CN108864001A - A kind of new method synthesizing ranitidine - Google Patents
A kind of new method synthesizing ranitidine Download PDFInfo
- Publication number
- CN108864001A CN108864001A CN201810702539.XA CN201810702539A CN108864001A CN 108864001 A CN108864001 A CN 108864001A CN 201810702539 A CN201810702539 A CN 201810702539A CN 108864001 A CN108864001 A CN 108864001A
- Authority
- CN
- China
- Prior art keywords
- ranitidine
- synthesis
- reaction
- solution
- sodium hydroxide
- 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Abstract
The invention discloses a kind of new methods for synthesizing ranitidine, and this method includes the synthesis of vinylidene chloride, the synthesis of 1,1- bis- chloro- 2- nitroethylene, ring closure reaction, the ring-opening reaction carried out under the conditions of existing for the desiccant, the synthesis of ranitidine.This method uses water-less environment in the preparation process of open-loop products, avoids the generation of the presence due to water and interference and impurity to reaction, reduces post-processing work, improves raw material availability.Preparation method of the present invention effectively increases the reaction yield of open-loop products, the purity for improving ring-opening reaction, reduces the reaction time, the yield and purity of product ranitidine are improved on this basis, production cost is reduced, industrialized production is more advantageous to.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of new method for synthesizing ranitidine.
Technical background
Ranitidine also known as ranitidine are potent histamine H2 receptor antagonist.Ranitidine is current with Cimetidine
The drug for the treatment canker being most widely used, but the effect of ranitidine is 5~8 times stronger than Cimetidine, and action time
More long.Because of its gastric acid secretion after capable of effectively inhibiting histamine, pentagastrin and carbaminoylcholine to stimulate because of it, and reduce
Gastric acid and gastric activity are clinically used for treatment duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux oesophagus
The treatment of scorching and Zhuo-Chinese mugwort syndrome etc..Therefore, ranitidine is always the research hotspot drug for treating canker, produces work
Skill is also research hotspot both domestic and external.
China was produced in 1985 by Shanghai No.6 Pharmaceutical Factory.Preparation process in relation to ranitidine has had the long period
Research, main technique is largely with 1,1,2- trichloroethanes for raw material at present, by ring closure reaction, ring-opening reaction,
It further reacts, obtains ranitidine, the dosage form being prepared mainly has tablet, capsule, injection etc..But current
In preparation process, reaction environment is not satisfactory, and the product yield friendship made is low, purity is lower, and processing cost is higher, is not suitable for big
The production of batch strictly limits a wide range of use of ranitidine.
Summary of the invention
To solve the above-mentioned problems, the present invention provides a kind of new method for synthesizing ranitidine, this method passes through to thunder
Buddhist nun replaces the change of fourth synthetic reaction environment, hence it is evident that the yield and purity for improving ranitidine reduce production cost, be conducive to
The large-scale industrial production of ranitidine.
The present invention is achieved by the following technical solutions
A kind of new method synthesizing ranitidine, this method includes the synthesis of vinylidene chloride, 1,1- bis- chloro- 2- nitro second
The synthesis of alkene, ring closure reaction, ring-opening reaction, the synthesis of ranitidine；It is specific as follows：
(1) use 1,1,2 trichloroethanes and sodium hydrate aqueous solution for Material synthesis vinylidene chloride；
(2) vinylidene chloride obtained using concentrated hydrochloric acid, concentrated nitric acid and step (1) is the chloro- 2- nitro of Material synthesis 1,1- bis-
Ethylene；
(3) cyclization is carried out with the chloro- 2- nitroethylene of 1,1- bis- that sodium hydroxide, Mercaptamine and step (2) obtain
Reaction, obtains cyclization product；
(4) cyclization product, desiccant that step (3) obtains are added in dehydrated alcohol and are uniformly mixed；After mixing,
In mixed solution and dripping methylamine solution, after methylamine solution is added dropwise, react 10~12 hours at room temperature, reaction is completed
Afterwards, it filters, filtrate is concentrated under reduced pressure, recrystallization obtains open-loop products；
(5) open-loop products, 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and the solid hydrogen-oxygen obtained step (4)
Changing sodium is that raw material is reacted, and after the reaction was completed, handles obtained substance, thunder Buddhist nun can be obtained after the completion of processing and replace
Fourth.
The new method of the synthesis ranitidine, the synthesis of step (1) described vinylidene chloride are specific as follows：At room temperature,
1,1,2 trichloroethanes is added in reaction flask, the aqueous solution of sodium hydroxide is then added dropwise into 1,1,2 trichloroethanes, side is added dropwise
Side stirring, obtains vinylidene chloride after the reaction was completed.
The new method of the synthesis ranitidine, the mass concentration of step (1) described sodium hydrate aqueous solution are 35%；Institute
The mass ratio for stating 1,1,2 trichloroethanes and sodium hydrate aqueous solution is 1：0.8~0.9.
The new method of the synthesis ranitidine, the synthesis of the chloro- 2- nitroethylene of step (2) 1, the 1- bis- are specially：
Concentrated hydrochloric acid is uniformly mixed first to obtain mixed acid with concentrated nitric acid, the vinylidene chloride that then step (1) is prepared is added dropwise
Into mixed acid, after being added dropwise to complete, react 2.5~5 hours at room temperature；After the reaction was completed, it is extracted using ethyl acetate/water two-phase
Method extracted, washs and (washed using saturated salt solution to organic phase), dry (anhydrous sodium sulfate is added at room temperature to having
Machine is mutually dried 0.5 hour), filter, concentration (be evaporated under reduced pressure), the chloro- 2- nitroethylene of 1,1- bis- can be obtained；
Mass ratio of concentrated hydrochloric acid and concentrated nitric acid is 1 during this:1, the mass ratio of concentrated hydrochloric acid and vinylidene chloride is 1:0.8
~0.9.
The new method of the synthesis ranitidine, ring closure reaction described in step (3) are specially：In the water-soluble of sodium hydroxide
Addition Mercaptamine, which is uniformly mixed, in liquid obtains mixed solution；Then it under the conditions of 45~50 DEG C, is dripped into mixed solution
The chloro- 2- nitroethylene of 1,1- bis- for adding step (2) to obtain, after being added dropwise to complete, reacts 1~2 hour under the conditions of 45~50 DEG C；Instead
It after the completion of answering, is extracted using ethyl acetate/water two-phase extraction, organic phase is washed (using saturated salt solution pair
Organic phase is washed), dry (it is 0.5 hour dry to organic phase at room temperature that anhydrous sodium sulfate is added), is concentrated under reduced pressure and (depressurizes
Distillation), obtain cyclization product；
Mass concentration of sodium hydroxide solution is 20% during this；The sodium hydroxide solution and cysteamine hydrochloric acid
The mass ratio of salt is 1:0.1~0.2, sodium hydroxide solution and 1, the mass ratio of the chloro- 2- nitroethylene of 1- bis- is 1:0.1~0.2.
The new method of the synthesis ranitidine, methylamine solution described in step (4) are the ethanol solution of methylamine, methylamine
Mass concentration is 30%；
The amount ratio of the dehydrated alcohol and cyclization product is 3ml：1g；The ethanol solution of the dehydrated alcohol and methylamine
Amount ratio is 2.7ml:1ml；The amount ratio of the dehydrated alcohol and desiccant is 100ml：(1~10) g.
The new method of the synthesis ranitidine, the desiccant are to include silica gel, quick lime, anhydrous calcium chloride, anhydrous
Magnesium sulfate or molecular sieve.Preferably quick lime.
The new method of the synthesis ranitidine, step (5) open-loop products and 2- [(dimethylamino) methyl] -5 chlorine
Methyl-ribofuranosyl and the detailed process of solid sodium hydroxide reaction are：Open-loop products, the 2- [(diformazan that step (4) is obtained first
Amino) methyl] -5 Chloromethyl-furans and solid sodium hydroxide be added in distilled water, be uniformly mixed；After mixing in 45 DEG C of items
It is reacted 1.5~2 hours under part；After the reaction was completed, it is concentrated under reduced pressure and removes moisture, absolute ethyl alcohol and stirring, suction filtration, concentration is then added
Then twice using dehydrated alcohol recrystallization ranitidine can be obtained in filtrate；
During being somebody's turn to do, the amount ratio of the distilled water and open-loop products is 1ml：(0.3~0.4) g；The open-loop products with
The mass ratio of 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and solid sodium hydroxide is 1：1：0.3~0.4.
Compared with prior art, the present invention has following positive beneficial effect
The present invention uses reaction reagent for dehydrated alcohol during preparing open-loop products, and joined desiccant, i.e.,
Be completely secured the reaction process be carry out in anhydrous conditions (presence for avoiding having water in solvent, disturbing reaction carry out, lead
It causes a large amount of impurity to generate, that is, effectively prevents a large amount of impurity and generate to the waste of subsequent processing bring manpower and material resources, also avoid
The waste of raw material), it effectively increases the reaction yield of open-loop products, improve the purity of ring-opening reaction, when reducing reaction
Between；The yield and purity for preparing ranitidine are improved on the basis of again, reduces production cost, are more advantageous to industrial metaplasia
It produces；
For the present invention in the preparation process of ranitidine, the reagent of use is innocuous agents, does not influence, subtracts on environment
Lack the influence caused by environment in ranitidine preparation process, reduces the manpower object that the later period is processing environment pollution and consuming
Power further reduced the production cost of this production process；
The present invention is not influencing environment, on the basis of reducing production cost, improves the yield of product ranitidine
And purity, it is more advantageous to the large-scale industrial production of ranitidine.
Detailed description of the invention
Fig. 1 is the liquid chromatogram that embodiment 2 prepares ranitidine；
Fig. 2 is the liquid chromatogram enlarged drawing that embodiment 2 prepares ranitidine；
Fig. 3 is that embodiment 2 prepares ranitidine liquid phase detection data result；
Fig. 4 is the liquid chromatogram that embodiment 3 prepares ranitidine；
Fig. 5 is the liquid chromatogram enlarged drawing that embodiment 3 prepares ranitidine；
Fig. 6 is that embodiment 3 prepares ranitidine liquid phase detection data result.
Specific embodiment
The present invention is described in more details below by specific embodiment, but be not intended to restrict the invention
Protection scope.
Embodiment 1
A kind of new method synthesizing ranitidine, this approach includes the following steps：
(1) use 1,1,2 trichloroethanes and sodium hydrate aqueous solution for Material synthesis vinylidene chloride：At room temperature, by 1,
1,2 trichloroethanes is added in reaction flask, and the water for the sodium hydroxide that mass concentration is 35% is then added dropwise into 1,1,2 trichloroethanes
Solution is stirred when being added dropwise, and obtains vinylidene chloride after the reaction was completed；Wherein, described 1,1,2 trichloroethanes and sodium hydroxide
The mass ratio of aqueous solution is 1：0.8~0.9；
(2) vinylidene chloride obtained using concentrated hydrochloric acid, concentrated nitric acid and step (1) is the chloro- 2- nitro of Material synthesis 1,1- bis-
Ethylene：Concentrated hydrochloric acid is uniformly mixed first to obtain mixed acid with concentrated nitric acid, the vinylidene chloride that then step (1) is prepared
It is added drop-wise in mixed acid, after being added dropwise to complete, reacts 2.5~5 hours at room temperature；After the reaction was completed, using ethyl acetate/water two-phase
Extraction is extracted, and is washed, is added in organic phase after washing anhydrous to organic phase using saturated salt solution after extraction
Sodium sulphate is dried 0.5~1 hour at room temperature, is filtered, concentration (being evaporated under reduced pressure), and the chloro- 2- nitro second of 1,1- bis- can be obtained
Alkene；
Mass ratio of concentrated hydrochloric acid and concentrated nitric acid is 1 during this:1, the mass ratio of concentrated hydrochloric acid and vinylidene chloride is 1：0.8
~0.9；
(3) cyclization is carried out with the chloro- 2- nitroethylene of 1,1- bis- that sodium hydroxide, Mercaptamine and step (2) obtain
Reaction, obtains cyclization product：It is equal for addition Mercaptamine mixing in the aqueous solution of 20% sodium hydroxide in mass concentration
It is even to obtain mixed solution；Then under the conditions of 45~50 DEG C, the chloro- 2- of 1,1- bis- that is obtained to mixed solution and dripping step (2)
Nitroethylene after being added dropwise to complete, reacts 1~2 hour under the conditions of 45~50 DEG C；After the reaction was completed, double using ethyl acetate/water
Phase extraction is extracted, and is washed using saturated salt solution to organic phase after extraction, nothing is added after washing in organic phase
Aqueous sodium persulfate is dried 0.5~1 hour at room temperature, is concentrated under reduced pressure and (is evaporated under reduced pressure), and cyclization product is obtained；
The mass ratio of the sodium hydroxide solution and Mercaptamine is 1:0.1~0.2, sodium hydroxide solution and 1,1-
The mass ratio of two chloro- 2- nitroethylenes is 1:0.1~0.2；
(4) cyclization product, desiccant that step (3) obtains are added in dehydrated alcohol and are uniformly mixed；After mixing,
In mixed solution and dripping methylamine solution, after methylamine solution is added dropwise, react 10~12 hours at room temperature, reaction is completed
Afterwards, it filters, filtrate is concentrated under reduced pressure, recrystallization obtains open-loop products；
During being somebody's turn to do, the methylamine solution is the ethanol solution of methylamine, and the mass concentration of methylamine is 30%；It is described anhydrous
The amount ratio of ethyl alcohol and cyclization product is 3ml：1g；The amount ratio of the ethanol solution of the dehydrated alcohol and methylamine is 2.7ml:
1ml；The amount ratio of the dehydrated alcohol and desiccant is 100ml：(1~10) g；
The drying machine used can be silica gel, quick lime, anhydrous calcium chloride, anhydrous magnesium sulfate or molecular sieve, preferably make a living
Lime.
(5) open-loop products, 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and the solid hydrogen-oxygen obtained step (4)
Changing sodium is that raw material is reacted, and after the reaction was completed, handles obtained substance, thunder Buddhist nun can be obtained after the completion of processing and replace
Fourth：Open-loop products, 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and the solid sodium hydroxide that step (4) is obtained first
It is added in distilled water, is uniformly mixed；It is reacted 1.5~2 hours under the conditions of 45 DEG C after mixing；After the reaction was completed, it depressurizes dense
Contracting removes moisture, absolute ethyl alcohol and stirring, suction filtration, concentration filtrate is then added, then twice using dehydrated alcohol recrystallization
Obtain ranitidine；
During being somebody's turn to do, the amount ratio of the distilled water and open-loop products is 1ml：(0.3~0.4) g；The open-loop products with
The mass ratio of 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and solid sodium hydroxide is 1：1：0.3~0.4.
Specifically prepare product as illustrated in the examples below：
Embodiment 2
(1) synthesis of vinylidene chloride
At room temperature, in the 1 of 100g, 1,2- trichloroethanes be added dropwise mass concentration be 35% sodium hydroxide solution 85g into
Row reaction, obtains vinylidene chloride 72g, yield 97% after the reaction was completed；
(2) synthesis of the chloro- 2- nitroethylene of 1,1- bis-
It carries out 75g concentrated hydrochloric acid and 75g concentrated nitric acid to be mixed to get mixed acid, at room temperature a dropping step (1) into mixed acid
The vinylidene chloride 62g of preparation is stirred to react 2.5 hours after being added dropwise；After the reaction was completed, using ethyl acetate/water two-phase
Extraction is extracted, and is washed using saturated salt solution to organic phase after extraction, is added after the completion of washing, in organic phase
Enter anhydrous sodium sulfate to dry 0.5 hour at room temperature, organic phase is evaporated under reduced pressure after the completion of dry, is concentrated, it is chloro- to obtain 1,1- bis-
2- nitroethylene 85g, yield 93%.
(3) ring closure reaction
In the sodium hydrate aqueous solution that 350g mass concentration is 20%, 46g Mercaptamine is added and is stirred
It is even, 45 DEG C are then heated to, the chloro- 2- of 1,1- bis- that in the solution being uniformly mixed prepared by a dropping step (2) after heating
Nitroethylene 57g；After being added dropwise, continues stirring 2 hours under the conditions of 45 DEG C, stop reaction after the completion of stirring, using acetic acid
Ethyl ester/water two-phase extraction is extracted, and is washed using saturated salt solution to organic phase after the completion of extraction, after the completion of washing
Anhydrous sodium sulfate is added in organic phase, dries 0.5 hour at room temperature, is evaporated under reduced pressure after the completion of dry, concentration, obtains cyclization product
52g, yield 90%.
(4) ring-opening reaction
Cyclization product 50g, quick lime 10g and dehydrated alcohol the 150ml mixing that step (3) preparation is added in reaction flask are equal
It is even；After mixing, the methylethylolamine solution 55ml that mass concentration is 30% is added dropwise thereto, the ethanol solution of methylamine drips
10h is reacted at room temperature after finishing；End of reaction filters reaction solution, filter cake twice of ethanol washing (30ml/ all over), filtrate decompression
Concentration, recrystallization, obtains open-loop products 57.3g, yield 95%.
(5) synthesis of ranitidine
Distilled water 150ml is added in reaction flask, open-loop products 48g, 2- [(dimethylamino) that step (4) is prepared
Methyl] -5- Chloromethyl-furan 48g and solid sodium hydroxide 18g be uniformly mixed, it is warming up to 45 DEG C after mixing, 45
It is reacted 1.5 hours under the conditions of DEG C；Water is concentrated under reduced pressure after the reaction was completed and is removed, 70ml absolute ethyl alcohol and stirring is then added, is filtered,
Filtrate is concentrated, then is recrystallized 2 times with dehydrated alcohol, obtains ranitidine 75g, yield 89%.
After preparing product, the ranitidine being prepared is detected using high performance liquid chromatograph, as a result such as Fig. 1
And shown in Fig. 2；
Embodiment 3
(1) synthesis of vinylidene chloride
At room temperature, in the 1 of 100g, 1,2- trichloroethanes be added dropwise mass concentration be 35% sodium hydroxide solution 85g into
Row reaction, obtains vinylidene chloride 74g, yield 98% after the reaction was completed；
(2) synthesis of the chloro- 2- nitroethylene of 1,1- bis-
It carries out 75g concentrated hydrochloric acid and 75g concentrated nitric acid to be mixed to get mixed acid, at room temperature a dropping step (1) into mixed acid
The vinylidene chloride 62g of preparation is stirred 4 hours after being added dropwise；After the reaction was completed, using ethyl acetate/water two-phase extraction
It is extracted, organic phase is washed using saturated salt solution after extraction, is added in organic phase after the completion of washing anhydrous
Sodium sulphate is dried 1 hour at room temperature, is evaporated under reduced pressure, is concentrated to organic phase after the completion of dry, obtains the chloro- 2- nitro of 1,1- bis-
Ethylene 87g, yield 95%.
(3) ring closure reaction
In the sodium hydroxide solution that 350g mass concentration is 20%, 46g Mercaptamine is added and is uniformly mixed,
50 DEG C are then heated to, the dropwise addition 1 that in the solution being uniformly mixed prepared by a dropping step (2) after heating, the chloro- 2- of 1- bis-
Nitroethylene 57g after being added dropwise, continues stirring 1 hour under the conditions of 50 DEG C, stops reaction after the completion of stirring, using acetic acid
Ethyl ester/water two-phase extraction is extracted, and is washed using saturated salt solution to organic phase after the completion of extraction, after the completion of washing
Anhydrous sodium sulfate is added in organic phase, dries 1 hour at room temperature, is evaporated under reduced pressure after the completion of dry, concentration, obtains cyclization product
50g, yield 88%.
(4) ring-opening reaction
Cyclization product 50g, quick lime 10g and the dehydrated alcohol 150ml mixing that step (3) preparation is added in reaction flask are equal
It is even；After mixing, the methylethylolamine solution 55ml that mass concentration is 30% is added dropwise thereto, reacts 12h at room temperature.It has reacted
Finish, reaction solution is filtered, filter cake is washed twice (30ml/ times) with dehydrated alcohol, filtrate decompression concentration, and recrystallization obtains open loop
Product 56g, yield 93%.
(5) synthesis of ranitidine
Distilled water 150ml is added in reaction flask, open-loop products 48g, 2- [(dimethylamino) that step (4) is prepared
Methyl] -5- Chloromethyl-furan 48g and solid sodium hydroxide 18g be uniformly mixed, it is warming up to 45 DEG C after mixing, 45
It is reacted 2 hours under the conditions of DEG C；Water is concentrated under reduced pressure after the reaction was completed and is removed, 70ml absolute ethyl alcohol and stirring is then added, is filtered, it is dense
Contracting filtrate, then recrystallized 2 times with dehydrated alcohol, obtain ranitidine 76g, yield 90%.
After preparing product, the ranitidine being prepared is detected using high performance liquid chromatograph, as a result such as Fig. 3
And shown in Fig. 4.
As can be seen from Figure：Ranitidine purity with higher prepared by the present invention, and yield is higher.This hair
It is bright that the yield of open-loop products is significantly improved by the control of anhydrous condition during the preparation process, thunder is finally prepared to improve
Buddhist nun replaces the purity of fourth.The yield and purity of product ranitidine are significantly improved by simple and safe, environmentally protective operation,
It has a good application prospect.
Claims (8)
1. a kind of new method for synthesizing ranitidine, this method includes the synthesis of vinylidene chloride, 1,1- bis- chloro- 2- nitroethylene
Synthesis, ring closure reaction, ring-opening reaction, the synthesis of ranitidine；It is characterized in that,
(1) use 1,1,2 trichloroethanes and sodium hydrate aqueous solution for Material synthesis vinylidene chloride；
(2) vinylidene chloride obtained using concentrated hydrochloric acid, concentrated nitric acid and step (1) is the chloro- 2- nitroethylene of Material synthesis 1,1- bis-；
(3) ring closure reaction is carried out with the chloro- 2- nitroethylene of 1,1- bis- that sodium hydroxide, Mercaptamine and step (2) obtain,
Obtain cyclization product；
(4) cyclization product, desiccant that step (3) obtains are added in dehydrated alcohol and are uniformly mixed；After mixing, mixed
It closes in solution and methylamine solution is added dropwise, after methylamine solution is added dropwise, reacts 10~12 hours, after the reaction was completed, take out at room temperature
Filtrate is concentrated under reduced pressure in filter, washing, and recrystallization obtains open-loop products；
(5) open-loop products, 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and the solid sodium hydroxide obtained step (4)
It is reacted for raw material, after the reaction was completed, obtained substance is handled, ranitidine can be obtained after the completion of processing.
2. the new method of synthesis ranitidine according to claim 1, which is characterized in that step (1) inclined two chloroethene
The synthesis of alkene is specific as follows：At room temperature, 1,1,2 trichloroethanes is added in reaction flask, is then added dropwise into 1,1,2 trichloroethanes
The aqueous solution of sodium hydroxide is stirred when being added dropwise, and obtains vinylidene chloride after the reaction was completed.
3. the new method of synthesis ranitidine according to claim 1 or 2, which is characterized in that step (1) described hydroxide
The mass concentration of sodium water solution is 35%；The mass ratio of 1,1,2 trichloroethanes and sodium hydrate aqueous solution is 1：0.8~
0.9。
4. the new method of synthesis ranitidine according to claim 1, which is characterized in that step (2) 1, the 1- bis- is chloro-
The synthesis of 2- nitroethylene is specially：Concentrated hydrochloric acid is uniformly mixed first to obtain mixed acid with concentrated nitric acid, then makes step (1)
Standby obtained vinylidene chloride is added drop-wise in mixed acid, after being added dropwise to complete, is reacted 2.5~5 hours at room temperature；After the reaction was completed,
It extracted, washed, dried, filtered, be evaporated under reduced pressure using ethyl acetate/water two-phase extraction, the chloro- 2- of 1,1- bis- can be obtained
Nitroethylene；
Mass ratio of concentrated hydrochloric acid and concentrated nitric acid is 1 during this:1, the mass ratio of concentrated hydrochloric acid and vinylidene chloride is 1:0.8~
0.9；
The washing is to be washed using saturated salt solution to organic phase；The drying is anhydrous to be added in organic phase
Sodium sulphate is dried 0.5~1 hour at room temperature.
5. the new method of synthesis ranitidine according to claim 1, which is characterized in that cyclization described in step (3) is anti-
Should be specially：Addition Mercaptamine, which is uniformly mixed, in the aqueous solution of sodium hydroxide obtains mixed solution；Then 45~
Under the conditions of 50 DEG C, the chloro- 2- nitroethylene of 1,1- bis- obtained to mixed solution and dripping step (2), after being added dropwise to complete, 45~
It is reacted 1~2 hour under the conditions of 50 DEG C；After the reaction was completed, it is extracted using ethyl acetate/water two-phase extraction, to organic phase
It washed, dried, be evaporated under reduced pressure, obtain cyclization product；
Mass concentration of sodium hydroxide solution is 20% during this；The sodium hydroxide solution and Mercaptamine
Mass ratio is 1:0.1~0.2, sodium hydroxide solution and 1, the mass ratio of the chloro- 2- nitroethylene of 1- bis- is 1:0.1~0.2；
Wherein, the washing is to be washed using saturated salt solution to organic phase；The drying is to be added in organic phase
Anhydrous sodium sulfate is dried 0.5~1 hour at room temperature.
6. the new method of synthesis ranitidine according to claim 1, which is characterized in that methylamine described in step (4) is molten
Liquid is the ethanol solution of methylamine, and the mass concentration of methylamine is 30%；The amount ratio of the dehydrated alcohol and cyclization product is 3ml：
1g；The amount ratio of the ethanol solution of the dehydrated alcohol and methylamine is 2.7ml:1ml；The dosage of the dehydrated alcohol and desiccant
Than for 100ml：(1~10) g.
7. the new method of synthesis ranitidine according to claim 1 or 6, which is characterized in that the desiccant is to include
Silica gel, quick lime, anhydrous calcium chloride, anhydrous magnesium sulfate or molecular sieve.
8. the new method of synthesis ranitidine according to claim 1, which is characterized in that described to synthesize the new of ranitidine
Method, step (5) open-loop products are reacted with 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and solid sodium hydroxide
Detailed process is：Open-loop products, 2- [(dimethylamino) methyl] -5 Chloromethyl-furans and the solid that step (4) is obtained first
Sodium hydroxide is added in distilled water, is uniformly mixed；It is reacted 1.5~2 hours under the conditions of 45 DEG C after mixing；Reaction is completed
Afterwards, it is concentrated under reduced pressure and removes moisture, absolute ethyl alcohol and stirring, suction filtration, concentration filtrate is then added, is then recrystallized using dehydrated alcohol
Twice, ranitidine can be obtained；
During being somebody's turn to do, the amount ratio of the distilled water and open-loop products is 1ml：0.3~0.4g；The open-loop products and 2- [(two
Methylamino) methyl] mass ratio of -5 Chloromethyl-furans and solid sodium hydroxide is 1：1：0.3~0.4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810702539.XA CN108864001A (en) | 2018-06-30 | 2018-06-30 | A kind of new method synthesizing ranitidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810702539.XA CN108864001A (en) | 2018-06-30 | 2018-06-30 | A kind of new method synthesizing ranitidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108864001A true CN108864001A (en) | 2018-11-23 |
Family
ID=64297582
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810702539.XA Pending CN108864001A (en) | 2018-06-30 | 2018-06-30 | A kind of new method synthesizing ranitidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108864001A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4128658A (en) * | 1976-08-04 | 1978-12-05 | Allen & Hanburys Limited | Aminoalkyl furan derivatives |
| US4399294A (en) * | 1980-12-30 | 1983-08-16 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| US4413135A (en) * | 1980-01-08 | 1983-11-01 | Glaxo Group Limited | Intermediates in the preparation of ranitidine |
| CN1168669A (en) * | 1994-12-08 | 1997-12-24 | 赫彻斯特马里恩鲁斯公司 | Novel processes for preparing ranitidine |
| CN106892885A (en) * | 2017-04-21 | 2017-06-27 | 苏州弘森药业股份有限公司 | A kind of method for synthesizing ranitidine |
-
2018
- 2018-06-30 CN CN201810702539.XA patent/CN108864001A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4128658A (en) * | 1976-08-04 | 1978-12-05 | Allen & Hanburys Limited | Aminoalkyl furan derivatives |
| US4413135A (en) * | 1980-01-08 | 1983-11-01 | Glaxo Group Limited | Intermediates in the preparation of ranitidine |
| US4399294A (en) * | 1980-12-30 | 1983-08-16 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| CN1168669A (en) * | 1994-12-08 | 1997-12-24 | 赫彻斯特马里恩鲁斯公司 | Novel processes for preparing ranitidine |
| CN106892885A (en) * | 2017-04-21 | 2017-06-27 | 苏州弘森药业股份有限公司 | A kind of method for synthesizing ranitidine |
Non-Patent Citations (2)
| Title |
|---|
| KOSARY, JUDIT 等: "A modified synthesis of 2-{[1-(methylamino)-2-nitroethenyl]amino}ethanethiol", 《PHARMAZIE》 * |
| 韩祖凤 等: "雷尼替丁合成路线概述", 《医药工业》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100513401C (en) | Method for preparing epoxy chloropropane by using glycerol method | |
| CN105985362B (en) | A kind of method for preparing zeolite imidazole ester frame structure material | |
| CN105622609B (en) | A kind of Li Gelieting preparation method | |
| CN103709143A (en) | Preparation method of esomeprazole and magnesium salt thereof | |
| CN105254721B (en) | Purification and salt conversion method of micafungin | |
| CN103420908B (en) | The preparation method of montelukast chiral intermediate | |
| CN101885506A (en) | Method for preparing analytically pure basic cupric carbonate | |
| CN108864001A (en) | A kind of new method synthesizing ranitidine | |
| CN109265369A (en) | A kind of preparation method of N- cyanoethyl-Phenhenzamine | |
| CN106065005B (en) | Preparation method of R- (+) -2- [4- (hydroxyphenoxy) ] propionate | |
| CN108786778B (en) | Zirconium silicate modified mesoporous silicon oxide catalyst and preparation method and application thereof | |
| CN108997591B (en) | Visible-light response hafnium-based metal organic framework material and preparation method thereof | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| CN103709174B (en) | The one-step synthesis of the bromo-3H-oxazole of 6-also [4,5-b] pyridin-2-ones | |
| CN102993131B (en) | Method for utilizing o-chlorocyclohexanol to prepare cyclohexene oxide by cyclization | |
| CN104478974A (en) | Synthesis method of 20,23-dipiperidino-5-O-mycaminose-tylosin lactone | |
| CN113200910A (en) | Preparation method of rupatadine fumarate intermediate 5-methyl nicotinate methanol solution | |
| CN108329218B (en) | Preparation method of (R) -epinephrine | |
| CN113801104A (en) | Preparation method of epivimos macrocyclic lactone hydrolysis impurities | |
| CN103664653B (en) | Method for preparing 2-[(N-benzyl-N-phenyl)amino]ethanol | |
| CN104327049A (en) | Preparation method of right-handed rabeprazole sodium monohydrate crystal | |
| CN103950979A (en) | Simple, efficient and energy-saving preparation method of niobic acid | |
| CN115124473B (en) | Method for synthesizing cimetidine related substance B | |
| CN110724276B (en) | Preparation method of acid-alkali difunctional MOFs material and method for synthesizing 3, 4-dimethylfurazan by using acid-alkali difunctional MOFs material as catalyst | |
| CN110642770B (en) | Preparation method of 5-methoxyindole |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181123 |