nun, yield 81.7%, purity 99.1%.
Embodiment 12: the happy synthesis cut down for Buddhist nun
It weighs and (changes according to 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea of (1) the step of embodiment 1 and (2) preparation Close object E) 30.0g (132mmol), chloro- 7- methoxy quinoline -6- amide (compound F) 24.14g (102mmol) of 4-, hydroxide Potassium 8.01g (143mmol), water 8ml are added 220mLDMSO, are placed in 70 DEG C of stirrings under nitrogen protection in 500ml round-bottomed flask Reaction, TLC monitoring reaction.It is cooled to room temperature after reaction, the stirring of 300mL water is added, gradually has solids generation in system, Filter mixed liquor, washing filter cake obtain crude product.The crude product is beaten with aqueous acetone solution (6/18=acetone (v)/water (v)), Available solid product pleasure is dried after filtering to cut down for the total 36.6g of Buddhist nun, yield 84.0%, purity 99.0%.

Claims (12)

1. a kind of preparation method of 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea, which comprises the steps of:
(1) prepare N- cyclopropyl -1H- imidazoles -1- formamide: by cyclopropylamine and N, N'- carbonyl dimidazoles react to obtain N- ring Propyl -1H- imidazoles -1- formamide；And
(2) 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is prepared: by N- cyclopropyl -1H- imidazoles -1- formamide and 4- ammonia Base -3- chlorophenol reacts to obtain 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea.
2.1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea, which is characterized in that the compound passes through the preparation side of claim 1 Method obtains, wherein is cooled down to obtain the 1- (2- chloro-4-hydroxyl phenyl) -3- ring to reaction system obtained in step (2) Propyl urea, the 1- contained (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea purity are greater than 98.5%, preferably greater than 99%.
3. the preparation method that a kind of pleasure is cut down for Buddhist nun, the pleasure is cut down for shown in Buddhist nun's structural formula such as following structural formula (Le):
It is characterized in that, this method comprises the following steps:
(1) prepare N- cyclopropyl -1H- imidazoles -1- formamide: by cyclopropylamine and N, N'- carbonyl dimidazoles react to obtain N- ring Propyl -1H- imidazoles -1- formamide；
(2) 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is prepared: by N- cyclopropyl -1H- imidazoles -1- formamide and 4- ammonia Base -3- chlorophenol reacts to obtain intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea；And
(3) preparation pleasure is cut down for Buddhist nun: by intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea and the chloro- 7- methoxyl group quinoline of 4- Quinoline -6- formamide obtains final product pleasure and cuts down for Buddhist nun.
4. preparation method according to claim 1 or 3, wherein in step (1), cyclopropylamine and N, N'- carbonyl dimidazoles Molar ratio be 1:0.5-2, preferably 1:(0.9-1.8), further preferably 1:(1.6-1.8).
5. preparation method described according to claim 1 or 3 or 4, wherein the reaction of step (1) carries out in a solvent, step Suddenly the usage ratio of cyclopropylamine and solvent is calculated as 10g:(20-150 with g/ml in (1)) ml, preferably 10g:(30-120) ml；
Further preferably solvent is water, and the usage ratio of cyclopropylamine and water is calculated as 10g:(30-100 with g/ml) ml, preferably 10g:(30-70) ml is further 10g:50ml.
6. according to claim 1 or the described in any item preparation methods of 3-5, wherein reaction temperature described in step (1) is 0 DEG C ~60 DEG C, preferably 0 DEG C~30 DEG C, be further 0-25 DEG C.
7. according to claim 1 or the described in any item preparation methods of 3-6, wherein the reaction of step (1) in a solvent into Row, the solvent are preferably selected from one of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate or two kinds More than, the more preferably mixture of water or methylene chloride or water and methylene chloride is even more preferably water.
8. according to claim 1 or the described in any item preparation methods of 3-7, wherein N- cyclopropyl -1H- imidazoles -1- in step (2) The molar ratio of formamide and 4- amino -3- chlorophenol is 1:(0.5-1.5), preferably 1:(0.59-1.0), further preferred 1: (0.59-0.85)。
9. according to claim 1 or the described in any item preparation methods of 3-8, wherein the reaction temperature of step (2) is 0 DEG C~100 DEG C, preferably 60 DEG C~90 DEG C, further preferably 78 DEG C.
10. according to claim 1 or the described in any item preparation methods of 3-9, wherein the reaction of step (2) carries out in a solvent, The solvent is preferably selected from one of water, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, propyl acetate Or two kinds or more, more preferably water or ethyl acetate or tetrahydrofuran or water and ethyl acetate or water and tetrahydrofuran is mixed Close object；It is even more preferably water.
11. according to the described in any item preparation methods of claim 3-10, wherein in step (3), 1- (2- chloro-4-hydroxyl benzene Base) molar ratio of -3- cyclopropyl urea and the chloro- 7- methoxy quinoline -6- amide of 4- is 1:(0.5-1.5)), preferably 1:(0.7- 1)。
The step (3) is reacted in the presence of alkali and solvent；It is preferred that the alkali is selected from potassium carbonate, cesium carbonate, potassium hydroxide, hydrogen One of sodium oxide molybdena, potassium tert-butoxide or sodium tert-butoxide or two kinds or more, more preferably cesium carbonate, potassium hydroxide or the tert-butyl alcohol Potassium；
In the step (3), the solvent is selected from methylene chloride, chloroform, acetonitrile, tetrahydrofuran, DMF, ethyl acetate, acetic acid third One of ester, dimethyl sulfoxide or two kinds or more, the preferably mixing of dimethyl sulfoxide or DMF or dimethyl sulfoxide and DMF Object.
12. according to claim 1 or the described in any item preparation methods of 3-11, in step (1), cyclopropylamine elder generation and compound N, N'- carbonyl dimidazoles react to obtain the reaction system containing N- cyclopropyl -1H- imidazoles -1- formamide without post-processing, then directly It taps into row step (2) reaction and obtains intermediate 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea.
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