WO2022193577A1 - 单硝酸异山梨酯的合成方法及应用 - Google Patents
单硝酸异山梨酯的合成方法及应用 Download PDFInfo
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- WO2022193577A1 WO2022193577A1 PCT/CN2021/118254 CN2021118254W WO2022193577A1 WO 2022193577 A1 WO2022193577 A1 WO 2022193577A1 CN 2021118254 W CN2021118254 W CN 2021118254W WO 2022193577 A1 WO2022193577 A1 WO 2022193577A1
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- isosorbide mononitrate
- reaction
- nitrate
- sorbitol
- isosorbide
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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 55
- 229960003827 isosorbide mononitrate Drugs 0.000 title claims abstract description 48
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 26
- 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 claims abstract description 12
- 239000000600 sorbitol Substances 0.000 claims abstract description 12
- 238000006396 nitration reaction Methods 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 8
- 239000007924 injection Substances 0.000 claims abstract description 8
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 7
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 5
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 238000010189 synthetic method Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical group [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 6
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 235000010344 sodium nitrate Nutrition 0.000 claims description 3
- 239000004317 sodium nitrate Substances 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000010333 potassium nitrate Nutrition 0.000 claims description 2
- 239000004323 potassium nitrate Substances 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 4
- 229960002479 isosorbide Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 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 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- -1 Tetrahydroborates Chemical class 0.000 description 1
- NEZQWZBCEHOWJS-UTINFBMNSA-N [(3s,3ar,6r,6ar)-6-acetyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl] acetate Chemical compound CC(=O)O[C@H]1CO[C@@H]2[C@H](OC(=O)C)CO[C@@H]21 NEZQWZBCEHOWJS-UTINFBMNSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000011944 chemoselective reduction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CMWCOKOTCLFJOP-UHFFFAOYSA-N titanium(3+) Chemical compound [Ti+3] CMWCOKOTCLFJOP-UHFFFAOYSA-N 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the field of pharmaceutical synthesis, and relates to a synthesis method and application of isosorbide, in particular to isosorbide mononitrate.
- Sorbitan mononitrate chemical name: 1,4,3,6-dianhydro-D-sorbitol-5-mononitrate, also known as 5-isosorbide mononitrate, is the isosorbide dinitrate in the body
- the main biologically active substitute activates guanylate cyclase by releasing nitric oxide, relaxes vascular smooth muscle and dilates peripheral arteries and veins.
- 5-Isosorbide mononitrate is suitable for the long-term treatment of coronary heart disease, the prevention of angina pectoris, and the treatment of persistent angina pectoris after myocardial infarction.
- the first route adopts the indirect nitration method, among which patents US4371703, US4065488, CN1618798A; Yan Fuan et al. "Synthesis of 5-isosorbide mononitrate (I) (Wuhan Journal of Chemical Industry, 1997, 19(1): 25-27) ", Yan Fuan et al. "Synthesis of 5-isosorbide mononitrate (II) (Fine Chemical Industry, 1998, 15(3): 50-53)", Liu Hongxia “Synthesis of isosorbide acetate in ionic liquid (application Chemistry, 2008, 25(12): 1502-1504)” and other literatures reported such methods, and the chemical reaction formula is:
- the route can be summarized as starting with isosorbide, protecting the 2-position by acetyl esterification, then nitrating the 5-position, and finally hydrolyzing the 2-position ethyl ester group to obtain 5-isosorbide mononitrate.
- the synthesis route of this route is long, and some routes adopt catalyst catalysis reaction, resulting in high cost.
- the selective acylation process conditions are difficult to control, and the generated by-products are not easy to remove, resulting in difficult product purification, and it is difficult to improve the yield between 50 and 60%;
- isosorbide is used as a raw material, and fuming nitric acid is used for direct nitration, and the resulting substance is a mixture, and the post-treatment adopts methods such as column chromatography.
- the yield of this route is low, fuming nitric acid is used in the nitrification process, and the toxic gas is volatilized, and the post-treatment adopts methods such as column chromatography, which is not suitable for industrialized production;
- the third line is the selective reduction method, patent US4381400, EP0201067, CN1609108A; Zheng Lianyi et al. "Synthesis of 5-isosorbide mononitrate (Journal of Hebei University of Science and Technology, 2002, 23(4): 25-27)", Bai Yinjuan “Research progress of sodium borohydride in organic synthesis (Applied Chemistry, 2002, 19(5); 409-415)", K.S.Ravikumar "Highlychemoselective reduction of 2,5-dinitro-1,4,3,6- dianhydro-D-glucitiol with titanium(III) (Tetrahydroborates Synthesis, 1994(4); 1031-1034)” and other literatures have reported such methods, and the chemical reaction formula is:
- the present invention aims to provide a one-pot synthesis of isosorbide mononitrate using cheap raw materials, so as to simplify the process route of isosorbide mononitrate and reduce production costs.
- a method for synthesizing isosorbide mononitrate which comprises taking sorbitol and adding it to concentrated sulfuric acid, performing dehydration and cyclization, cooling and cooling after the reaction, adding nitrate, and carrying out nitration reaction, and after the reaction, adding a reducing agent to carry out a nitration reaction.
- Reduction reaction after the completion of the reaction, the reaction solution is poured into ice water, the pH is adjusted to weakly alkaline with alkaline solution, and then concentrated and dried to obtain the isosorbide mononitrate, and its chemical reaction formula is:
- the volume weight ratio of the concentrated sulfuric acid and sorbitol is 1-1.5:1; the weight ratio of the nitrate to sorbitol is 1.5-2.5:1; the weight of the reducing agent and sorbitol is 1.5-2.5:1.
- the ratio is 0.8 ⁇ 1.2:1;
- the nitrate is sodium nitrate, potassium nitrate or calcium nitrate;
- the reducing agent is zinc powder, iron powder or magnesium bar;
- the lye is 1N sodium hydroxide aqueous solution;
- the pressure of the dehydration ring closure is -0.6 ⁇ -0.8MPa, the temperature is 120 ⁇ 150°C, and the time is 2 ⁇ 4h;
- the temperature of the nitration reaction is 0-5°C and the time is 6-10h;
- the temperature of the reduction reaction is 10-15° C. and the time is 7-9 h;
- the invention also provides an application of isosorbide mononitrate synthesized by the synthesis method of isosorbide mononitrate, and the isosorbide mononitrate is used for preparing isosorbide mononitrate for injection.
- the present invention has the following beneficial effects:
- the synthetic method of isosorbide mononitrate provided by the present invention adopts one-pot method, shortens the synthetic route of original isosorbide mononitrate, can fully utilize the vitriol oil, reduces the discharge of waste liquid, simultaneously Use cheaper sorbitol instead of isosorbide to reduce industrial production costs;
- the synthetic method of isosorbide mononitrate provided by the present invention has the advantages of simple technological process, high utilization rate of raw materials, and industrial production cost saving.
- the invention is suitable for the synthesis of isosorbide mononitrate, and the synthesized isosorbide mononitrate is used for preparing isosorbide mononitrate for injection.
- Fig. 1 is the HPLC of isosorbide mononitrate A1 in the embodiment of the present invention 1;
- Fig. 2 is the detection diagram of isosorbide mononitrate for injection in the embodiment of the present invention 7.
- Embodiment 1 A kind of synthetic method of isosorbide mononitrate A1
- the present embodiment provides a kind of synthetic method of isosorbide mononitrate A1, and its chemical reaction formula is:
- Embodiments 2 to 5 of the present invention respectively provide the synthetic methods of isosorbide mononitrate A2 to A5, which are basically the same as those of embodiment 1, except that some process parameters are different.
- the specific process parameters are shown in Table 1.
- Table 1 Process parameter table for synthesizing isosorbide mononitrate A2 ⁇ A5
- Embodiment 7 The preparation method of isosorbide mononitrate for injection
- This embodiment provides a preparation method for preparing isosorbide mononitrate for injection by selecting any one of isosorbide mononitrate prepared in the above-mentioned embodiments 1 to 6, which is to inject 8L water for injection into the liquid preparation tank , lowered to room temperature, respectively weighed 1kg of isosorbide mononitrate and 0.2kg of mannitol, stirred and dissolved. Add 2L water for injection, stir evenly, add 0.03g activated carbon, stir at room temperature for 30min, decarbonize and sample through a 0.45 ⁇ m filter element (the test results are shown in Figure 2). Filling room, filling and half plugging, then freeze-drying, and fully pressing the plug to obtain isosorbide mononitrate for injection.
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Abstract
本发明属于药物合成领域，公开了一种单硝酸异山梨酯的合成方法及应用。本发明所提供的单硝酸异山梨酯的合成方法是采用一锅法，取山梨醇加入至浓硫酸中，脱水合环后加入硝酸盐，进行硝化反应，再加入锌粉进行还原反应后，即得单硝酸异山梨酯。该合成方法工艺流程简单，原料利用率高，节约生产成本。本发明适用于单硝酸异山梨酯的合成，所得单硝酸异山梨酯用于制备注射用单硝酸异山梨酯。
Description
本发明属于药物合成领域，涉及异山梨醇酯的合成方法及应用,具体地说是一种单硝酸异山梨酯。
单硝酸山梨醇酯，化学名：1,4,3,6-二脱水-D-山梨醇-5-单硝酸酯，又名5-单硝酸异山梨酯，是硝酸异山梨醇酯在体内的主要生物活性代物，通过释放一氧化氮激活鸟苷酸环化酶，松弛血管平滑肌使外周动脉和静脉扩张。5-单硝酸异山梨酯适用于冠心病的长期治疗、心绞痛的预防、心肌梗死后持续心绞痛的治疗，自八十年代上市以来，广泛应用于临床，受到广大患者的普遍欢迎。
但因合成5-单硝酸异山梨酯的工艺与纯化步骤繁琐、收率低，导致成本较高，所以工业化生产受限。目前具有工业价值的路线主要有三条：
第一条路线采用间接硝化法，其中专利US4371703、US4065488、CN1618798A；闫福安等“5-单硝酸异山梨酯的合成研究(I)(武汉化工学报，1997,19(1)：25-27)”、闫福安等“5-单硝酸异山梨酯的合成研究(II)(精细化工，1998,15(3)：50-53)”、刘红霞“离子液体中乙酸异山梨醇酯的合成(应用化学，2008,25(12)：1502-1504)”等文献报道了此类方法，其化学反应式为：
该路线可总结为以异山梨醇为起始原料，通过乙酰酯化2位进行保护，再进行硝化5位，最后水解2位乙酯基，得5-单硝酸异山梨酯。但该路线合成工艺路线长、部分路线采用催化剂催化反应，导致成本过高。同时，选择性酰化工艺条件难控制，生成副产物不易除去，导致产物纯化困难、收率在50～60％之间很难有所提高；
第二条线路是采用直接硝化法，其中专利US3886186、JP5529996、German Pat.No.2221080；I.G.Czizmadia，L.D.Hayward“Photochem.Photobiol.4657(1965)”、L.D.Hayward“Synthesis of isosorbide-5-mononitrate(Can.J.Chem，1967，(45)：2191)”、Lucchi O.De.“Chemoselective reduction of isosorbide-2,5-dinitrate(Gazzetta Chimica Italiana，1897，(17)：173)”等文献报道了此类方法，其化学反应式为：
该路线以异山梨醇为原料，用发烟硝酸直接硝化，生成物质为混合物，后处理采用柱层析等方法。但该路线收率低，硝化过程中用到发烟硝酸，挥发有毒气体，且后处理采用柱层析等方法，不适应工业化生产；
第三条线路是选择性还原法，专利US4381400、EP0201067、CN1609108A；郑连义等“5-单硝酸酸异山梨醇酯的合成(河北科技大学学报，2002,23(4)：25-27)”、白银娟“硼氢化钠在有机合成中的研究进展(应用化学，2002，19(5)；409-415)”、K.S.Ravikumar“Highlychemoselective reduction of 2,5-dinitro-1,4,3,6-dianhydro-D-glucitiol with titanium(III)(Tetrahydroborates Synthesis，1994(4)；1031-1034)”等文献报道了此类方法，其化学反应式为：
该路线的不足之处在于选择性还原剂、催化剂使用频率较多，导致成本过高。
发明内容
为解决现有技术中存在的以上不足，本发明旨在提供一种使用廉价原料通过一锅法合成单硝酸异山梨酯，以达到简化单硝酸异山梨酯的工艺路线，降低生产成本的目的。
为实现上述目的，本发明所采用的技术方案如下：
一种单硝酸异山梨酯的合成方法，它是取山梨醇加入到浓硫酸中，进行脱水合环，反应结束后，降温冷却，加入硝酸盐，进行硝化反应，反应结束后，加入还原剂进行还原反应，反应完毕后，将反应液倒入冰水中，用碱液调节pH至弱碱性，再经浓缩，干燥，即得所述单硝酸异山梨酯，其化学反应式为:
作为本发明的限定，所述浓硫酸与山梨醇的体积重量比为1～1.5:1；所述硝酸盐与山梨醇的重量比为1.5～2.5:1；所述还原剂与山梨醇的重量比为0.8～1.2:1；
作为本发明的另一种限定，所述硝酸盐为硝酸钠、硝酸钾或硝酸钙；所述还原剂为锌粉、铁粉或镁条；所述碱液为1N氢氧化钠水溶液；
作为本发明的第三种限定，所述脱水合环的压力为-0.6～-0.8MPa、温度为120～150℃、时间为2～4h；
作为本发明的第四种限定，所述硝化反应的温度为0～5℃、时间为6～10h；
作为本发明的第五种限定，所述还原反应的温度为10～15℃、时间为7～9h；
本发明还提供利用单硝酸异山梨酯的合成方法所合成的单硝酸异山梨酯的一种应用，所述单硝酸异山梨酯用于制备注射用单硝酸异山梨酯。
由于采用了上述的技术方案，本发明与现有技术相比，所取得的有益效果是：
(1)本发明所提供的单硝酸异山梨酯的合成方法，采用一锅法，缩短了原有的单硝酸异山梨酯的合成路线，能够充分利用浓硫酸，降低废液的排放量，同时采用较为廉价的山梨醇代替异山梨醇酯，降低工业生产成本；
(2)本发明所提供的单硝酸异山梨酯的合成方法，使用单一强酸，既防止了频繁更换强酸的种类所产生的安全隐患，同时也避免了在处理中间体的过程中，残留的强酸对下一步反应所产生的副反应，干扰反应，从而影响最终产物的获得。
综上所述，本发明所提供的单硝酸异山梨酯的合成方法，工艺流程简单，原料利用率高，节约工业生产成本。
本发明适用于单硝酸异山梨酯的合成，所合成的单硝酸异山梨酯用于制备注射用单硝酸异山梨酯。
下面结合附图及具体实施例对本发明作更进一步详细说明。
图1为本发明实施例1中单硝酸异山梨酯A1的HPLC；
图2为本发明实施例7中注射用单硝酸异山梨酯的检测图。
以下结合附图对本发明的优选实施例进行说明。应当理解，此处所描述的优选实施例仅用于说明和理解本发明，并不用于限定本发明。
实施例1 一种单硝酸异山梨酯A1的合成方法
本实施例提供一种单硝酸异山梨酯A1的合成方法，其化学反应式为：
称取1.82kg山梨醇，加入至2.73L浓硫酸，进行搅拌，减压至-0.8MPa，加热至150℃，反应2h，TLC监控反应进度，反应结束后，自然降温到40℃，冰水浴使反应 液进一步降温至0℃，称取1.28kg硝酸钠，分三批加入至反应液中，搅拌10h，TLC监控反应结束后，自然升温至15℃，加入0.52kg锌粉，在15℃下持续搅拌9h，TLC监控反应结束后，停止反应，将反应液倒入5L冰水中，通过1N氢氧化钠水溶液，调节pH＝7，加入3L二氯甲烷萃取，反复萃取三次，合并有机相，浓缩，干燥，即得1.53kg单硝酸异山梨酯A1(收率为80％，纯度为99.6％，HPLC如图1所示，其它数据均符合药典要求)。
实施例2-5 单硝酸异山梨酯A2～A5的合成方法
本发明实施例2～5分别提供了单硝酸异山梨酯A2～A5的合成方法，与实施例1基本相同，区别仅在于部分工艺参数不同，具体工艺参数见表1。
表1：合成单硝酸异山梨酯A2～A5的工艺参数表
其它参数与实施例1相同。
实施例7 注射用单硝酸异山梨酯的制备方法
本实施例提供了一种选用上述实施例1～6中所制备的任意一种单硝酸异山梨酯制备注射用单硝酸异山梨醇酯的制备方法，它是向配液罐内注入8L注射用水，降至室温，分别称取1kg的单硝酸异山梨酯和0.2kg甘露醇，搅拌溶解。补加2L注射用水，搅拌均匀，加入0.03g活性炭，室温搅拌30min，经0.45μm滤芯脱炭取样检测(检测结果如图2所示)，检测合格后，经两道0.22μm滤芯过滤输送到灌装间，灌装加半塞，再进行冻干，全压塞，即得注射用单硝酸异山梨酯。
需要说明的是，以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照上述实施例对本发明进行了详细的说明，对于本领域技术人员来说，其依然可以对上述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (7)
- 一种单硝酸异山梨酯的合成方法，其特征在于：所述合成方法为取山梨醇加入到浓硫酸中，进行脱水合环，反应结束后，降温冷却，加入硝酸盐，进行硝化反应，反应结束后，加入还原剂进行还原反应，反应完毕后，将反应液倒入冰水中，用碱液调节pH至弱碱性，再经浓缩，干燥，即得所述单硝酸异山梨酯，其化学反应式为:
- 根据权利要求1所述的单硝酸异山梨酯的合成方法，其特征在于：所述浓硫酸与山梨醇的体积重量比为1～1.5L:1kg；所述硝酸盐与山梨醇的重量比为1.5～2.5:1；所述还原剂与山梨醇的重量比为0.8～1.2:1。
- 根据权利要求1或2所述的单硝酸异山梨酯的合成方法，其特征在于：所述硝酸盐为硝酸钠、硝酸钾或硝酸钙；所述还原剂为锌粉、铁粉或镁条；所述碱液为1N氢氧化钠水溶液。
- 根据权利要求1或2所述的单硝酸异山梨酯的合成方法，其特征在于：所述脱水合环的压力为-0.6～-0.8MPa、温度为120～150℃、时间为2～4h。
- 根据权利要求1或2所述的单硝酸异山梨酯的合成方法，其特征在于：所述硝化反应的温度为0～5℃、时间为6～10h。
- 根据权利要求1或2所述的单硝酸异山梨酯的合成方法，其特征在于：所述还原反应的温度为10～15℃、时间为7～9h。
- 根据权利要求1～6中任意一项所述的单硝酸异山梨酯的合成方法所合成的单硝酸异山梨酯的一种应用，其特征在于：所述单硝酸异山梨酯用于制备注射用单硝酸异山梨酯。
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