CN1618798A - Preparation process of isosorbide mononitrate - Google Patents
Preparation process of isosorbide mononitrate Download PDFInfo
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- CN1618798A CN1618798A CN 200410006318 CN200410006318A CN1618798A CN 1618798 A CN1618798 A CN 1618798A CN 200410006318 CN200410006318 CN 200410006318 CN 200410006318 A CN200410006318 A CN 200410006318A CN 1618798 A CN1618798 A CN 1618798A
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- Prior art keywords
- aceticanhydride
- acid
- compound
- preparation
- nitric acid
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- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 title claims abstract description 17
- 229960003827 isosorbide mononitrate Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 36
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 15
- 230000000802 nitrating effect Effects 0.000 claims abstract description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- 235000015320 potassium carbonate Nutrition 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 4
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 1
- 239000012346 acetyl chloride Substances 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 abstract description 7
- 239000000600 sorbitol Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract 1
- XMLJCSFKQSJZLS-UHFFFAOYSA-L [K+].[K+].OC.[O-]C([O-])=O Chemical compound [K+].[K+].OC.[O-]C([O-])=O XMLJCSFKQSJZLS-UHFFFAOYSA-L 0.000 abstract 1
- 235000010356 sorbitol Nutrition 0.000 description 6
- 238000009413 insulation Methods 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- -1 compound isosorbide mononitrate Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A process for preparing the isosorbide mononitrate from sorbitol includes dewatering sorbitol by p-methylphenyl sulfonic acid to obtain anhydrosorbitol, protecting by acetic oxide under existance of N,N-dimethylaminopyridine, nitrating by nitric acid/acetic oxide/acetic acid system, and removing protection by potassium carbonate-methanol system. It can be used to treat angina pectoris.
Description
Technical field
The present invention is the preparation method of compound isosorbide mononitrate (1,4:3,6-two dehydration-D-sorbyl alcohol-5-nitric ether), belongs to chemical industry and chemical field of medicaments.
Background technology
Isosorbide mononitrate (Isosorbide Mononitrate) is 1,4:3, and the popular name of 6-two dehydration-D-sorbyl alcohol-5-nitric ether, its structural formula is:
It is long-acting nitrate esters antianginal drug, and the sixties are found in the cylinder metabolism-ure of sorbide nitrate.The eighties at first pushes market by German Bochringer Cnbh, thereafter in the listing successively of American-European more than ten countries, and is widely used in clinical.China is subjected to the popular welcome of extensive patients in this medicine of import in 1988.Its synthetic route mainly contains:
Other synthetic routes also have the (C of employing
6H
5)
3CCl, CH
3SO
2After Cl or paranitrobenzoyl chloride etc. are protected anhydro sorbitol, carry out the nitrated compound (1) that obtains with nitric acid again.Above route technological operation more complicated, reaction is difficult to control, and yield is lower, and cost is higher, and the route that has adopts the bigger solvents of toxicity such as dimethylbenzene, benzene, and environment is had bigger pollution.The present invention adopts p-methyl benzenesulfonic acid to obtain anhydro sorbitol as dewatering agent; adopt aceticanhydride that a hydroxyl is protected afterwards; it is nitrated to adopt the mixing nitrating agent to carry out, and adopts salt of wormwood/methanol system to carry out deprotection at last, obtains the higher isosorbide mononitrate of purity (1).The present invention's operation is comparatively simple, the reaction conditions gentleness, and cost is lower, is suitable for suitability for industrialized production.
Summary of the invention
The present invention is by exploring optimum reaction condition, reduce solvent and use, and make every effort to obtain a kind of easy and simple to handle, yield is high, cost is low, purity is high, be suitable for the method for preparing isosorbide mononitrate of suitability for industrialized production.
It is raw material that the present invention adopts sorbyl alcohol, obtains anhydro sorbitol by adopting p-methyl benzenesulfonic acid to dewater, the protection of aceticanhydride list, and nitric acid nitrating, deprotection obtain isosorbide mononitrate (1).Route is:
In the reaction of synthetic anhydro sorbitol (3), we successively adopt the vitriol oil, methylsulfonic acid and p-methyl benzenesulfonic acid to experimentize as dewatering agent, when finding to use the vitriol oil and methylsulfonic acid to react, reaction conditions is relatively harsher, yield is lower, yield is 71% when wherein using the vitriol oil to react, and yield is 57% when using methylsulfonic acid to react.And adopt p-methyl benzenesulfonic acid to react as dewatering agent, and yield is up to 91%, and reaction conditions is relatively gentleer, has reduced operation easier, and yield is higher, and cost has obtained reduction.
The present invention is in the preparation of compound (4), we successively adopt and use wherein a kind of of aceticanhydride, chloroacetyl chloride and acetic acid to test and add small amount of N separately, the N-Dimethylamino pyridine is tested as catalyzer, find to adopt aceticanhydride and add small amount of N, the N-Dimethylamino pyridine during as catalyzer yield higher, purity is higher, impurity in products is less.
In the reaction of synthetic compound (5), adopt aceticanhydride/acetic acid/nitric acid system to carry out nitrated, can make and react relatively gentleer when dripping nitrating agent, effectively avoid the generation of side reaction, yield is than using separately nitric acid, nitric acid/aceticanhydride or nitric acid/acetic acid to carry out being significantly improved when nitrated, effectively reduce cost, improved the quality of compound (5).
In the process of synthetic compound (1); when adopting sodium hydroxide or potassium hydroxide to carry out the deprotection group, form the sodium or the sylvite of isosorbide mononitrate easily, need to carry out acidifying to generate isosorbide mononitrate with acid such as hydrochloric acid; the operation more complicated, yield is lower.React by systems such as test salt of wormwood, salt of wormwood/methyl alcohol, yellow soda ash/ethanol, we find to adopt salt of wormwood/methanol system to react can directly generate compound (1), and yield is 73%, and cost is lower.
Above-mentioned whole piece prepares that the route side reaction of isosorbide mononitrate is less, and yield is higher, and the isosorbide mononitrate purity that obtains is higher, only with the refining first product purity of chloroform greater than 99.5%.
Embodiment
Further specify the present invention by following example, but it has no intention to limit the scope of application.Description in the following example all obtains by method known to those skilled in the art.
Example one
Intermediate 1,4:3, synthesizing of the two dehydration-D-sorbyl alcohols of 6-: the sorbyl alcohol of 310 grams 70% under agitation is incubated and slowly adds 9.5 milliliters of p-methyl benzenesulfonic acids under 40 ℃, slowly heats up under the vacuum of 0.08Mpa afterwards and steams the water purification branch, and moisture steams substantially only when rising to about 117 ℃.Vacuum 0.096Mpa is lower than 220 ℃ and collects anhydro sorbitol, yield 91%.
Example two
The preparation of compound (4): after 100 gram anhydro sorbitols add 180 milliliters of acetic acid stirring rising temperature for dissolving, add 5 gram N, the N-Dimethylamino pyridine, 30 ℃ are stirred 45 ℃ of droppings of insulation aceticanhydride after 10 minutes, dropwise the back and continue 45 ℃ of insulations 30 minutes, reduce to 20 ℃ and stir 2 hours after-filtration of insulation, get solid chemical compound (4).Yield 95%.
Example three
The preparation of nitrating agent: after 38ml aceticanhydride, 32ml acetic acid mixed, slowly drip nitric acid 14ml, keep 15 ℃-20 ℃ of temperature in the dropping process, it is standby to dropwise back 15 ℃ of insulations.
Example four
The preparation of compound (5): 52 digest compound (4) adds and to be cooled to 10 ℃ after 80ml acetic acid stirs rising temperature for dissolving, 10-14 ℃ drips nitrating agent down, dripped off in about 1.5 hours, continue insulation 1.5 hours, add 260ml water, be neutralized to Ph=6-7 at the sodium hydroxide solution that adds 30% below 30 ℃, extract with ethyl acetate (240ml * 4), extracting solution merges the back and concentrates steaming except that ethyl acetate, obtains solid chemical compound (5), yield 92%.
Example five
The preparation of compound (1): 40 digest compound (5) adds in 150 ml methanol, adds 35 gram salt of wormwood, is warming up to 50 ℃ of reactions 3 hours, cooling, solids removed by filtration, filtrate is concentrated into dried, obtain the crude product of compound (1), chloroform is refining, obtains the elaboration of compound (1).
Claims (8)
1. one kind is raw material with the sorbyl alcohol, obtains compound by the acid dehydration
With
N, N-Dimethylamino pyridine are catalyzer, carry out the list protection with aceticanhydride and obtain compound
With nitric acid/aceticanhydride/acetic acid serves as to mix nitrated system to obtain compound
With carbon
Acid potassium/methanol system carries out the prepared in reaction compound
Method.
2. the preparation method of compound (3) according to claim 1 is characterized in that the acid of adopting is p-methyl benzenesulfonic acid, methylsulfonic acid, wherein is best with the p-methyl benzenesulfonic acid.
3. the preparation method of a compound as claimed in claim 1 (4) is characterized in that the protective material that adopts is aceticanhydride, acetic acid or Acetyl Chloride 98Min., wherein is best with the aceticanhydride.
4. the preparation method of a compound as claimed in claim 3 (4) is characterized in that adopting N, and the N Dimethylamino pyridine is a catalyzer.
5. the preparation method of a compound as claimed in claim 1 (5), it is characterized in that adopting nitric acid/aceticanhydride/acetate system or nitric acid/aceticanhydride is nitrating agent, is the best to adopt nitric acid/aceticanhydride/acetate system wherein.
6. the preparation method of a compound as claimed in claim 1 (1), the alkali that it is characterized by employing is sodium hydroxide, potassium hydroxide/aqueous systems, salt of wormwood/methanol system or yellow soda ash/ethanol system, is the best with salt of wormwood/methanol system wherein.
7. the preparation method as the said compound of claim 1 (5) is characterized in that the extraction solvent that adopts is ethyl acetate or methylene dichloride or chloroform, wherein is best with the ethyl acetate.
8. the preparation method as the said isosorbide mononitrate of claim 5 is characterized in that the nitrating agent ratio range that adopts is a nitric acid: acetic acid: aceticanhydride=1: (0.5-10): (0.5-10) (v/v/v).Its proportioning is with nitric acid: acetic acid: aceticanhydride=1: (1-3): (2-4) (v/v/v) is advisable.Optimum proportion is: nitric acid: acetic acid: aceticanhydride=1.00: 2.42: 2.90 (v/v/v).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410006318 CN1618798A (en) | 2004-02-25 | 2004-02-25 | Preparation process of isosorbide mononitrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410006318 CN1618798A (en) | 2004-02-25 | 2004-02-25 | Preparation process of isosorbide mononitrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1618798A true CN1618798A (en) | 2005-05-25 |
Family
ID=34763046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410006318 Pending CN1618798A (en) | 2004-02-25 | 2004-02-25 | Preparation process of isosorbide mononitrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1618798A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130815A (en) * | 2013-02-07 | 2013-06-05 | 浙江工业大学 | Isosorbide mononitrate derivative and preparation method and application thereof |
| US8486974B2 (en) | 2007-12-21 | 2013-07-16 | The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth | Efficient aspirin prodrugs |
| CN103641840A (en) * | 2013-11-28 | 2014-03-19 | 青岛黄海制药有限责任公司 | Method for synthesizing and purifying 5-isosorbide mononitrate |
| CN104876942A (en) * | 2015-05-08 | 2015-09-02 | 天津梅花生物医药科技有限公司 | Isosorbide mononitrate hemihydrate |
| CN104892623A (en) * | 2015-06-11 | 2015-09-09 | 山东新时代药业有限公司 | Preparation method for isosorbide 5-mononitrate |
| CN110407846A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5- Isosorbide Mononitrate |
| CN112759598A (en) * | 2019-11-01 | 2021-05-07 | 中国科学院大连化学物理研究所 | Method for preparing 2-acetic acid-5-nitric acid isosorbide ester from sorbitol |
-
2004
- 2004-02-25 CN CN 200410006318 patent/CN1618798A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8486974B2 (en) | 2007-12-21 | 2013-07-16 | The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth | Efficient aspirin prodrugs |
| CN103130815A (en) * | 2013-02-07 | 2013-06-05 | 浙江工业大学 | Isosorbide mononitrate derivative and preparation method and application thereof |
| CN103641840A (en) * | 2013-11-28 | 2014-03-19 | 青岛黄海制药有限责任公司 | Method for synthesizing and purifying 5-isosorbide mononitrate |
| CN103641840B (en) * | 2013-11-28 | 2016-03-16 | 青岛黄海制药有限责任公司 | A kind of synthesis of 5-isosorbide mononitrate and purification process |
| CN104876942A (en) * | 2015-05-08 | 2015-09-02 | 天津梅花生物医药科技有限公司 | Isosorbide mononitrate hemihydrate |
| CN104892623A (en) * | 2015-06-11 | 2015-09-09 | 山东新时代药业有限公司 | Preparation method for isosorbide 5-mononitrate |
| CN110407846A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of preparation method of 5- Isosorbide Mononitrate |
| CN112759598A (en) * | 2019-11-01 | 2021-05-07 | 中国科学院大连化学物理研究所 | Method for preparing 2-acetic acid-5-nitric acid isosorbide ester from sorbitol |
| CN112759598B (en) * | 2019-11-01 | 2022-04-19 | 中国科学院大连化学物理研究所 | Method for preparing 2-acetic acid-5-nitric acid isosorbide ester from sorbitol |
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