CN103073546A - Preparation method of mebhydrolin napadisylate - Google Patents
Preparation method of mebhydrolin napadisylate Download PDFInfo
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- CN103073546A CN103073546A CN2013100375493A CN201310037549A CN103073546A CN 103073546 A CN103073546 A CN 103073546A CN 2013100375493 A CN2013100375493 A CN 2013100375493A CN 201310037549 A CN201310037549 A CN 201310037549A CN 103073546 A CN103073546 A CN 103073546A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229960004934 mebhydrolin Drugs 0.000 title claims abstract description 16
- FQQIIPAOSKSOJM-UHFFFAOYSA-N mebhydrolin Chemical compound C1N(C)CCC2=C1C1=CC=CC=C1N2CC1=CC=CC=C1 FQQIIPAOSKSOJM-UHFFFAOYSA-N 0.000 title claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 23
- 239000000047 product Substances 0.000 claims abstract description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000010992 reflux Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 5
- 239000012312 sodium hydride Substances 0.000 claims abstract description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- OTNNTCJQDSEITO-UHFFFAOYSA-N 1-methylpiperidin-2-one;hydrochloride Chemical compound Cl.CN1CCCCC1=O OTNNTCJQDSEITO-UHFFFAOYSA-N 0.000 claims abstract description 4
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 4
- 239000007921 spray Substances 0.000 claims abstract description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 3
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910000831 Steel Inorganic materials 0.000 claims description 6
- 239000010959 steel Substances 0.000 claims description 6
- YZYNUBVNXXPWOE-UHFFFAOYSA-N (2-benzylphenyl)hydrazine;hydrochloride Chemical compound Cl.NNC1=CC=CC=C1CC1=CC=CC=C1 YZYNUBVNXXPWOE-UHFFFAOYSA-N 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 4
- YGSZNSDQUQYJCY-UHFFFAOYSA-L disodium;naphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O YGSZNSDQUQYJCY-UHFFFAOYSA-L 0.000 claims description 4
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 230000003068 static effect Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims 3
- 230000000630 rising effect Effects 0.000 claims 3
- 238000001953 recrystallisation Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- SQMOOVFBFVTTGF-UHFFFAOYSA-N 1-benzyl-1-phenylhydrazine Chemical compound C=1C=CC=CC=1N(N)CC1=CC=CC=C1 SQMOOVFBFVTTGF-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract 2
- 238000010438 heat treatment Methods 0.000 abstract 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 150000005690 diesters Chemical class 0.000 abstract 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 238000005086 pumping Methods 0.000 abstract 1
- 238000006277 sulfonation reaction Methods 0.000 abstract 1
- 238000012856 packing Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 0 CCN1CC(*(*)C=O)C2OC2CC1 Chemical compound CCN1CC(*(*)C=O)C2OC2CC1 0.000 description 5
- CJUOSBUQOWKEKJ-UHFFFAOYSA-N Mebhydrolin napadisilate Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O.C1N(C)CCC2=C1C1=CC=CC=C1N2CC1=CC=CC=C1.C1N(C)CCC2=C1C1=CC=CC=C1N2CC1=CC=CC=C1 CJUOSBUQOWKEKJ-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- -1 1-methyl piperidine keto hydrochloride Chemical compound 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000002804 anti-anaphylactic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 150000005524 benzylchlorides Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000003153 cholinolytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 206010040400 serum sickness Diseases 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
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Abstract
The invention relates to a preparation method of mebhydrolin napadisylate, which is characterized in that the preparation method comprises the following steps of (1) stirring methyl acrylate and methylamine gas for reaction at 15-30 DEG C, pumping low-boiling-point substances with a water pump, (2) adding toluene, diester, sodium hydride and liquid sodium methylate, stirring to initiate reaction, dropping a hydrochloric acid solution under violent stirring, conducting heating reflux, obtaining a hydrochloric acid solution of 1-methyl-piperidone hydrochloride, (3) adding phenylhydrazine, toluene and triethylamine, stirring, heating, slowly and dropwise adding benzyl chloride for reaction, and (4) adding the hydrochloric acid solution of 1-methyl-piperidone hydrochloride into an ethanol solution of a product from Step (3), adding 1,5-naphthalenedisulfonate for reaction, reducing to a room temperature, conducting swing filtration, using methanol and water to wash successively, obtaining a crude product through the swing filtration, using DMF (dimethyl formamide) and ammonia water to recrystallize, using methanol to spray, and obtaining high-purity mebhydrolin napadisylate. The method avoids using sulfuric acid for acidification, and a sulfonation reaction is facilitated. A technology is simple; a yield is high; and the product quality is good.
Description
Technical field
The present invention relates to a kind of preparation method of medical compounds, be specifically related to a kind of preparation method of Mebhydrolin napadisilate.
Background technology
The Mebhydrolin napadisilate is white crystalline powder, molecular formula (C
19H
20N
2)
2C
10H
8O
6S
2, nontoxic, non-corrosiveness, "dead", nonflammable, non-explosive, belong to antihistaminic; And cholinolytic and sedative effect are arranged, be used for various allergic diseases.Be used for clinically urticaria, rhinitis, vasodilation and serum sickness, antianaphylactic curative effect is 10 times of Toldrin, and preparation is tablet.
United States Patent (USP) was reported synthetic (patent No. 2786059) of Y-carboline derivative in 1975, Chinese patent CN03150674.7 had also reported mehailuolin-1 in 2005, the preparation method of 5 napadisilates, technique shown in this patent shows that its flow process is to prepare first Mebhydrolin vitriol, convert thereof into again sulfonate, because sulfate ion is residual, the conversion reaction of p-sulfonic acid salt is impacted, the sulfate ion residual concentration is relatively high, and purifying products is difficulty relatively.
Summary of the invention
The objective of the invention is to propose a kind of preparation method of Mebhydrolin napadisilate, high, the steady quality of the product purity of the method preparation.
The object of the present invention is achieved like this, its chemical equation is as follows:
Concrete synthetic method step is as follows:
1. the preparation of dibasic acid esters thing:
Add the methyl acrylate of charging capacity in glassed steel reaction vessels, stirring temperature control is 15-30 ℃, directly passes into methylamine gas in the reactor, temperature control is in 35-45 ℃ of reaction, (with the cooling water control temperature of ventilating, controlling consumption with weight reduction), logical finish censorship, reach requirement content after.In 30-35 ℃ of stirring 40 minutes, water rushed pump and takes out low-boiling-point substance.Need not to concentrate, the dibasic acid esters substrate concentration is on the not impact of quality of later stage finished product herein.
2. cyclization, decarboxylation:
In reactor, add toluene, dibasic acid esters, be cooled to 20 ℃, add sodium hydride and liquid methanol sodium, stir initiation reaction in 30 minutes, interior temperature is no more than 45 ℃, is down to normal-temperature reaction 30 minutes, to clarifying thickness.Above reactant is cooled to 0 ℃, splashing into 20% hydrochloric acid to solution in 0-10 ℃ under the violent stirring clarifies, static layering, divide and get toluene, extract toluene twice with concentrated hydrochloric acid, merge the hydrochloric acid layer, stir lower reflux, until till no longer including carbonic acid gas and emitting, (refluxing 6 hours) gets the hydrochloric acid soln of 1-methyl-piperidone hydrochloride.Decompression steams hydrochloric acid, adds ethanol.
The sulfuric acid of herein former decarboxylation being used changes hydrochloric acid into, reduces reflux temperature, reduces return time, improves service life of equipment.Return time was 12 hours in the past, was kept to now 6 hours.
3. the preparation of benzyl hydrazinobenzene hydrochloride salt:
In glassed steel reaction vessels, pass into nitrogen protection, add phenylhydrazine, toluene, triethylamine, stir and heat up in 35 ~ 65 ℃ of slow Benzyl Chlorides that drip, temperature control drips 1 hour below 85 ℃, drips to finish.In 85-95 ℃ of reaction 1 hour, slowly be warming up to again and refluxed 4 hours, then be cooled to 30 ~ 60 ℃ of filtrations, the filter cake toluene wash.Decompression is steamed toluene to doing.
Behind the triethylamine salt soda acid, recycling has reduced solid waste, has improved the service efficiency of material.
4. the preparation of finished product:
With step 3 products obtained therefrom, add in the ethanolic soln of step 2, be warming up to 84 ℃ and refluxed 4 hours, be cooled to 60 ℃, add again 1,5-naphthalene disulfonic acid sodium salt, being warming up to 84 ℃ refluxed 3 hours, be down to the room temperature rejection filter, use the methanol wash filter cake, the filter cake still that enters to pull an oar, add the making beating of 2T water, be warming up to 45 ℃, stirred 1 hour, rejection filter gets crude product.The DMF of 8 times of crude product weight of vacuum suction adds crude product and ammoniacal liquor and stirs to clarify suction filtration, filtrate control steams 2/3(less than 70 ℃ of decompressions has solid to separate out), be chilled to the room temperature rejection filter, filter cake sprays with methyl alcohol, distillate is applied mechanically, and the mother liquor distillate is applied mechanically, and the pin material is processed.
5. packing is put in storage:
To be transported to through the wet product after centrifugal drying room and carry out the sabot oven dry, drying temperature is controlled in 85 ℃, and dry about 6 hours, when sampling detects moisture content≤0.3%, close baking oven steam, it is cooled to below 40 ℃ naturally, pulverize, mix rear packing.Pack into after packing with plastic inner bag fiber drum or metal bucket, (sampling is chemically examined before the barrelling) packing specifications is 20kg/ bucket or 25kg/ bucket, labels after quality test is qualified and puts in storage.
Advantage of the present invention is: the present invention avoids using sulfuric acid acidation, is conducive to sulfonated reaction.Technique is simple, and yield is high, good product quality.Every batch products can be stablized and reaches content more than 99.0%, and the foreign matter contents such as sulfate radical, heavy metal are all below the limit of quality standard regulation.
Description of drawings
Fig. 1 is production technological process of the present invention.
Embodiment
As shown in Figure 1, production craft step of the present invention is:
1. the preparation of dibasic acid esters thing:
The methyl acrylate that in glassed steel reaction vessels, adds 90Kg, stirring temperature control is 25 ℃, and methylamine gas 30Kg is directly passed in the reactor, temperature control is in 35 ℃ of reactions, logically finishes censorship, reach requirement content after.In 30-35 ℃ of stirring 40 minutes, water rushed pump and takes out low-boiling-point substance.
2. cyclization, decarboxylation:
In reactor, add 130Kg toluene and dibasic acid esters, be cooled to 20 ℃, add sodium hydride 20Kg and liquid methanol sodium 1000ml, stir initiation reaction in 30 minutes, interior temperature is no more than 45 ℃, is down to normal-temperature reaction 30 minutes, to clarifying thickness.Above reactant is cooled to 0 ℃, splash into 20% hydrochloric acid 470L in 0-10 ℃ under the violent stirring and clarify to solution, static layering is divided and is got toluene, extract toluene twice with concentrated hydrochloric acid, merge the hydrochloric acid layer, stir lower reflux, until till no longer including carbonic acid gas and emitting, (refluxing 6 hours), get the hydrochloric acid soln of 1-methyl piperidine keto hydrochloride, decompression steams hydrochloric acid, adds ethanol.
3. the preparation of benzyl hydrazinobenzene hydrochloride salt:
In glassed steel reaction vessels, pass into nitrogen protection, add phenylhydrazine 28kg, toluene 130Kg, triethylamine 35Kg, stir and heat up in 50 ℃ of slow Benzyl Chloride 35Kg that drip, temperature control drips 1 hour below 85 ℃, drips to finish.In 90 ℃ of reactions 1 hour, slowly be warming up to again and refluxed 4 hours, then be cooled to 50 ℃ of filtrations, the filter cake toluene wash, decompression is steamed toluene to doing.
4. the preparation of finished product:
With step 3 products obtained therefrom, add in the ethanolic soln of step 2, be warming up to 84 ℃ and refluxed 4 hours, be cooled to 60 ℃, add again 1,5-naphthalene disulfonic acid sodium salt 90Kg, being warming up to 84 ℃ refluxed 3 hours, be down to the room temperature rejection filter, with 30Kg methanol wash filter cake, the filter cake still that enters to pull an oar, add the making beating of 2T water, be warming up to 45 ℃, stirred 1 hour, rejection filter gets crude product.The DMF of vacuum suction 900Kg adds crude product and 10Kg ammoniacal liquor and stirs to clarify, suction filtration, and filtrate is controlled at less than 70 ℃ of lower decompressions and steams 2/3, has solid to separate out, and is chilled to the room temperature rejection filter, and filter cake sprays with a small amount of methyl alcohol.
5. packing is put in storage:
To be transported to through the wet product after centrifugal drying room and carry out the sabot oven dry, drying temperature is controlled in 85 ℃, and dry about 6 hours, when sampling detects moisture content≤0.3%, close baking oven steam, it is cooled to below 40 ℃ naturally, pulverize, mix rear packing.Pack into after packing with plastic inner bag fiber drum or metal bucket, packing specifications is 20kg/ bucket or 25kg/ bucket, labels after quality test is qualified and puts in storage.
Claims (7)
1. the preparation method of a Mebhydrolin napadisilate is characterized in that the preparation method may further comprise the steps:
(1) preparation of dibasic acid esters thing: add methyl acrylate in glassed steel reaction vessels, stirring temperature control is 15-30 ℃, and methylamine gas is directly passed in the reactor, and temperature control was in 30-35 ℃ of stirring 40 minutes, and water rushes pump and takes out low-boiling-point substance;
(2) cyclization, decarboxylation: in reactor, add toluene, dibasic acid esters, cooling adds sodium hydride and liquid methanol sodium, stir initiation reaction, to clarifying thickness, reactant is cooled to 0 ℃, splash into 20% hydrochloric acid to solution under the violent stirring and clarify, static layering is divided and is got toluene, extract toluene twice with concentrated hydrochloric acid, merge the hydrochloric acid layer, stirred lower reflux 6 hours, get the hydrochloric acid soln of 1-methyl-piperidone hydrochloride, decompression steams hydrochloric acid, adds ethanol;
(3) preparation of benzyl hydrazinobenzene hydrochloride salt: in glassed steel reaction vessels, pass into nitrogen protection, add phenylhydrazine, toluene, triethylamine, stirring heats up in slow dropping Benzyl Chloride, reacts 1 hour, and slow temperature rising reflux is 4 hours again, then the filter cake toluene wash is filtered in cooling;
(4) preparation of finished product: with step 3 products obtained therefrom, add in the ethanolic soln of step 2, temperature rising reflux 4 hours, cooling add 1,5-naphthalene disulfonic acid sodium salt, temperature rising reflux is 3 hours again, be down to the room temperature rejection filter, successively get crude product with methyl alcohol, water washing rejection filter, use again DMF and ammoniacal liquor recrystallization, with the methyl alcohol spray, get high purity product at last.
2. a kind of preparation method of Mebhydrolin napadisilate as claimed in claim 1 is characterized in that step (1) temperature control is in 35-45 ℃ of reaction.
3. a kind of preparation method of Mebhydrolin napadisilate as claimed in claim 1 is characterized in that step (2) adds sodium hydride and liquid methanol sodium mixture reaction.
4. a kind of new preparation method of Mebhydrolin napadisilate as claimed in claim 1 is characterized in that step (2) adopts hydrochloric acid to carry out decarboxylic reaction.
5. a kind of preparation method of Mebhydrolin napadisilate as claimed in claim 1 is characterized in that step (3) directly prepares benzyl hydrazinobenzene hydrochloride salt solid, rather than benzyl phenylhydrazine oily liquids.
6. a kind of preparation method of Mebhydrolin napadisilate as claimed in claim 1, it is characterized in that step (4) adopts benzyl hydrazinobenzene hydrochloride salt solid and 1,5-naphthalene disulfonic acid sodium salt directly prepares the Mebhydrolin napadisilate, and must not use sulfuric acid acidation early stage.
7. a kind of preparation method of Mebhydrolin napadisilate as claimed in claim 1 is characterized in that the purification step of step (4) product adopts methyl alcohol, repeatedly drip washing of water, and with DMF and ammoniacal liquor recrystallization.
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| CN2013100375493A CN103073546A (en) | 2013-01-31 | 2013-01-31 | Preparation method of mebhydrolin napadisylate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483375A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate 4- piperidones |
| CN116410190A (en) * | 2022-09-06 | 2023-07-11 | 辽宁惠风生物医药科技有限公司 | Method for preparing mehtaline naphthalene disulfonate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2786059A (en) * | 1951-04-30 | 1957-03-19 | Schenley Ind Inc | Derivatives of 2-nu-methyl-1, 2, 3, 4-tetrahydro-gamma-carbolines |
| CN1590387A (en) * | 2003-08-29 | 2005-03-09 | 上海子能高科股份有限公司 | Preparation method of mehailuolin -1,5- naphthaline disulfonate |
-
2013
- 2013-01-31 CN CN2013100375493A patent/CN103073546A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2786059A (en) * | 1951-04-30 | 1957-03-19 | Schenley Ind Inc | Derivatives of 2-nu-methyl-1, 2, 3, 4-tetrahydro-gamma-carbolines |
| CN1590387A (en) * | 2003-08-29 | 2005-03-09 | 上海子能高科股份有限公司 | Preparation method of mehailuolin -1,5- naphthaline disulfonate |
Non-Patent Citations (1)
| Title |
|---|
| 张帆 等: "抗组胺原料药美海曲林萘二磺酸盐合成方法的改进", 《江西化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483375A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate 4- piperidones |
| CN116410190A (en) * | 2022-09-06 | 2023-07-11 | 辽宁惠风生物医药科技有限公司 | Method for preparing mehtaline naphthalene disulfonate |
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Application publication date: 20130501 |