CN108440505A - The total synthesis method of eptapirone - Google Patents
The total synthesis method of eptapirone Download PDFInfo
- Publication number
- CN108440505A CN108440505A CN201810295529.9A CN201810295529A CN108440505A CN 108440505 A CN108440505 A CN 108440505A CN 201810295529 A CN201810295529 A CN 201810295529A CN 108440505 A CN108440505 A CN 108440505A
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- azepine
- dissolved
- diketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of eptapirone, include the following steps:(1) 2 [2 (amino carbonyl) hydrazono-] (CD 1) are obtained via series reaction as raw material using amino urea hydrochloride and trichloroacetaldehyde;(2) 6 azepine urea pyrimidines (CD 2) are synthesized under the action of sodium hydroxide using 2 [2 (amino carbonyl) hydrazono-s];(3) 2 acetyl group 2H [1,2,4] triazine, 3,5 (2H, 4H) diketone (CD 3) is obtained using 6 azepine urea pyrimidines and acetic anhydride;(4) 3 methyl, 6 azepine urea pyrimidine (CD 4) is obtained by the reaction using 2 acetyl group 2H [1,2,4] triazine, 3,5 (2H, 4H) diketone;(5) 2 (4 chlorobutyl) 4 methyl 1,2,4 triazine 3,5 (2H, 4H) diketone (CD 5) are obtained by the reaction using 3 methyl, 6 azepine urea pyrimidine;(6) 4 (2 base of pyrimidine) piperazine, 1 t-butyl formate (CD 6) is obtained using 2 Bromopyrimidines, 1 Boc piperazines and triethylamine react, 2 (1 piperazinyl) pyrimidine hydrochlorides (1: 1) (CD 7) is further obtained by the reaction;(7) with by 2 (4 chlorobutyl) 4 methyl 1 in step (5), 2, eptapirone (CD 8) is obtained by the reaction in 2 (1 piperazinyl) pyrimidine hydrochlorides in 4 triazine, 3,5 (2H, 4H) diketone and step (6).The product purity and high income of the present invention are suitble to industrialized production.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of synthetic method of eptapirone.
Background technology
Eptapirone is a kind of anxiolytic, belongs to one kind in 5-HT1A acceptor portion agonist major class.Anxiety disorder
It is a kind of depressed with mood (mood), thinking delay and psychomotor inhibit the psychosomatic disease as potential symptom, in prosperity
Country and developing country cause huge physiology and financial burden, and mental disease treatment is limited.5-HT1A acceptor portions
Agonist can be played by the presynaptic receptor of the postsynaptic 5-HT1A receptor rather than nuclei of median raphe of exciting hippocampus and amygdaloid nucleus
Angst resistance effect.As a kind of effective 5-HT1A acceptor portion agonists, eptapirone in related medical scientific research and testing and
There is prodigious demand in clinical treatment, therefore the synthesis of eptapirone has extremely important realistic meaning.
In the prior art, the relevant report temporarily without eptapirone total synthesis method.In addition, about eptapirone it is main in
Mesosome 2- (1- piperazinyls) pyrimidine, the prior art report some methods few in number, such as 2006, Duncton groups
It reports with 2- chlorine pyrimidine and N-Boc- piperazines (4) in acetonitrile, is reacted at 140 DEG C, 2- (1- can be obtained with 46% yield
Piperazinyl) pyrimidine (Tetrahedron Letters, 2006,47 (15), 2549-2552), but this method reaction temperature mistake
Height, the possibility that method large-scale production causes more side reactions can also greatly increase.In addition, Salituro groups report in 2011
2- Bromopyrimidines and N-Boc- piperazine palladium chtalysts carry out Bulchward-Hartwig coupling reactions, with 40% yield obtain 2-
(1- piperazinyls) pyrimidine (WO2011072174), but palladium catalyst is expensive, reaction cost is high, and later stage patent medicine needs in addition
Metal is strictly removed, purifying cost increases.
Chemical synthesis eptapirone can provide larger demand for modern medicine field, and synthetic method is significant.
The fully synthetic technique of comparison system, low cost and environmental protection at present has not been reported;Intermediate synthetic method few in number there is also
Severe reaction conditions, using costliness and can retain causes drug heavy metal to be difficult to the technical problems such as qualified catalyst;This field
It is badly in need of a kind of eptapirone total synthesis method of mild, the suitable industry's enlarging production of reaction condition.
Invention content
Simple, inexpensive, heavy metal free residual that present invention aims at a kind of product purities of offer and high income, step,
The total synthesis method of eptapirone that is environmentally friendly, being suitble to industrialized production.
The total synthesis method of eptapirone of the present invention, includes the following steps:
Step (1) reacts semicarbazides and trichloroacetaldehyde, obtains 2- [2- (amino carbonyl) hydrazono-] (CD-1);
6- azepine urea pyrimidines (CD-2) are made in 2- [2- (amino carbonyl) hydrazono-] cyclization by step (2);
Step (3) reacts 6- azepine urea pyrimidines with acylating reagent, obtains 2- acyl group protections -2H- [1,2,4] triazine -3,
5 (2H, 4H)-diketone (CD-3);
2- acyl group protections -2H- [1,2,4] triazine -3,5 (2H, the 4H)-diketone and methylating reagent that step (4) will obtain
Methylation reaction is carried out, after reaction reacts product with acid, 3- methyl -6- is made in the acyl protective groups of removing 2-
Azepine urea pyrimidine (CD-4);
3- methyl -6- azepine urea pyrimidines and the halogenated -4- chlorobutanes of 1- are carried out N- alkylated reactions by step (5), obtain 2-
(4- chlorobutyls) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5);Halogenated -4- the chlorobutanes of the 1- are 1-
Bromo- 4- chlorobutanes or the iodo- 4- chlorobutanes of 1-;
The piperazine that step (6) is protected 2- Bromopyrimidines, one of N by blocking group is anti-at reaction solvent A, alkali A
It answers, further through sour water solution, removes the blocking group on piperazine N, obtain 2- (1- piperazinyls) pyrimidine (CD-7);
Step (7) will be by 2- (4- chlorobutyls) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-two made from step (5)
2- (1- piperazinyls) pyrimidines (CD-7) made from ketone (CD-5) and step (6) react, and obtain eptapirone (CD-8).
The present invention provides a kind of total synthesis method of eptapirone for the first time;It is set by the innovation of the process line
Meter, avoids heavy metal etc. and is easy to remain in drug and drug heavy metal is caused to be easy exceeded drawback, further, since described
Synthetic line rational design, the by-product of each intermediate product and final purpose product can be reduced, promote the yield of product
And purity.
Synthetic method of the present invention is one, and without metal catalytic, reaction condition is mild, controllable suitable big of by-product
The synthetic method of large-scale production;It is led to using two cheap raw materials of formamide (semicarbazides) and trichloroacetaldehyde as starting material
It crosses 6 steps and CD-5 has been obtained by the reaction, then two segments of itself and CD-7 are docked, it is fully synthetic to obtain the eptapirone.Synthesize road
Line 9 step in total, gross production rate is up to 10.8%.The fully synthetic route advantage of the innovation is:(1) route reaction is milder, operation
Substantially than more conventional operation, without many special reaction conditions;(2) high temperature and pressure or low temperature are not needed, is reacted
It is special that one phase will not require.The three wastes of this route are less, and there are no pollution to the environment, and the solvent after reaction can recycle again sharp
With;(3) the whole yield of this route is higher, can effectively control cost.
The total synthesis method of eptapirone of the present invention, synthetic line square formula 1:
In equation 1, the A in CD-3 is that acylating reagent reacts the acylation residue generated with CD-2;It is selected in step (6)
It is connected with blocking group Y on a N in piperazine raw material, base known in the art can be used in the blocking group
Group, such as Boc-, acylated blocking group etc..
In the present invention, in the step (1), semicarbazides and trichloroacetaldehyde are dissolved in reaction dissolvent, heating reaction, instead
Through cooling, suction filtration, washing, drying after should terminating, 2- [2- (amino carbonyl) hydrazono-] (CD-1) is obtained.
Preferably, the semicarbazides is amino urea hydrochloride.
In step (1), trichloroacetaldehyde to add equivalent slightly excessive.Preferably, semicarbazides and trichloroacetaldehyde molar ratio are
0.8: 1~1.2: 1.
Preferably, in step (1), reaction dissolvent is water.
Preferably, in step (1), reaction temperature is room temperature (RT)~100 DEG C;Further preferably 80~100 DEG C.
In step (1), the reaction time be 12~for 24 hours;Further preferably 12h.
In step (2), 2- [2- (amino carbonyl) hydrazono-] and alkali metal hydroxide are dissolved in ethylene glycol, 80
10~20h (preferably 12h) is stirred to react at~100 DEG C, be cooled to 10 DEG C and it is following after, add methanol, it is (excellent to stand 10~20h
Select 12h), be then adjusted with acid the pH < 3 of solution system, be cooled to after being stirred to react 10 DEG C and it is following after, recycle to obtain 6- azepines
Urea pyrimidine (CD-2.
Preferably, in step (3), the acylating reagent is acyl chlorides or acid anhydrides;Preferably acid anhydrides, further preferably
Acetic anhydride.
Acylating reagent adds excess relative to CD-2, preferably, the molar ratio of acylating reagent and CD-2 are 5~10: 1;
Further preferably 7.2: 1.
The temperature of acylation reaction is 130~150 DEG C;Further preferably 140 DEG C.
The acylation reaction time can be confirmed by chromatogram tracking, such as be determined by thin-layer chromatography or HPLC.
Preferably, the acylation reaction time is 6~12h;Further preferably 10h.
After acylation reaction, through cooling, solvent is evaporated, toluene is added, through filtering, being dried to obtain CD-3.
In step (4), the deprotection after existing method is methylated and methylated to CD3 can be used;In order into one
Step, which is promoted, prepares effect, in currently preferred step (4), by -2H- [1,2,4] triazine -3,5 of obtained 2- acyl groups protection
(2H, 4H)-diketone (present invention refer to 0 DEG C and less) under protective atmosphere and ice bath is dissolved in alkali B in DMF, stirs 1 at room temperature
~2h (preferably 1h), subsequent methylate reagent is stirred to react, through evaporating solvent, organic solvent extraction, salt washing after
Wash, anhydrous sodium sulfate drying after concentration with toluene-4-sulfonic acid be dissolved in ethyl alcohol, be stirred to react, deprotection group obtains 3- first
Base -6- azepine urea pyrimidines (CD-4).
During acid deprotection group, reaction temperature is preferably 50~70 DEG C, preferably 60 DEG C;Acid deprotection group stirs
It is preferably 11~16h of Ei to mix the time;Preferably 12h.
The alkali B is NaH or cesium carbonate.
The methylating reagent is potassium iodide, dimethyl suflfate or iodomethane.
In the present invention, alkali B, the dosage of methylating reagent are excessive relative to CD-3.
Preferably, the molar ratio that adds of alkali B, CD-3 are 1.5~3: 1.
Preferably, the molar ratio that adds of methylating reagent (in terms of methylation sites), CD-3 are 1.5~4: 1.
The acid is toluene-4-sulfonic acid.The effect being deprotected using the acid is more excellent.
During deprotection, sour dosage is 1: 1.5~3 relative to the molar ratio of CD-3.
After acid deprotection, solvent is evaporated, then dissolves out purpose product with DCM, concentrated drying is to get 3- methyl -6- nitrogen
Miscellaneous urea pyrimidine (CD-4).
The operation of one pot reaction described in step (4) and the control of parameter through the invention, without to intermediate product into
Row separation improves yield and purity in addition, can also reduce by-product.
Preferably, in the step (4), alkali B and 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone is
It is successively dissolved in DMF in batches in being stirred continuously;It is added in batches for example, the raw material is divided into 2~3 equal portions, so
Reaction effect it is more preferable.
In step (5), the alkylated reaction that existing method carries out 4- can be used.In currently preferred step (5),
It is dissolved in DMF with alkali C under protective atmosphere by 3- methyl -6- azepine ureas are phonetic, after 1~2h of stirring (preferably 1h), 1- is added dropwise
Halogenated -4- chlorobutanes after reacting 10~20h (preferably 12h) at room temperature, through organic solvent extraction, washing, dry, purifying, obtain
2- (4- chlorobutyls) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5).
The alkali C is NaH or cesium carbonate.
In step (5), the halogenated -4- chlorobutanes of 1- are slightly excessive relative to CD-4 raw materials, and preferably 1~2: 1.
In step (5), the molar ratio that adds phonetic with 3- methyl -6- azepine ureas alkali C is 8~15: 1;Preferably 11~12:
1。
It is successively to be dissolved in DMF in batches in being stirred continuously that NaH and 3- methyl -6- azepine ureas are phonetic in the step (5)
In.
Halogenated -4- the chlorobutanes of the 1- are the bromo- 4- chlorobutanes of 1-.
In step (5), the halogenated -4- chlorobutanes of 1- are excessive relative to the molar ratio of CD-4, and preferably 1.2~2: 1.
The organic solvent of extraction is ethyl alcohol.
Protective atmosphere is nitrogen atmosphere.
In step (5) washing need to first with ultrapure washing, after washed with salt.
In addition to the innovation of above-mentioned CD-5 synthetic lines, another main innovation of the present invention is the wound of the synthesis condition of CD-7
Newly, by the synthesis, by-product can be reduced, promotes the yield of product, avoids the use of harmful heavy metal catalyst.This
It is a little particularly important for industrial practical amplification production, because, it is generally the case that as medicinal API (medicine materials
Medicine) it needs to control heavy metal in 5PPM hereinafter, CD-7 is the upper level intermediate of final purpose product, quality is for example with much money
The quality of final product will be directly affected by belonging to content etc..
In step (6), existing conventional material can be used by the piperazine that blocking group is protected in one of described N, preferably
For 1-Boc- piperazines.
The present invention is the study found that in step (6), and under the use for avoiding heavy metal catalyst, the present inventor further grinds
Study carefully discovery, using suitable reaction dissolvent, the type of reaction temperature and alkali A, is affected to the yield of product.
The alkali A is triethylamine, K2CO3、Cs2CO3, at least one of NaOH, Py (pyridine).
The study found that when the alkali A is triethylamine, the yield highest of product, quality is best.
Alkali A is excessive relative to the dosage of 2- Bromopyrimidines, preferred molar ratio 1.5~2.5: 1;Further preferably 1.8
~2: 1.
Piperazine is excessive relative to the dosage of 2- Bromopyrimidines, preferred molar ratio 1~2: 1;1.2~1.5: 1.
The reaction dissolvent is ethyl alcohol, THF, DCM, CH3CN、H2At least one of O.
The study found that when the reaction dissolvent is ethyl alcohol, the yield highest of product, quality is best.
Preferably, in step (6), reaction temperature is 25~80 DEG C.The study found that temperature is higher, impurity increases.
Further preferably, in step (6), reaction temperature is 25~50 DEG C.
In step (6), under the reaction condition, the reaction time is not less than 12H;Preferably 16~24H.
In the present invention, in step (6), by the dissolving of 2- Bromopyrimidines, 1-Boc- piperazines and triethylamine in ethanol and 25~
50 DEG C are stirred overnight 16~24 hours, through cooling, filtering, obtain 4- (pyrimidine -2-base) piperazine -1- t-butyl formates (CD-6).
Under the conditions of this is preferred, the yield for promoting product can be unexpectedly cooperateed with.
In step (6), after the completion of reaction, through cooling, filtering, CD-6 is obtained;Hydrophobic organic solvent and acid is then added,
The blocking group for removing piperidines obtains CD-7 using filter, drying.
In step (6), it is deprotected during group, the hydrophobic organic solvent is preferably EA;The acid is preferably
For HCl.
In step (6), the ratio of 2- (1- piperazinyls) pyrimidine and hydrochloric acid in obtained 2- (1- piperazinyls) pyrimidine hydrochloride
It is 1: 1.
In step (7), CD-5 and CD-7 is reacted at alkali D and catalyst, obtains the eptapirone.
The molar ratio of CD-5 and CD-7 is 1: 1~1.2;Further preferably 1: 1.1.
Preferably, the alkali D is at least one of potassium carbonate, sodium carbonate, cesium carbonate.
Preferably, the catalyst is at least one of sodium iodide, potassium iodide, tetrabutylammonium iodide.Described
Catalyst is catalytic amount.
Preferably, in step (7), reaction dissolvent is at least one of acetonitrile, dioxane, tetrahydrofuran.
In step (7), the temperature of reaction process is RT~60 DEG C.Reaction time is 6~12H.
Preferably, in step (7), CD-5 and sodium iodide are dissolved in acetonitrile in advance, 1h is stirred at 60 DEG C, step is added
(6) 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) in and potassium carbonate are stirred overnight at 50 DEG C.Through cooling, suction filtration, washing, steaming
After sending out solvent, it is dissolved in DCM, washed, dry, concentration obtains eptapirone (CD-8).
A kind of synthetic method of preferred eptapirone of the present invention, includes the following steps, the substance generated in step point
It is not indicated with CD1-CD8:(1) amino urea hydrochloride and trichloroacetaldehyde are dissolved in water, heating reaction overnight, through cooling, suction filtration,
Washing, drying, obtain 2- [2- (amino carbonyl) hydrazono-] (CD-1);(2) by 2- [2- (amino carbonyl) hydrazono-] and hydroxide
Sodium is dissolved in ethylene glycol, is stirred overnight at 80 DEG C, after cooling, is added methanol, is stood overnight, with salt acid for adjusting pH < 3,80
Half an hour is stirred at DEG C, is cooled to certain temperature with brine ice, through suction filtration, washing, drying, obtains 6- azepine urea pyrimidines (CD-
2);(3) 6- azepine urea pyrimidines are dissolved in acetic anhydride, 10h is stirred at 140 DEG C, through cooling, evaporate solvent, toluene, warp is added
It filters, be dried to obtain 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone (CD-3);(4) the 2- acetyl that will be obtained
Base -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone is dissolved in NaH in DMF under protective atmosphere and ice bath, is stirred at room temperature
It mixes 1 hour, dimethyl suflfate, reaction is added to be stirred overnight, through evaporating solvent, organic solvent extraction, salt water washing, anhydrous sodium sulfate
After dry concentration, it is dissolved in ethyl alcohol with toluene-4-sulfonic acid, is stirred overnight at 60 DEG C, evaporated solvent, be dissolved in DCM, it is dense through drying
Contracting obtains 3- methyl -6- azepine urea pyrimidines (CD-4);(5) by 3- methyl -6- azepine ureas it is phonetic under protective atmosphere with NaH dissolve
In DMF, after stirring 1 hour, the bromo- 4- chlorobutanes of 1- are added dropwise, overnight, water on the rocks through organic solvent extraction, is washed for reaction at room temperature
It washs, dry, purify, obtain 2- (4- chlorobutyls) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5);(6) by 2- bromines
Pyrimidine, 1-Boc- piperazines and triethylamine dissolving are stirred overnight 16 hours in ethanol and at 50 DEG C, through cooling, filtering, obtain 4-
(pyrimidine -2-base) piperazine -1- t-butyl formates (CD-6) are added EA and HCl/EA, stir 16h at room temperature, through filtering, drying,
Obtain 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) (CD-7).(7) by 2- (4- chlorobutyls) -4- methyl-1s in step (5),
2,4- triazines -3,5 (2H, 4H)-diketone and sodium iodide are dissolved in acetonitrile, and 1h is stirred at 60 DEG C, and the 2- (1- in step (6) are added
Piperazinyl) pyrimidine hydrochloride (1: 1) and potassium carbonate, it is stirred overnight at 50 DEG C.It is molten after cooling, suction filtration, washing, evaporation solvent
In DCM, washed, dry, concentration obtains eptapirone (CD-8).
Wherein, amino urea hydrochloride and trichloroacetaldehyde molar ratio are 0.8: 1~1.2: 1 in the step (1).
With cooling down it is to be cooled to 10 DEG C using brine ice in the step (2).
The organic solvent extracted in the step (4) is ethyl alcohol, and protective atmosphere is nitrogen atmosphere.
NaH and 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone is to be stirred continuously in the step (4)
Middle priority is dissolved in DMF in batches.
It is successively to be dissolved in DMF in batches in being stirred continuously that NaH and 3- methyl -6- azepine ureas are phonetic in the step (5)
In.
The organic solvent extracted in step (5) is ethyl alcohol, merges organic phase afterwards twice with ethyl alcohol extraction liquid separation herein, protects
Atmosphere is nitrogen atmosphere.
In step (5) washing need to first with ultrapure washing, after washed with salt.
The ratio of 2- (1- piperazinyls) pyrimidine and hydrochloric acid in 2- (1- piperazinyls) pyrimidine hydrochloride obtained in the step (6)
Example is 1: 1.
It is all made of sodium sulphate dry matter in the step (4), (5), (7), is vacuum in step (1), (2), (3), (6)
It is dry.
In the synthesis step of the present invention, raw material proportioning and the preferred preferred plan of each response parameter are by real in detail below
The scheme of applying provides, and has obtained purity and the best eptapirone product of yield.
The advantage of the synthetic method of the present invention is:(1) route reaction is milder, and operation is substantially than more conventional
Operation, without many special reaction conditions;(2) high temperature and pressure or low temperature are not needed, one phase of reaction will not require spy
Very.The three wastes of this route are less, and there are no pollution to the environment, and the solvent after reaction can be with recycling;(3) entirety of this route
Yield is higher, can effectively control cost.Meanwhile inventor passes through further to preparing the raw material ratio during eptapirone
Value and other parameters are optimized, obtain product purity and yield are relatively high, environmentally friendly, cost is relatively low, be suitble to industry
The synthetic method of the eptapirone of metaplasia production.
Description of the drawings
【Fig. 1】For the synthetic route chart of eptapirone of the present invention
【Fig. 2】For the nuclear magnetic resonance H spectrograms of CD-8
【Fig. 3】For the nuclear magnetic resonance C spectrograms of CD-8
Specific implementation mode
All chemicals are analysis level, and it is no it is any be further processed in the case of use, in addition to dimethyl
Sulfoxide (DMSO) needs to purify come drying by calcium hydride (CaH 2).By stirring and vacuum distillation in 48 hours, obtain anhydrous
DMSO.Nuclear magnetic resonance (NMR, 1H NMR and 13C are recorded using tetramethylsilane (TMS) as interior target Avance III 500M
NMR it) composes.Using DMSO, DMSO-d6, chloroform-d or deuterium oxide as NMR solvents.All reactions are monitored by thin-layer chromatography,
And carry out analysis TCL on Silica Gel 60-F254 (Mark, Darmstadt).Use Milli-Q water purification systems
(Millipore, Milford, MA) produces ultra-pure water.
It illustrates the following examples are further illustrations of the invention, embodiment as described herein is only used for explaining this hair
It is bright, rather than limit the present invention.
The synthetic reaction equation of Examples 1 to 7 is shown in Fig. 1:
In the present invention, described stays overnight unless specified or limited otherwise, refers both to 10~12h;Room temperature refers to 25~30 DEG C.
Embodiment 1
(1) synthesis of 2- [2- (amino carbonyl) hydrazono-] (CD-1)
Amino urea hydrochloride 50g (0.448mo1), trichloroacetaldehyde 68g (0.481mol), ultra-pure water 1L add above-mentioned reactant
Enter into the three-neck flask of 2L, mixed dissolution in water, heats 100 DEG C of reaction 12h;It is cooled to room temperature, filters and with ultrapure
Water wash, obtains pale yellow solid 39g, vacuum dried 2- [2- (amino carbonyl) hydrazono-] (CD-1) 33.9g
(0.259mol, yield:57.8%).
The spectrogram information of CD-1:
1H NMR:(400MHz, DMSO-d6) δ 12.33 (s, 1H, COOH), 10.93 (s, 1H ,=CH), 7.13 (s, 1H,
NH), 6.80 (s, 1H, NH2)
13C NMR:(101MHz, DMSO-d6) δ 164.69 (s, 1-carboxyl, COOH), 156.21 (s, N-urea, O
=CN2), 129.80 (s, 1-imine, N=CN)
Embodiment 2
(2) synthesis of 6- azepines urea pyrimidine (CD-2)
2- [2- (amino carbonyl) hydrazono-] 33.9g (0.259mol) and sodium hydroxide 51g (1.275mol) are weighed to be dissolved in
In 150ml ethylene glycol, 12h is reacted in 80 DEG C of oil baths of magnetic agitation.After cooling water cooling, 250ml methanol is added, stands 12h, warp
It filtering, solvent recovery obtains the wet products of 41.9g, is dissolved in 60ml water, with salt acid for adjusting pH < 3, is then heated to 80 DEG C,
Persistently stir half an hour after, cooled to 10 DEG C with brine ice, through filter and use ultrapure water wash, be dried in vacuo obtain 6- nitrogen
Miscellaneous urea pyrimidine (CD-2) 18g (0.159mol, yield:61.6%).
CD-2 spectrogram informations:
1H NMR:(400MHz, DMSO-d6) δ 12.32 (s, 1H, NH), 11.95 (s, 1H, NH), 7.39 (s, 1H, CH=
N).
13C NMR:(101MHz, DMSO-d6):δ 157.78 (s, 1-amide, O=CN), 149.50 (s, N-urea, O=
CN2), 135.92 (s, 1H, 1-imine, N=CH)
Embodiment 3
(3) synthesis of 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone (CD-3)
It weighs 6- azepine urea pyrimidine 28.5g (0.252mol) to be dissolved in 200ml acetic anhydrides, 10h is stirred at 140 DEG C, pass through
It is cooled to room temperature, rotary evaporation recycling design, toluene is added, through filtering, solvent recovery, solid matter is dried to obtain 2- acetyl
Base -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone (CD-3) 33.8g (0.245mol, yield:98.58%)
CD-3 spectrogram informations:
1H NMR:(400MHz, DMSO-d6) δ 12.30 (s, 1H, NH), 7.67 (s, 1H ,=CH), 2.49 (s, 3H,
CH3);
13C NMR:(101MHz, DMSO-d6):δ 169.79 (s, 1-amide, O=CN), 156.60 (s, 1-amide, O
=CN), 146.79 (s, N-urea, O=CN2), 137.61 (s, 1-imine, N=CH), 25.81 (s, aliphatic, CH3)
Embodiment 4
(4) synthesis of 3- methyl -6- azepine ureas pyrimidine (CD-4)
3.2gNaH (0.133mo1) is dissolved in 150mlDMF in batches under nitrogen protection and ice bath, weighs 2- acetyl
Base -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone 19g, is added portionwise, and stirs 1 hour at room temperature, adds 18.5g dimethyl sulfates
Ester, reaction at room temperature is stirred overnight, and after the completion of reaction, reaction mixture is added in ultra-pure water simultaneously rotary evaporation recycling design
Extracted with EA, organic layer is washed with brine, and is dried with anhydrous sodium sulfate, obtains 10g intermediates, be added 1g toluene-4-sulfonic acids and
50ml ethyl alcohol is stirred overnight at 60 DEG C after mixing, and after rotary evaporation recycling design, mixture is dissolved in DCM,
It is dried to obtain 3- methyl -6- azepine urea pyrimidines (CD-4) with sodium sulphate
CD-4 spectrogram informations:
1H NMR:(400MHz, DMSO-d6) δ 12.55 (s, 1H, NH), 7.48 (s, 1H ,=CH), 3.12 (s, 3H, CH3)
13C NMR:(101MHz, DMSO-d6) δ 156.96 (s, N-urea, O=CN2), 149.82 (s, 1-amide, O=
CN), 134.80 (s, 1-imine, C=N), 26.05 (q, aliphatic, CH3)
Embodiment 5
(5) 2- (4- chlorobutyls) -4- methyl-1s, the synthesis of 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5)
31gNaH (1.292mol) is dissolved in 140mlDMF in batches under nitrogen protection and ice bath, weighs 3- methyl-
The phonetic 14g of 6- azepine ureas (0.110mol), is dissolved in DMF in batches, after stirring 1 hour, the bromo- 4- chlorobutanes 20g of 1- is added dropwise, instead
It should continue at room temperature overnight, then reaction mixture is added in ice water and be extracted twice with EA.Combined organic phase is used
Salt water washing is dried over anhydrous sodium sulfate and concentrates.By silica gel chromatography residue, solid product 2- (4- chlorine is obtained
Butyl) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5) 9g (0.041mol, yield:72%)
CD-5 spectrogram informations:
1H NMR:(400MHz, DMSO-d6) δ 7.57 (s, 1H, NH), 3.93-3.90 (m, 2H, CH2), 3.68-3.65
(m, J=5.8Hz, 2H, CH2), 3.15 (s, 3H, CH3), 1.81-1.74 (dt, J=6.3,3.3Hz, 4H, CH2)
13C NMR:(101MHz, DMSO-d6) δ 156.49 (s, N-urea, O=CN2), 149.06 (s, 1-amide, O=
C-N), 134.34 (s, 1-imine, N=CH), 50.68 (d, aliphatic, Cl-CH2), 45.31 (d, aliphatic, N-
CH2), 29.41 (s, aliphatic, CH3), 26.84 (t, aliphatic, CH2), 25.60 (s, aliphatic, CH2).
Embodiment 6
(6) synthesis of 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) (CD-7)
2- Bromopyrimidines 21g (0.132mo1), 1-Boc- piperazines 35g (0.188mo1) and triethylamine 25g (0.247mol) are molten
Solution is stirred overnight 16 hours, after the completion of reaction in 100ml ethyl alcohol at 50 DEG C, and reaction mixture is cooled to room temperature and is filtered,
Obtain white solid 4- (pyrimidine -2-base) piperazine -1- t-butyl formates (CD-6) 25g (0.095mol, yield:63.1%);Add
Enter 50mlEA and 50mlHCl/EA (3N), stirs 16h at room temperature, it is finally, dry after reaction mixture is filtered, obtain 16g productions
Object 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) (CD-7) (0.080mol, yield:86.48%).
The spectrogram information of CD-6 is:
1H NMR:(400MHz, Chloroform-d) δ 8.31 (d, J=4.8Hz, 2H, CH=), 6.51 (t, J=
4.7Hz, 1H, CH=), 3.84-3.77 (m, 4H, CH2), 3.53-3.46 (m, 4H, CH2), 1.49 (s, 9H, CH3).
13C NMR:(101MHz, DMSO-d6):δ 8.31 (d, J=4.8Hz, 2H, CH=), 6.51 (t, J=4.7 Hz,
1H, CH=), 3.84-3.77 (m, 4H, CH2), 3.53-3.46 (m, 4H, CH2), 1.49 (s, 9H, CH3).
The spectrogram information of CD-7 is:
1H NMR:(400MHz, Deuterium Oxide) δ 8.53 (dd, J=5.3,1.0Hz, 2H), 7.01 (td, J=
5.3,1.0Hz, 1H), 4.10-4.02 (m, 4H), 3.42-3.34 (m, 4H)
13C NMR:(101MHz, DMSO-d6) δ 159.89 (s, pyrimidine, N=CN2), 158.34 (s,
Pyrimidine, N=CH × 2), 111.46 (s, pyrimidine ,=CH), 42.57 (s, cyclohexane like, N-
CH2× 2), 40.95 (s, cyclohexane like, N-CH2×2).
The present invention presses embodiment 6, and the screening and optimization of CD-6 synthesis conditions as described in Table 1 have been carried out to parameter
React serial number | Alkali | Solvent | Temperature | Time | Yield |
1 | K2CO3 | THF | RT | 12h | 31.9% |
2 | K2CO3 | DCM | RT | 12h | 29.7% |
3 | K2CO3 | CH3CN | RT | 12h | 33.4% |
4 | K2CO3 | EtOH | RT | 12h | 36.8% |
5 | K2CO3 | H2O | RT | 12h | 21.2% |
6 | Cs2CO3 | EtOH | RT | 12h | 38.9% |
7 | NaOH | EtOH | RT | 12h | 31.4% |
8 | TEA | EtOH | RT | 12h | 47.3% |
9 | Py | EtOH | RT | 12h | 27.3% |
10 | TEA | EtOH | 50℃ | 12h | 61.9% |
11 | TEA | EtOH | reflux | 12h | 60.2% |
12 | TEA | EtOH | 50℃ | 16h | 63.1% |
13 | TEA | EtOH | 50℃ | 24h | 62.8% |
* if do not pointed out, RT room temperatures refer both to 25 DEG C.
Known to table 1, potassium carbonate does alkali, using different solvents system, reacts 12h at room temperature, is carried out to reaction dissolvent
After screening (reaction serial number 1-5), it is found that (reaction serial number 4) can be with 36.8% maximum output under conditions of ethyl alcohol makees solvent
Obtain compound CD-7.After establishing using ethyl alcohol as reaction dissolvent, next, we are respectively with cesium carbonate, triethylamine, pyrrole
Alkali is done in pyridine, has been done to alkali and has been screened (reaction serial number 4,6-9), obtained conclusion can be obtained most under conditions of doing alkali with triethylamine
High yield is 47.3% (reaction serial number 8).We attempt to increase reaction temperature promotion reaction yield, it is found that yield is most at 50 DEG C
High by 61.9% (reaction serial number 10), is continuously heating to alcohol reflux temperature, from the point of view of thin-layer chromatography monitors situation, plate layer will appear
Some small miscellaneous points, 60.2% (reaction serial number 11) can be fallen to by obtaining yield also.Finally, we attempt after extending the reaction time,
It was found that after extending the reaction time to 16 hours, the yield of reaction can be improved to 63.1% (reaction serial number 12), further be extended
To 24 hours, yield had no apparent variation (reaction serial number 13).So far, we have obtained one without metal catalytic, mild,
The synthesis condition for the synthesis segment CD-7 that can be mass produced, i.e., do alkali with triethylamine, and ethyl alcohol does solvent, 50 DEG C of reaction temperature
The lower reaction of degree 16 hours finally obtains compound CD-7 (reaction serial number 12) with 63.1% yield.
Embodiment 7
The synthesis of eptapirone (CD-8)
Weigh 2- (4- chlorobutyls) -4- methyl-1s in step (5), 2,4- triazines -3,5 (2H, 4H)-diketone 10g
(0.046mo1) and sodium iodide 10g are dissolved in 100ml acetonitriles, and mixture stirs 1h at 60 DEG C, and the 2- in step (6) is added
(1- piperazinyls) pyrimidine hydrochloride (1: 1) 10g (0.050mol) and potassium carbonate 20g is stirred overnight at 50 DEG C.After the completion of reaction,
Residue is cooled to room temperature, is eluted by collected by suction solid matter and with EA.Organic phase solvent is recycled by rotary evaporation,
Mixture is dissolved in DCM, with ultra-pure water and salt water washing, is dried with sodium sulphate, finally, obtains required product eptapirone
(CD-8) 8g, (0.023mol, yield:49.6%)
Eptapirone1H NMR spectras are shown in Fig. 2,13C NMR spectras are shown in Fig. 3 figures.
Eptapirone spectrogram information:
1H NMR:(400MHz, DMSO-d6) δ 8.34 (d, J=4.7Hz, 2H, CH=), 7.58 (s, 1H, CH=), 6.61
(t, J=4.7Hz, 1H, CH=), 3.91 (t, J=7.0Hz, 2H, CH2), 3.70 (t, J=5.0Hz, 4H, CH2), 3.16 (s,
3H, CH3), 2.38 (t, J=5.1Hz, 4H, CH2), 2.31 (t, J=7.2Hz, 2H, CH2), 1.69 (q, J=7.4Hz, 2H,
CH2), 1.50 (q, J=7.7Hz, 2H, CH2).
13C NMR:(101MHz, DMSO-d6) δ 161.69 (s, pyrimidine, N=CN2), 158.31 (s,
Pyrimidine, N-C=× 2), 156.57 (s, N-urea, O=CN2), 149.06 (s, 1-amide ,-CN=O), 134.31
(s, 1-imide ,-C=N), 110.48 (s, pyrimidine ,-C=), 57.84 (s, cyclohexane like, N-CH2×
2), 53.04 (s, cyclohexane like, N-CH2× 2), 51.31 (s, aliphatic, N-CH2× 2), 43.79 (s,
Aliphatic, N-CH2× 2), 26.96 (s, aliphatic, CH3), 26.11 (s, aliphatic, CH2), 23.54 (s,
Aliphatic, CH2)。
Claims (10)
1. the total synthesis method of eptapirone, which is characterized in that include the following steps:
Step (1) reacts semicarbazides and trichloroacetaldehyde, obtains 2- [2- (amino carbonyl) hydrazono-] (CD-1);
6- azepine urea pyrimidines (CD-2) are made in 2- [2- (amino carbonyl) hydrazono-] cyclization by step (2);
Step (3) reacts 6- azepine urea pyrimidines with acylating reagent, obtain 2- acyl group protections -2H- [1,2,4] triazine -3,5 (2H,
4H)-diketone (CD-3);
Step (4) carries out obtained 2- acyl group protections -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone and methylating reagent
Methylation reaction, after reaction reacts product with acid, and 3- methyl -6- azepines are made in the acyl protective groups of removing 2-
Urea pyrimidine (CD-4);
3- methyl -6- azepine urea pyrimidines and the halogenated -4- chlorobutanes of 1- are carried out N- alkylated reactions by step (5), obtain 2- (4- neoprenes
Base) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5);Halogenated -4- the chlorobutanes of the 1- are the bromo- 4- chlorine of 1-
Butane or the iodo- 4- chlorobutanes of 1-;
Step (6) is reacted 2- Bromopyrimidines, one of N by the piperazine that blocking group is protected at reaction solvent A, alkali A, into one
Step removes the blocking group on piperazine N, obtains 2- (1- piperazinyls) pyrimidine (CD-7) through sour water solution;
Step (7) will be by 2- (4- chlorobutyls) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone made from step (5)
(CD-5) it is reacted with 2- (1- piperazinyls) pyrimidines (CD-7) made from step (6), obtains eptapirone (CD-8).
2. total synthesis method according to claim 1, which is characterized in that in the step (1), the semicarbazides is ammonia
Base urea hydrochloride;
Semicarbazides and trichloroacetaldehyde molar ratio are 0.8: 1~1.2: 1;
Reaction dissolvent is water;Reaction temperature is room temperature~100 DEG C.
3. total synthesis method according to claim 1, which is characterized in that in the step (2), by 2- [2- (amino carbonyls
Base) hydrazono-] it is dissolved in ethylene glycol with alkali metal hydroxide, it is stirred to react 10~20h at 80~100 DEG C, is cooled to
10 DEG C and it is following after, add methanol, stand 10~20h, be then adjusted with acid the pH < 3 of solution system, be cooled to after being stirred to react
10 DEG C and it is following after, recycle to obtain 6- azepine urea pyrimidines CD-2.
4. synthetic method according to claim 1, which is characterized in that in step (3), the acylating reagent be acyl chlorides or
Acid anhydrides;Preferably acid anhydrides, further preferably acetic anhydride;
The temperature of acylation reaction is 130~150 DEG C.
5. total synthesis method according to claim 1, which is characterized in that by obtained 2- acyl groups protection -2H- [1,2,
4] triazine -3,5 (2H, 4H)-diketone is dissolved in alkali B in DMF under protective atmosphere and ice bath, stirs 1~2h at room temperature, then
Methylate reagent, is stirred to react 12h, through evaporating solvent, organic solvent extraction, the drying of salt water washing, anhydrous sodium sulfate after
It is dissolved in ethyl alcohol with toluene-4-sulfonic acid again after concentration, is stirred to react, it is phonetic to obtain 3- methyl -6- azepine ureas for deprotection group
Pyridine;
The alkali B is NaH or cesium carbonate;
The methylating reagent is potassium iodide, dimethyl suflfate or iodomethane;
The acid is toluene-4-sulfonic acid.
6. total synthesis method according to claim 1, which is characterized in that in step (5), 3- methyl -6- azepine ureas is phonetic
Be dissolved in DMF with alkali C under protective atmosphere, stir 1~2h after, be added dropwise the halogenated -4- chlorobutanes of 1-, at room temperature react 10~
After 20h, through organic solvent extraction, washing, dry, purifying, 2- (4- chlorobutyls) -4- methyl-1s are obtained, 2,4- triazines -3,5 (2H,
4H)-diketone (CD-5);
The alkali C is NaH or cesium carbonate;
The molar ratio that adds phonetic with 3- methyl -6- azepine ureas alkali C is 8~15: 1;
Halogenated -4- the chlorobutanes of 1-, CD-4 molar ratios are 1~2: 1.
7. total synthesis method according to claim 1, which is characterized in that in step (6), one of described N is protected
The piperazine for protecting radical protection is 1-Boc- piperazines;
The alkali A is triethylamine, K2CO3、Cs2CO3, at least one of NaOH, Py;
Molar ratios 1.5~2.5: 1 of the alkali A relative to 2- Bromopyrimidines;
Molar ratio 1~2: 1 of the piperazine relative to 2- Bromopyrimidines;
The reaction dissolvent is ethyl alcohol, THF, DCM, CH3CN、H2At least one of O.
8. total synthesis method according to claim 1, which is characterized in that in step (6), reaction temperature is 25~80 DEG C;
Reaction time is not less than 12H.
9. total synthesis method according to claim 1, which is characterized in that CD-5 and CD-7 is anti-at alkali D and catalyst
It answers, obtains the eptapirone;
The molar ratio of CD-5 and CD-7 is 1: 1~1.2;
Preferably, the alkali D is at least one of potassium carbonate, sodium carbonate, cesium carbonate;
Preferably, the catalyst is at least one of sodium iodide, potassium iodide, tetrabutylammonium iodide;
Preferably, in step (7), reaction dissolvent is at least one of acetonitrile, dioxane, tetrahydrofuran;
The temperature of reaction process is RT~60 DEG C;
Reaction time is 6~12H.
10. total synthesis method according to claim 1, which is characterized in that include the following steps:
Amino urea hydrochloride and trichloroacetaldehyde are dissolved in water by step (1), and heating reaction overnight, through cooling, suction filtration, washing, is done
It is dry, obtain 2- [2- (amino carbonyl) hydrazono-] (CD-1);
2- [2- (amino carbonyl) hydrazono-] and sodium hydroxide are dissolved in ethylene glycol by step (2), are stirred overnight at 80 DEG C, are passed through
After cooling, add methanol, stand overnight, with salt acid for adjusting pH < 3, half an hour is stirred at 80 DEG C, with brine ice cool to
Certain temperature obtains 6- azepine urea pyrimidines (CD-2) through suction filtration, washing, drying;
6- azepine urea pyrimidines are dissolved in acetic anhydride by step (3), and 10h is stirred at 140 DEG C, through cooling, evaporate solvent, first is added
Benzene, through filtering, being dried to obtain 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone (CD-3);
Step (4) is by obtained 2- acetyl group -2H- [1,2,4] triazine -3,5 (2H, 4H)-diketone under protective atmosphere and ice bath
It is dissolved in DMF with NaH, stirs 1 hour at room temperature, dimethyl suflfate, reaction is added to be stirred overnight, through evaporating solvent, You Jirong
After agent extraction, salt water washing, anhydrous sodium sulfate drying concentration, it is dissolved in ethyl alcohol with toluene-4-sulfonic acid, is stirred overnight at 60 DEG C,
Solvent is evaporated, is dissolved in DCM, 3- methyl -6- azepine urea pyrimidines (CD-4) are concentrated to give through drying;
Step (5) is dissolved in DMF under protective atmosphere with NaH by 3- methyl -6- azepine ureas are phonetic, and after stirring 1 hour, 1- is added dropwise
Bromo- 4- chlorobutanes, overnight, water on the rocks obtains 2- (4- neoprenes through organic solvent extraction, washing, dry, purifying for reaction at room temperature
Base) -4- methyl-1s, 2,4- triazines -3,5 (2H, 4H)-diketone (CD-5);
The dissolving of 2- Bromopyrimidines, 1-Boc- piperazines and triethylamine is stirred overnight 16 hours by step (6) in ethanol and at 50 DEG C, is passed through
Cooling, filtering, obtains 4- (pyrimidine -2-base) piperazine -1- t-butyl formates (CD-6), and EA and HCl/EA is added, stirs at room temperature
16h obtains 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) (CD-7) through filtering, drying;
Step (7) is by 2- (4- chlorobutyls) -4- methyl-1s in step (5), 2,4- triazines -3,5 (2H, 4H)-diketone and iodate
Sodium is dissolved in acetonitrile, and 1h is stirred at 60 DEG C, and 2- (1- piperazinyls) pyrimidine hydrochloride (1: 1) and potassium carbonate in step (6) is added,
It is stirred overnight at 50 DEG C;After cooling, suction filtration, washing, evaporation solvent, be dissolved in DCM, it is washed, dry, concentrate, obtain according to he
Grand (CD-8).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810295529.9A CN108440505A (en) | 2018-03-30 | 2018-03-30 | The total synthesis method of eptapirone |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810295529.9A CN108440505A (en) | 2018-03-30 | 2018-03-30 | The total synthesis method of eptapirone |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108440505A true CN108440505A (en) | 2018-08-24 |
Family
ID=63199114
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810295529.9A Pending CN108440505A (en) | 2018-03-30 | 2018-03-30 | The total synthesis method of eptapirone |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108440505A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115557910A (en) * | 2022-11-04 | 2023-01-03 | 苏州艾缇克药物化学有限公司 | Synthetic method of 6-azauracil |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5977106A (en) * | 1994-12-02 | 1999-11-02 | Pierre Fabre Medicament | 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives |
WO2003011841A1 (en) * | 2001-08-02 | 2003-02-13 | Neurocrine Biosciences, Inc. | 1,2,4-triazin-3,5-diones as gonadotropin-releasing hormone receptor (gnrh) antagonists |
CN102481300A (en) * | 2009-06-29 | 2012-05-30 | 安吉奥斯医药品有限公司 | Therapeutic compounds and compositions |
CN102918031A (en) * | 2010-05-28 | 2013-02-06 | 通用电气健康护理有限公司 | Radiolabeled compounds and methods thereof |
-
2018
- 2018-03-30 CN CN201810295529.9A patent/CN108440505A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5977106A (en) * | 1994-12-02 | 1999-11-02 | Pierre Fabre Medicament | 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives |
WO2003011841A1 (en) * | 2001-08-02 | 2003-02-13 | Neurocrine Biosciences, Inc. | 1,2,4-triazin-3,5-diones as gonadotropin-releasing hormone receptor (gnrh) antagonists |
CN102481300A (en) * | 2009-06-29 | 2012-05-30 | 安吉奥斯医药品有限公司 | Therapeutic compounds and compositions |
CN102918031A (en) * | 2010-05-28 | 2013-02-06 | 通用电气健康护理有限公司 | Radiolabeled compounds and methods thereof |
Non-Patent Citations (2)
Title |
---|
ALI MOHAMMADI等: "《Synthesis of novel 3-substituted-5H-benzo[5,6][1, 4]thiazino[3,2-e][1,2,4]triazines and their 15-lipoxygenase inhibitory activity》", 《JOURNAL OF THE IRANIAN CHEMICAL SOCIETY》 * |
J.S. DILEEP KUMARA, B,等: "《Synthesis and evaluation of arylpiperazines derivatives of 3,5-dioxo-(2H,4H)-1,2,4-triazine as 5-HT1AR ligands.》", 《BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115557910A (en) * | 2022-11-04 | 2023-01-03 | 苏州艾缇克药物化学有限公司 | Synthetic method of 6-azauracil |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103664912B (en) | A kind of synthesis technique of prucalopride | |
CN106146502A (en) | End for Larry this synthetic method and prepare intermediate | |
CN108440505A (en) | The total synthesis method of eptapirone | |
CN102532109B (en) | Synthetic method of lapatinib and salt of lapatinib | |
CN111777618A (en) | Method for preparing medical intermediate 4H-chromene [2, 3-b ] pyridine-3-nitrile through catalysis | |
CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
CN110818680A (en) | Preparation method of cyclohexane derivative | |
CN111233745B (en) | (E)1- (9-alkyl-carbazole-3-) -acrylic acid and preparation method thereof | |
CN107445964A (en) | A kind of synthetic method of Vardenafil hydrochloric acid impurity | |
CN106279114B (en) | A kind of synthetic method of Taladegib | |
CN104163798A (en) | Synthesis method of 3-amino-8-trifluoromethyl quinoline | |
CN110563721A (en) | Preparation method of azasetron hydrochloride | |
CN112979563B (en) | Preparation method of medical intermediate 2, 3-diaryl-2, 3-dihydroquinazoline-4 [1H ] -ketone | |
CN110804007B (en) | Polysubstituted pyrrole derivative and preparation method thereof | |
CN111574540B (en) | Preparation method of Degatinib | |
CN111606929B (en) | Preparation method of Degatinib | |
CN115124457B (en) | Synthesis method of 1-methyl-4- (4-piperidinyl) piperazine hydrochloride | |
CN118271213A (en) | Preparation method of linker drug conjugate intermediate | |
CN109796448B (en) | Preparation process of dasatinib | |
CN113087650A (en) | Preparation method of 2-maleimidoacetic acid N-hydroxysuccinimide ester | |
CN115572262A (en) | Isoquinoline derivative and preparation method thereof | |
CN118164991A (en) | Preparation method of aminopyrimidino pyrazole/pyrrole derivative | |
CN113372215A (en) | Novel esterification method for synthesizing p-halomethyl benzoate | |
CN113480523A (en) | Preparation method of pimobendan | |
CN117447459A (en) | Method for synthesizing rotigorskite key intermediate by using chiral phase transfer catalyst as catalyst |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180824 |
|
RJ01 | Rejection of invention patent application after publication |