CN105837524A - 5-azacytosine synthesis method - Google Patents
5-azacytosine synthesis method Download PDFInfo
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- CN105837524A CN105837524A CN201610271929.7A CN201610271929A CN105837524A CN 105837524 A CN105837524 A CN 105837524A CN 201610271929 A CN201610271929 A CN 201610271929A CN 105837524 A CN105837524 A CN 105837524A
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- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
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Abstract
The invention discloses a 5-azacytosine synthesis method .The method comprises the following steps that 1, dicyandiamide, formic acid and a catalyst p-toluenesulfonic acid are added into an airtight reaction device and heated to react to obtain emulsion matter; 2, the product obtained in the step 1 is refined through hydrochloric acid to obtain the 5-azacytosine .A high-pressure reaction kettle is utilized, under the p-toluenesulfonic acid catalysis condition, the dehydration reaction temperature of guanylurea formate is effectively lowered, anhydrous formic acid in a system is directly utilized as a dehydrating agent, the steps of a synthesis process are simplified, side reactions are reduced, the product quality is ensured, the productivity is improved, and reaction yield is higher than 80% based on dicyandiamide .
Description
Technical field
The invention belongs to organic synthesis field, particularly relate to the synthetic method of a kind of 5-azepine cytimidine.
Background technology
5-azepine cytimidine is the basic material of chemical synthesis azasugar aminoglycoside.Curative with 5-azepine cytimidine as raw material
Thing has 5-azacitidine, trade name Vidaza.Also have decitabine, trade name Decitabine.They are
Belong to demethylation medicine, there is the therapy mechanism of the methylated transferase inhibitor of uniqueness.It is clinically for myelosis
Abnormal syndrome, marrow sexual cell leukaemia, sickle-cell anemia and the curative effect in some entity tumors have obtained U.S.
The certification of state FDA.
In the clinical practice in past, the efficacy and saferry of 5-azacitidine class medicine has obtained continuous checking, and its indication is also
Extend along with various carrying out of application study, be gradually available for the treatment of multiple different malignant tumour, achieve well treatment
Effect.Along with economic fast development, the transformation of people's lives mode and the acceleration of aging population process, cancer has become
For ranked second the NCD having a strong impact on people's health of position after cardiovascular and cerebrovascular disease.Therefore green low cost
The exploitation of 5-azepine cytimidine synthesis technique will assist in 5-azacitidine class medicine further clinical application research and carry out,
The most effectively reduce the cost of China's malignant tumor patient treatment.
Report about 5-azepine cytimidine is the Orundmann et al. a kind of method (Grundmann at report in 1954 the earliest
Et al.Zur Kenntnis der Amino-triazine Chemische Berichte, 1954 (87), 19-23.): by dicyandiamide
After directly mixing with formic acid, after reacting 3 hours under conditions of 130 DEG C in flask, obtain substantial amounts of pasty solid, add
Ethanol wash, finally obtain 5-azepine cytimidine (chemical equation is as follows), the yield of this method less than 20%, Er Qie
Course of reaction produces substantial amounts of dicyandiamide copolymers, it is difficult to separating-purifying.
Another scheme be utilize dicyandiamidines and triethyl orthoformate react (PCT Patent, Bigatti, Ettore et al,
WO2010017374. United States Patent (USP), Bigatti, E.et al.；US201035354；Czech patents, Piskala, Alois et al.
CZ269077), in DMF, backflow obtains 5-azepine cytimidine, and the yield of this reaction can reach 28%.Guo Gang et al. (G.
Guo,Synthesis and antiproliferative activities of 5-azacytidine analogs in human leukemia cells,
Molecules, 13 (7), 2008,1487-1500) utilize trimethyl orthoformate can obtain the yield of 85% for raw material.But reacted
Cheng Zhongyong unstable chemcial property and be not belonging to the dicyandiamidines of large marketable material, synthesizes (chemical equation with high costs relatively
As follows).
(Niedballa U, the and Vobr H.A General Synthesis of N-glycosides V.Synthesis of such as Niedballa
5-Azacytidines.Journal of Organic Chemistry, 1974,39,3762-3764.) with dicyanamide and formic acid for raw material in second
In acid anhydride, 140 DEG C of backflow 2h, obtain 5-azepine cytimidine, productivity 34.6% (chemical equation is as follows).This scheme employs
Three kinds of raw materials, follow-up byproduct is difficult to recycle.
Vujjini(Vujjini,S.K.An Improved and Scalable Process for the Synthesis of 5-Azacytidine:
An Antineoplastic Drug, Organic Process Research&Development, 17 (2), 2013,303-306, Zhang Wensheng
Deng, 5-azepine cytimidine synthesis technique, Wuhan University Journal (Edition), 2003,49 (4), 454-456) et al. use two-step method
Technique, with dicyandiamide and formic acid as raw material, first reaction obtains intermediate product dicyandiamidines formates, after purification dehydration preparation 5-azepine
Cytimidine (chemical equation is as follows), synthesis yield can reach 60%.
In recent years, along with international overall Fine Chemical Industry shifts to China, the medical material medicine industry development of China was rapid, state
The yield of interior azacytidine class medicine rises year by year.The technique used at present substantially with dicyandiamide and formic acid as raw material, choosing
Select suitable solvent and carry out liquid phase synthesis.But the debirs and the waste water that produce in course of reaction are more, and environmental pollution pressure is big.
Especially its final products subtractive process uses substantial amounts of alcohol, process safety control and liquid waste processing all difficulty are increased.Cause
This green low emission is the main direction of studying of current this type of material medicine new technique for synthesizing exploitation.
Summary of the invention
The purpose of the present invention is contemplated to solve the problems referred to above, it is provided that the synthetic method of a kind of 5-azepine cytimidine, and it has and feeds intake
Simplicity, side reaction is few, and production cost is low, it is possible to realize industrialized production advantage.
To achieve these goals, the present invention adopts the following technical scheme that
The synthetic method of a kind of 5-azepine cytimidine, comprises the following steps:
(1) in confined reaction device, add dicyandiamide, formic acid and catalyst p-methyl benzenesulfonic acid, after adding thermal response, obtain milk；
(2) i.e. can get 5-azepine cytimidine after the product obtained by hydrochloric acid purification step (1).
Concrete chemical equation is as follows:
Preferably: described step (1) is carried out in autoclave.
Preferably: described formic acid is (1-2) with the mass ratio that feeds intake of dicyandiamide: (2-4), more preferably 3:5.
Preferably: the addition of described toluenesulfonic acid is the 0.1%-0.5% of dicyandiamide quality, more preferably 0.2%.
Preferably: the mass fraction of described formic acid is 98%-99.5%.
Preferably: the reaction condition in step (1): reaction temperature is 100-120 DEG C (more preferably: 100 DEG C), the reaction time is
1-2 hour (more preferably: 1.5 hours).
Preferably: in described step (2), the mass fraction of hydrochloric acid is 5%, feed intake volume and the formic acid in step (1) of described hydrochloric acid
The volume ratio that feeds intake is (7-10): 1 (more preferably: 8:1), the temperature that described hot-air oven is dried is 80-85 DEG C.
Preferably: the concrete steps of described step (2): the product that step (1) obtains is transferred in reactor, adds dilute salt
Acid, is heated to reflux to solution becoming clarification, at crystallization kettle, mixed liquor is added ammoniacal liquor regulation through filter cylinder heat filtering to crystallization kettle, filtrate
After pH, separate out white crystal, after centrifugation, be dried through hot-air oven and i.e. can get 5-azepine cytimidine.
Preferably: the mass fraction of described ammoniacal liquor is 30%, regulation pH to 5-7 (more preferably pH is 6).
Preferably, described formic acid, dicyandiamide, p-methyl benzenesulfonic acid, hydrochloric acid, ammoniacal liquor are chemical pure.
The present invention is with formic acid, dicyandiamide as raw material, and p-methyl benzenesulfonic acid is catalyst, use high pressure reaction assembly, utilize formic acid and
The heat produced in dicyandiamide course of reaction raises kettle pressure, reduces the reaction temperature of formic acid system, it is to avoid dicyandiamide
The generation of polymerization side reactions.Mother liquor can recycle, it is achieved the greenization of whole synthesis technique.
Formic acid and dicyandiamide react generation 5-azepine cytimidine and are divided into two steps from the angle of kinetics, are first that dicyandiamide exists
Under acid condition, cyano group aquation generates dicyandiamidines, and then dicyandiamidines occurs intermolecular dehydration cyclization to react generation 5-azepine again with formic acid
Cytimidine.The first step of reaction needs water as reactive material, and can slough the water of two molecules between second step formic acid and dicyandiamidines.
If the water yield is excessive in system, under strongly acidic conditions, cyano group can be hydrolyzed to carboxyl further and makes dicyandiamide under the high temperature conditions
Decompose ammonification.Therefore present invention adds p-methyl benzenesulfonic acid as dehydration and hydrolysis co-catalysis agent, improve reaction second
The efficiency of condensation dehydration, directly utilizes the water participation first step dicyandiamide aquation that second step dehydration produces, and avoid system can simultaneously
The generation of energy side reaction.
Generally using two-step method to synthesize in prior art, first formic acid and dicyandiamide prepares dicyandiamidines formates, then amidino groups
The dehydration under conditions of the strong dehydrating agent such as high temperature or acetic anhydride exists of urea formates obtains 5-azepine cytimidine.Wherein due to dicyandiamidines first
The stability of hydrochlorate own is not enough, and cyan-hydrolysis byproduct is many, and therefore final overall yield is on the low side.
Two-step reaction is united two into one by the present invention, on the one hand simplifies dosing procedure, improves production efficiency, on the other hand adds
Anhydrous formic acid in the water of trace cause after dicyandiamide aquation is dicyandiamidines, utilize anhydrous formic acid itself as dehydrating agent, to first
Under benzene sulfonic acid catalytic condition, dehydration produces 5-azepine cytimidine, and the water of abjection promotes dicyandiamide aquation further, plays hydrolytic process
To promoting to add the double action of protection, reduce production cost, reduce side reaction and generate, improve reaction yield and product purity.
The invention has the beneficial effects as follows,
1, the present invention is to utilize autoclave, under the conditions of Catalyzed by p-Toluenesulfonic Acid, significantly reduces dicyandiamidines formates
Dehydration temperature, directly utilizes the anhydrous formic acid in system as dehydrating agent, simplifies the step of synthesis technique, decrease pair
Reaction generation, it is ensured that product, to quality, improves productivity, reaction yield in terms of dicyandiamide higher than 80%.
2, the present invention is in the case of anhydrous formic acid slightly excess, can be effectively improved dicyandiamide conversion yields, greatly reduce
The production cost of 5-azepine cytimidine.
3, whole reaction is carried out in the reaction system closed, and almost without three waste discharge in production process, purifying technique process produces
Waste liquid by concentrate cooling can isolate ammonium chloride.A small amount of efflux wastewater is prone to biochemical degradation and processes.
Accompanying drawing explanation
Fig. 1 is the 1H NMR spectra of the embodiment of the present invention 1 synthetic product；
Fig. 2 is the FTIR spectrogram of the embodiment of the present invention 1 synthetic product；
Fig. 3 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 1 synthetic product, chromatographic condition: detection wavelength 317nm, flowing
Mutually pure methyl alcohol, test sample purity is higher than 95%；
Fig. 4 is the high-efficient liquid phase chromatogram of comparative example of the present invention 2-in-1 one-tenth product, chromatographic condition: detection wavelength 317nm, flowing
Mutually pure methyl alcohol, test sample purity is higher than 95%.
Detailed description of the invention
The invention will be further described with embodiment below in conjunction with the accompanying drawings.
Embodiment 1
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst (0.005Kg).Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 110 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.8kg (with
The dicyandiamide rate of collecting is 85%).
By Fig. 1 and Fig. 2 it can be seen that product prepared by the present invention is 5-azepine cytimidine, Fig. 3 draw, pass through high-efficient liquid
Phase chromatogram can be seen that purity is higher than 95%.
Embodiment 2
(1) in 10L autoclave, anhydrous formic acid (98%) 1.3Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst (0.005Kg).Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 100 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separates out white crystal, after centrifugation, is dried through hot-air oven and i.e. can get 5-azepine cytimidine 2.65kg
(with the dicyandiamide rate of collecting for 80%).
Drawn by Fig. 4, can be seen that purity is higher than 95% by high-efficient liquid phase chromatogram.
Embodiment 3
(1) in 10L autoclave, anhydrous formic acid (99.5%) 2.0Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst (0.005Kg).Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 120 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.8kg (with
The dicyandiamide rate of collecting is 85%).
Embodiment 4
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst 0.0025Kg.Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 110 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 1.9kg (with
The dicyandiamide rate of collecting is 58%).
Embodiment 5
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst 0.01Kg.Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 110 DEG C, after reaction terminates, slow
The slow reaction temperature that reduces, to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.7kg (with
The dicyandiamide rate of collecting is 81%).
Embodiment 6
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst 0.005Kg.Under sealing stirring, reactor is pressurizeed and is to slowly warm up to reaction temperature, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 5, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.4kg (with
The dicyandiamide rate of collecting is 72%).
Embodiment 7
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst 0.005Kg.Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 110 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 7, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.8kg (with
The dicyandiamide rate of collecting is 85%).
Embodiment 8
(1) in 10L autoclave, anhydrous formic acid (98%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst 0.005Kg.Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 110 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.4kg (with
The dicyandiamide rate of collecting is 72%).
Embodiment 9
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst (0.005Kg).Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 100 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.0kg (with
The dicyandiamide rate of collecting is 60%).
Embodiment 10
(1) in 10L autoclave, anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg it are sequentially added into and to toluene sulphur
Acid catalyst (0.005Kg).Under sealing stirring, reactor is pressurizeed and is to slowly warm up to 130 DEG C, after reaction terminates,
Slowly reduction reaction temperature is to room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 2.8kg (with
The dicyandiamide rate of collecting is 85%).
Contrast experiment 1
(1) in 10L autoclave, it is sequentially added into anhydrous formic acid (98%) 1.5Kg, dicyandiamide 2.5Kg, does not adds catalyst.
Under sealing stirring, reactor pressurizeed and is to slowly warm up to 130 DEG C, after reaction terminates, slowly reducing reaction temperature extremely
Room temperature, obtains white solid.
(2) being transferred to by described white solid in 50L glass reaction still, adding 10L mass concentration is 5% watery hydrochloric acid.Heating
Reflux 30 minutes and become clarification to solution, mixed liquor is added 30% ammoniacal liquor through filter cylinder heat filtering to crystallization kettle, filtrate at crystallization kettle
Regulation pH to 6, separate out white crystal, after centrifugation, through hot-air oven be dried i.e. can get 5-azepine cytimidine 1.1kg (with
The dicyandiamide rate of collecting is 33%).
Contrast experiment 2
(1) in 1000mL there-necked flask, add 99.% anhydrous formic acid 100mL, be then dividedly in some parts dicyandiamide 84g, heat up
React 3 hours to 118-120 DEG C, in the thick white thing obtained, then add 100ml 95% ethanol, mistake after stirring
Leach precipitation, grind after drying, spread out straticulation, put into and toast 2 hours at 145 DEG C of baking oven, obtain white solid.
(2) thick product obtained in the previous step is added in 1000mL flask the watery hydrochloric acid of 300mL5%, is heated to reflux, live
Property carbon decoloring process after, filter while hot, filtrate with 30% aqueous ammonia conditions pH to 6. cooling standing, separate out substantial amounts of white crystals.
Filter, washing, after drying, obtain 60.3g 5-azepine cytimidine (collecting rate 54% with dicyandiamide).
Result shows: use technical scheme synthesis 5-azepine cytimidine to be substantially better than existing in comprehensive yield and cost
The production technology of document report.Embodiment, compared with comparative example, illustrates that the core of technical solution of the present invention is that toluenesulfonic acid is catalyzed
The use of agent, significantly reduces the dehydration temperature of dicyandiamidines formates, directly utilizes the anhydrous formic acid in system as de-
Aqua so that the dehydration of the hydration reaction of dicyandiamide and dicyandiamidines formates can be worked in coordination with under hydrothermal conditions and be carried out.Simplify
The step of synthesis technique, decreases the generation of side reaction, it is ensured that product, to quality, improves productivity, and reaction yield is with double
Cyanamide meter is higher than 80%.
Although the detailed description of the invention of the present invention is described by the above-mentioned accompanying drawing that combines, but not limit to scope
System, one of ordinary skill in the art should be understood that on the basis of technical scheme, and those skilled in the art need not pay
Go out various amendments or deformation that creative work can make still within protection scope of the present invention.
Claims (10)
1. a synthetic method for 5-azepine cytimidine, is characterized in that: comprise the following steps:
(1) in confined reaction device, add dicyandiamide, formic acid and catalyst p-methyl benzenesulfonic acid, after adding thermal response, obtain milk；
(2) i.e. can get 5-azepine cytimidine after the product obtained by hydrochloric acid purification step (1).
2. synthetic method as claimed in claim 1, is characterized in that: described step (1) is carried out in autoclave.
3. synthetic method as claimed in claim 1, is characterized in that: described formic acid is (1-2) with the mass ratio that feeds intake of dicyandiamide:
(2-4)。
4. synthetic method as claimed in claim 1, is characterized in that: the addition of described toluenesulfonic acid is dicyandiamide quality
0.1%-0.5%.
5. synthetic method as claimed in claim 1, is characterized in that: the mass fraction of described formic acid is 98%-99.5%.
6. synthetic method as claimed in claim 1, is characterized in that: the reaction condition in step (1): reaction temperature is
100-120 DEG C, the reaction time is 1-2 hour.
7. synthetic method as claimed in claim 1, is characterized in that: in described step (2), the mass fraction of hydrochloric acid is 5%.
8. synthetic method as claimed in claim 1, is characterized in that: the volume that feeds intake of described hydrochloric acid is thrown with formic acid in step (1)
Material volume ratio is (7-10): 1.
9. synthetic method as claimed in claim 1, is characterized in that: the concrete steps of described step (2): by step (1)
The product obtained is transferred in reactor, adds watery hydrochloric acid, is heated to reflux to solution becoming clarification, by mixed liquor through filter cylinder heat filtering
To crystallization kettle, filtrate after crystallization kettle adds ammoniacal liquor regulation pH, separates out white crystal, after centrifugation, does through hot-air oven
Dry i.e. can get 5-azepine cytimidine.
10. synthetic method as claimed in claim 9, is characterized in that: the mass fraction of described ammoniacal liquor is 30%.
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| EP2321302B1 (en) * | 2008-08-01 | 2014-10-29 | Dr. Reddy's Laboratories Ltd. | Azacitidine process and polymorphs |
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| 李飞龙等: "5-氮杂-5-脱氧胞苷的合成工艺优化及其对SKOV3作用", 《安徽医科大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020907A (en) * | 2018-09-07 | 2018-12-18 | 泰山医学院 | A kind of new synthetic method of 5- azepine cytimidine |
| CN109020907B (en) * | 2018-09-07 | 2022-02-01 | 山东第一医科大学(山东省医学科学院) | Novel synthesis method of 5-azacytosine |
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| Publication number | Publication date |
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| CN105837524B (en) | 2018-07-20 |
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