WO2022247065A1 - Synthesis method for pentoxifylline - Google Patents
Synthesis method for pentoxifylline Download PDFInfo
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- WO2022247065A1 WO2022247065A1 PCT/CN2021/118260 CN2021118260W WO2022247065A1 WO 2022247065 A1 WO2022247065 A1 WO 2022247065A1 CN 2021118260 W CN2021118260 W CN 2021118260W WO 2022247065 A1 WO2022247065 A1 WO 2022247065A1
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- pentoxifylline
- reaction
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- chloride
- synthetic method
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- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960001476 pentoxifylline Drugs 0.000 title claims abstract description 65
- 238000001308 synthesis method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 19
- HDLUVUAAPJKOBQ-UHFFFAOYSA-N 6-aminohexan-2-one Chemical compound CC(=O)CCCCN HDLUVUAAPJKOBQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- ALNXLWMJGLCJCX-UHFFFAOYSA-N 1-aminohexan-2-one Chemical compound CCCCC(=O)CN ALNXLWMJGLCJCX-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 4
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 16
- 239000012535 impurity Substances 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000007670 refining Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 229960004559 theobromine Drugs 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960003080 taurine Drugs 0.000 description 2
- 239000011726 vitamin B6 Substances 0.000 description 2
- 235000019158 vitamin B6 Nutrition 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000000558 Varicose Ulcer Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000004855 vascular circulation Effects 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
Definitions
- the invention belongs to the field of medicine synthesis, and relates to a synthesis method of a cerebrovascular medicine raw material, in particular to a synthesis method and application of pentoxifylline.
- Pentoxifylline Chemical name is 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione, white needle crystal .
- the molecular formula is C 13 H 18 N 4 O 3 , the molecular weight is 278.3, and the structural formula is:
- Pentoxifylline is an agent for improving cerebral circulation and peripheral vascular circulation disorders, which has the effect of expanding cerebral blood vessels and peripheral blood vessels, and improving blood circulation in the brain and extremities. In addition, it can improve the oxidation capacity of hypoxic tissues. It is mainly used for the improvement of cerebral circulation after ischemic stroke, and it can also be used for the treatment of peripheral vascular diseases, such as chronic obliterative vasculitis with intermittent claudication, etc. It can also be used for the treatment of duodenal ulcer and viral hepatitis , lower extremity venous ulcers and other diseases, widely used clinically.
- the Chinese patent with the patent number CN101896484B provides a new method for refining theobromine.
- the crude product solution of theobromine is dissolved by adding alkali, such as sodium hydroxide solution, decolorized, and filtered; Acidify at ⁇ 80°C to pH 5-6, filter and dry to obtain the finished product of theobromine.
- the Chinese patent with the patent number CN108164530A discloses an environment-friendly refining method of theobromine, comprising the following steps: (1) dissolving the crude product to produce sodium salt; (2) decolorizing; (3) acidifying and crystallizing.
- Theobromine in the crude product of theobromine is converted into sodium salt by adding sodium hydroxide solution, and the insoluble impurities are filtered out; the decolorization effect is ensured by the use of decolorizing agent, and the pigment impurities are removed; and then the pH value is controlled by acidification. Reduce the residual rate of theobromine in crystallization mother liquor, and improve the purity of theobromine in precipitated crystals.
- the refining of xanthine products mainly adopts dissolution in an alkaline environment, adding carbon and decolorizing with a reducing agent, and then acidifying and crystallizing to obtain the finished product.
- the inventor uses the above two methods to refine the recovered product of pentoxifylline. 0.1% or less. Adopting the above-mentioned refining method is not effective in removing impurities therein, and still cannot reach the finished product standard in the Pharmacopoeia after several times of refining.
- the Chinese patent application with the application number 201811636444.9 discloses a method for refining the recovered pentoxifylline product, which can reduce the impurity content in the recovered product of pentoxifylline, and reduce the maximum single impurity of the recovered product to less than 0.1% after refining.
- the total impurities are less than 0.5%, meeting the standard of the finished product pentoxifylline, improving the overall yield and reducing the reaction cost.
- the refining method comprises the following steps: (1) adding water to the recovered pentoxifylline under heating conditions, dissolving, adding an alkaline liquid to adjust the pH value to 10-14, adding a reducing agent, keeping the temperature, and then cooling to filter to obtain an alkaline solution; Wherein, in the recovery of pentoxifylline, single impurity ⁇ 5%, total impurity ⁇ 10%; (2) after fully mixing the alkaline solution obtained in step (1) with organic solvent A, leave it to stand for stratification, and after steaming the organic phase Obtain a viscous liquid; (3) add organic solvent B to dissolve the above viscous liquid, add activated carbon, filter the activated carbon after heat preservation, filter the filtrate below 20°C and dry it to obtain pentoxifylline.
- the Chinese patent application with application number 201610979262.6 discloses a pentoxifylline injection composition and its preparation method.
- the injection composition is prepared from pentoxifylline, taurine, vitamin B6, edetate disodium and other components made.
- the present invention aims to provide a synthesis method of pentoxifylline, so as to simplify the synthesis process, reduce the types of impurities, and reduce the difficulty of purification of pentoxifylline.
- a kind of synthetic method of pentoxifylline, described synthetic method is to get 4-(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone to be dissolved in organic solvent respectively, add bound Acidic agent carries out condensation reaction, and after the reaction finishes, promptly obtains pentoxifylline, and its reaction formula is:
- the molar ratio of the 4-(nitromethylacyl chloride)-1-methylimidazol-5-acyl chloride and amino-5-hexanone is 1:0.8 ⁇ 1.02; the acid-binding agent and 4
- the molar ratio of -(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and the total amount of aminohexanone is 1.8 ⁇ 3.3:1;
- the organic solvent is tetrahydrofuran (THF), 1,4-dioxane (dioxane) or N,N-dimethylformamide (DMF);
- the acid-binding agent is Triethylamine (TEA) and/or N,N-diisopropylethylamine (DIPEA);
- the reaction temperature of the condensation reaction is -15-5° C.
- the reaction time is 20-75 minutes.
- the synthetic method of pentoxifylline provided by the present invention has simple technique, and only has one-step reaction to synthesize pentoxifylline;
- the by-products produced in the reaction process of the synthetic method can be recycled and used, and the target product pentoxifylline can be synthesized again by changing the reaction conditions, thereby improving the reaction yield and the purity of pentoxifylline.
- the synthesis method of pentoxifylline provided by the present invention has a simple synthesis process, and the by-products produced during the synthesis of pentoxifylline can be recycled to synthesize pentoxifylline again.
- the invention is suitable for synthesizing pentoxifylline, and the synthesized pentoxifylline is used for preparing pentoxifylline for injection.
- Embodiment 1 A kind of synthetic method of pentoxifylline S1
- the present embodiment provides a synthetic method of pentoxifylline S1, the synthetic method is:
- Table 1 Process parameter table of pentoxifylline S2-S4
- the synthesis method provided in this comparative example is basically the same as that in Example 1, except that the reaction temperature is 10°C.
- the reaction temperature is 10°C.
- the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 393.4.
- its molecular formula was:
- the synthesis method provided in this comparative example is basically the same as that in Example 1, except that the reaction temperature is -30°C.
- the reaction temperature is -30°C.
- the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 314.1. After analysis, its molecular formula was:
- the synthetic method provided by this comparative example is basically the same as that of Example 1, except that the molar ratio of 4-(nitromethylacyl chloride)-1-methylimidazolium-5-acid chloride and amino-5-hexanone is 1:0.6 .
- the absorption peak of the raw material amino-5-hexanone disappeared, the new peak that appeared was different from the peak position of the absorption peak of pentoxifylline, and the molecular weight was 513.1. After analysis, its molecular formula was:
- the synthetic method provided by this comparative example is basically the same as that of Example 1, except that the molar ratio of 4-(nitromethylacyl chloride)-1-methylimidazolium-5-acid chloride and amino-5-hexanone is 1:1.1 .
- the absorption peak of raw material amino-5-hexanone disappeared, the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 393.4. After analysis, its molecular formula was:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the field of drug synthesis. Disclosed is a synthesis method for pentoxifylline. The synthesis method performs condensation and ring closure by means of 4-(nitrogen methyl chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone, thereby synthesizing a target product, i.e., pentoxifylline, using only a one-step reaction. The synthesis method for pentoxifylline provided by the present invention not only has a simple synthesis process, but also can recycle a by-product produced during a reaction process for further synthesis of pentoxifylline. The present invention is suitable for the synthesis of pentoxifylline, and the synthesized pentoxifylline is used for preparing pentoxifylline for injection.
Description
本发明属于药物合成领域，涉及一种脑血管药物原料的合成方法,具体地说是一种己酮可可碱的合成方法及应用。The invention belongs to the field of medicine synthesis, and relates to a synthesis method of a cerebrovascular medicine raw material, in particular to a synthesis method and application of pentoxifylline.
己酮可可碱(Pentoxifylline)化学名为3,7-二氢-3,7-二甲基-1-(5-氧代己基)-1H-嘌呤-2,6-二酮，白色针状结晶。分子式为C
13H
18N
4O
3，分子量为278.3，结构式为：
Pentoxifylline (Pentoxifylline) chemical name is 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione, white needle crystal . The molecular formula is C 13 H 18 N 4 O 3 , the molecular weight is 278.3, and the structural formula is:
己酮可可碱为脑循环及末梢血管循环障碍改善剂，具有扩张脑血管及外周血管的作用，改善脑和四肢的血液循环。此外还能改善缺氧组织的氧化能力。主要用于缺血性中风后脑循环的改善，同时可用于周围血管病，如伴有间歇性的跛行的慢性闭塞性脉管炎等的治疗，还可用于治疗十二指肠溃疡、病毒性肝炎、下肢静脉溃疡等疾病，临床用药广泛。Pentoxifylline is an agent for improving cerebral circulation and peripheral vascular circulation disorders, which has the effect of expanding cerebral blood vessels and peripheral blood vessels, and improving blood circulation in the brain and extremities. In addition, it can improve the oxidation capacity of hypoxic tissues. It is mainly used for the improvement of cerebral circulation after ischemic stroke, and it can also be used for the treatment of peripheral vascular diseases, such as chronic obliterative vasculitis with intermittent claudication, etc. It can also be used for the treatment of duodenal ulcer and viral hepatitis , lower extremity venous ulcers and other diseases, widely used clinically.
专利号为CN101896484B的中国专利，提供了一种精制可可碱的新方法，将可可碱粗品溶液通过加入碱，如氢氧化钠溶液溶解，脱色，过滤；还原剂视情况加入滤液中，再于60～80℃酸化至pH为5～6，过滤并干燥得可可碱成品。The Chinese patent with the patent number CN101896484B provides a new method for refining theobromine. The crude product solution of theobromine is dissolved by adding alkali, such as sodium hydroxide solution, decolorized, and filtered; Acidify at ~80°C to pH 5-6, filter and dry to obtain the finished product of theobromine.
专利号为CN108164530A的中国专利，公开了一种可可碱的环保精制方法，包括如下步骤：(1)粗品溶解制钠盐；(2)脱色；(3)酸化析晶。通过氢氧化钠溶液的加 入使可可碱粗品中的可可碱转化为钠盐，并滤除不溶性杂质；再通过脱色剂的使用来保证脱色效果，除去色素杂质；然后通过酸化时pH值的控制来减少结晶母液中可可碱的残留率，并提高析出晶体中可可碱的纯度。The Chinese patent with the patent number CN108164530A discloses an environment-friendly refining method of theobromine, comprising the following steps: (1) dissolving the crude product to produce sodium salt; (2) decolorizing; (3) acidifying and crystallizing. Theobromine in the crude product of theobromine is converted into sodium salt by adding sodium hydroxide solution, and the insoluble impurities are filtered out; the decolorization effect is ensured by the use of decolorizing agent, and the pigment impurities are removed; and then the pH value is controlled by acidification. Reduce the residual rate of theobromine in crystallization mother liquor, and improve the purity of theobromine in precipitated crystals.
上述专利，黄嘌呤类产品的精制主要采用碱性环境下溶解加碳及还原剂脱色，再酸化结晶得成品，发明人应用上述两个方法进行己酮可可碱回收品的精制，单杂无法达到0.1％以下。采用上述精制方法对其中的杂质去除效果不佳，数次精制后仍无法达到药典中的成品标准。In the above-mentioned patents, the refining of xanthine products mainly adopts dissolution in an alkaline environment, adding carbon and decolorizing with a reducing agent, and then acidifying and crystallizing to obtain the finished product. The inventor uses the above two methods to refine the recovered product of pentoxifylline. 0.1% or less. Adopting the above-mentioned refining method is not effective in removing impurities therein, and still cannot reach the finished product standard in the Pharmacopoeia after several times of refining.
申请号为201811636444.9的中国专利申请，公开了一种己酮可可碱回收品的精制方法，能降低己酮可可碱回收品中杂质含量，使回收品经精制后最大单杂降低到0.1％以下，总杂0.5％以下，满足成品己酮可可碱的标准，提高整体收率，降低反应成本。该精制方法含有如下步骤：(1)加热条件下将己酮可可碱回收品加入水，溶解，加碱性液体调pH值10～14，加入还原剂，保温，之后降温过滤得碱性溶液；其中，己酮可可碱回收中单杂<5％,总杂<10％；(2)将步骤(1)得到的碱性溶液与有机溶剂A充分混合后静置分层，蒸去有机相后得到粘稠液体；(3)加有机溶剂B溶解上述粘稠液体，加入活性炭，保温后过滤活性炭，滤液降至20℃以下后滤料并烘干，得到己酮可可碱。The Chinese patent application with the application number 201811636444.9 discloses a method for refining the recovered pentoxifylline product, which can reduce the impurity content in the recovered product of pentoxifylline, and reduce the maximum single impurity of the recovered product to less than 0.1% after refining. The total impurities are less than 0.5%, meeting the standard of the finished product pentoxifylline, improving the overall yield and reducing the reaction cost. The refining method comprises the following steps: (1) adding water to the recovered pentoxifylline under heating conditions, dissolving, adding an alkaline liquid to adjust the pH value to 10-14, adding a reducing agent, keeping the temperature, and then cooling to filter to obtain an alkaline solution; Wherein, in the recovery of pentoxifylline, single impurity<5%, total impurity<10%; (2) after fully mixing the alkaline solution obtained in step (1) with organic solvent A, leave it to stand for stratification, and after steaming the organic phase Obtain a viscous liquid; (3) add organic solvent B to dissolve the above viscous liquid, add activated carbon, filter the activated carbon after heat preservation, filter the filtrate below 20°C and dry it to obtain pentoxifylline.
该专利只是己酮可可碱的精制方法，无法控制其原料合成过程带来的工艺杂质。This patent is only a refining method of pentoxifylline, which cannot control the process impurities brought by the synthesis process of its raw materials.
申请号为201610979262.6的中国专利申请，公开了一种己酮可可碱注射剂组合物及其制备方法，该注射剂组合物由己酮可可碱、牛磺酸、维生素B6、依地酸二钠等组分制备而成。The Chinese patent application with application number 201610979262.6 discloses a pentoxifylline injection composition and its preparation method. The injection composition is prepared from pentoxifylline, taurine, vitamin B6, edetate disodium and other components made.
该专利在己酮可可碱药物组合物中加入了牛磺酸和维生素B6两种功能性原料，会改变其适应症，存在用药不合理的情况。In this patent, two functional raw materials, taurine and vitamin B6, are added to the pentoxifylline pharmaceutical composition, which will change its indications and cause unreasonable drug use.
针对目前己酮可可碱技术方面出现的问题，因此需开发一种从源头开始控制工艺杂质的制备工艺可以大大降低己酮可可碱原料的成品杂质，提高其纯度的合成方法 合成己酮可可碱。In view of the current problems in pentoxifylline technology, it is necessary to develop a preparation process to control process impurities from the source, which can greatly reduce the finished product impurities of pentoxifylline raw materials and improve its purity. Synthesis of pentoxifylline.
发明内容Contents of the invention
为解决现有技术中存在的以上不足，本发明旨在提供一种己酮可可碱的合成方法，以达到简化合成工艺，同时减少杂质种类，降低己酮可可碱的纯化难度的目的。In order to solve the above deficiencies in the prior art, the present invention aims to provide a synthesis method of pentoxifylline, so as to simplify the synthesis process, reduce the types of impurities, and reduce the difficulty of purification of pentoxifylline.
为实现上述目的，本发明所采用的技术方案如下：In order to achieve the above object, the technical scheme adopted in the present invention is as follows:
一种己酮可可碱的合成方法，所述合成方法为分别取4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基-5-己酮溶于有机溶剂中，加入缚酸剂进行缩合反应，反应结束后，即得己酮可可碱，其反应式为：A kind of synthetic method of pentoxifylline, described synthetic method is to get 4-(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone to be dissolved in organic solvent respectively, add bound Acidic agent carries out condensation reaction, and after the reaction finishes, promptly obtains pentoxifylline, and its reaction formula is:
作为本发明的限定，所述4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基-5-己酮的摩尔比为1:0.8～1.02；所述缚酸剂与4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基己酮总用量的摩尔比为1.8～3.3:1；As a limitation of the present invention, the molar ratio of the 4-(nitromethylacyl chloride)-1-methylimidazol-5-acyl chloride and amino-5-hexanone is 1:0.8～1.02; the acid-binding agent and 4 The molar ratio of -(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and the total amount of aminohexanone is 1.8～3.3:1;
作为本发明的另一种限定，所述有机溶剂为四氢呋喃(THF)、1,4-二氧六环(dioxane)或N,N-二甲基甲酰胺(DMF)；所述缚酸剂为三乙胺(TEA)和/或N,N-二异丙基乙胺(DIPEA)；As another limitation of the present invention, the organic solvent is tetrahydrofuran (THF), 1,4-dioxane (dioxane) or N,N-dimethylformamide (DMF); the acid-binding agent is Triethylamine (TEA) and/or N,N-diisopropylethylamine (DIPEA);
作为本发明的第三种限定，所述缩合反应的反应温度为-15～5℃、反应时间为20～75min。As a third limitation of the present invention, the reaction temperature of the condensation reaction is -15-5° C., and the reaction time is 20-75 minutes.
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：Owing to adopting above-mentioned technical scheme, compared with prior art, the beneficial effect that the present invention obtains is:
(1)本发明所提供的己酮可可碱的合成方法，工艺简单，只有一步反应合成己酮可可碱；(1) The synthetic method of pentoxifylline provided by the present invention has simple technique, and only has one-step reaction to synthesize pentoxifylline;
(2)本发明所提供的己酮可可碱的合成方法，所属合成方法的反应过程中所产生的副产物可以回收使用，改变反应条件可再次合成目标产物己酮可可碱，从而提高反应收率和己酮可可碱的纯度。(2) In the synthetic method of pentoxifylline provided by the present invention, the by-products produced in the reaction process of the synthetic method can be recycled and used, and the target product pentoxifylline can be synthesized again by changing the reaction conditions, thereby improving the reaction yield and the purity of pentoxifylline.
综上所述，本发明所提供的己酮可可碱的合成方法，具有简单的合成工艺，在己酮可可碱的合成过程中所产生的副产物可以再回收利用，再次合成己酮可可碱。In summary, the synthesis method of pentoxifylline provided by the present invention has a simple synthesis process, and the by-products produced during the synthesis of pentoxifylline can be recycled to synthesize pentoxifylline again.
本发明适用于合成己酮可可碱，所合成的己酮可可碱用于制备注射用己酮可可碱。The invention is suitable for synthesizing pentoxifylline, and the synthesized pentoxifylline is used for preparing pentoxifylline for injection.
以下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。Preferred embodiments of the present invention will be described below. It should be understood that the preferred embodiments described here are only used to illustrate and understand the present invention, not to limit the present invention.
实施例1 一种己酮可可碱S1的合成方法Embodiment 1 A kind of synthetic method of pentoxifylline S1
本实施例提供一种己酮可可碱S1的合成方法，其合成方法为：The present embodiment provides a synthetic method of pentoxifylline S1, the synthetic method is:
量取70mlTHF加入到反应容器中，开启搅拌并降温至-15℃，然后称取11.5g氨基-5-己酮加入到已经降温的THF中，加入27mlTEA，混合均匀后，保温-15℃，逐滴加入溶于20mlTHF的23.5g 4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯溶液，反应45min后，取少量反应液作样品，注入液相色谱仪检测，氨基-5-己酮的吸收峰消失，即可结束反应，其反应式为：Measure 70ml of THF into the reaction vessel, start stirring and cool down to -15°C, then weigh 11.5g of amino-5-hexanone into the cooled THF, add 27ml of TEA, mix well, keep warm at -15°C, gradually Add dropwise 23.5g 4-(nitromethylacyl chloride)-1-methylimidazole-5-acyl chloride solution dissolved in 20mlTHF, react for 45min, take a small amount of reaction solution as a sample, inject liquid chromatograph detection, amino-5- The absorption peak of hexanone disappears, and the reaction can be terminated, and its reaction formula is:
在-15℃下，向反应液中加入100ml纯化水搅拌10min，加入300ml乙酸乙酯继续搅拌5min后，静置分层，去除水相，保留有机相并向其中加入无水硫酸钠干燥，浓缩有机相至无溶剂蒸出，加入50ml无水乙醇，溶解蒸干的淡黄色油状物质，混合 均匀后，加入活性炭搅拌20min脱色，过滤后加入150ml石油醚，放入冰箱冷冻层冷冻析晶12h，过滤，干燥，即得己酮可可碱S1 20.63g收率为74.2％，取少量己酮可可碱A1作为检测样品，根据《中国药典》2015版二版(P50)提供的检测条件检测，所得结果的HPLC图如图1所示，纯度为99.3％。At -15°C, add 100ml of purified water to the reaction solution and stir for 10min, add 300ml of ethyl acetate and continue to stir for 5min, then let stand to separate layers, remove the water phase, keep the organic phase and add anhydrous sodium sulfate to it for drying and concentration Evaporate the organic phase until there is no solvent, add 50ml of absolute ethanol, dissolve the light yellow oily substance evaporated to dryness, mix well, add activated carbon and stir for 20min to decolorize, add 150ml of petroleum ether after filtration, put it in the freezer layer of the refrigerator to freeze and crystallize for 12h, Filter and dry to get 20.63g of pentoxifylline S1. The yield is 74.2%. A small amount of pentoxifylline A1 is taken as a test sample. According to the test conditions provided by the second edition (P50) of "Chinese Pharmacopoeia" 2015, the obtained result The HPLC figure is shown in Figure 1, and the purity is 99.3%.
实施例2-4 己酮可可碱S2-S4的合成方法The synthetic method of embodiment 2-4 pentoxifylline S2-S4
本实施例2-4所提供的己酮可可碱S2-S4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。The synthesis methods of pentoxifylline S2-S4 provided in Examples 2-4 are basically the same as those in Example 1, the only difference being that some process parameters are different, and the specific process parameters are shown in Table 1.
表1：己酮可可碱S2-S4的工艺参数表Table 1: Process parameter table of pentoxifylline S2-S4
其它参数均与实施例1相同。Other parameters are all the same as in Example 1.
对比例1 己酮可可碱的合成温度对比①Comparative example 1 The synthesis temperature comparison of pentoxifylline ①
本对比例所提供的合成方法与实施例1基本相同，区别仅在于反应温度为10℃。在监测反应过程中，原料氨基-5-己酮的吸收峰虽然消失，但出现的新峰与己酮可可碱的吸收峰出峰位置不同，分子量为393.4，经分析，其分子式为：The synthesis method provided in this comparative example is basically the same as that in Example 1, except that the reaction temperature is 10°C. During the monitoring reaction process, although the absorption peak of raw material amino-5-hexanone disappeared, the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 393.4. After analysis, its molecular formula was:
对比例2 己酮可可碱的合成温度对比②Comparative example 2 The synthesis temperature comparison of pentoxifylline②
本对比例所提供的合成方法与实施例1基本相同，区别仅在于反应温度为-30℃。在监测反应过程中，原料氨基-5-己酮的吸收峰虽然消失，但出现的新峰与己酮可可碱的吸收峰出峰位置不同，分子量为314.1，经分析，其分子式为：The synthesis method provided in this comparative example is basically the same as that in Example 1, except that the reaction temperature is -30°C. During the monitoring reaction process, although the absorption peak of raw material amino-5-hexanone disappeared, the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 314.1. After analysis, its molecular formula was:
对比例3 己酮可可碱的合成原料用量对比①Comparative example 3 Comparison of the amount of synthetic raw materials for pentoxifylline ①
本对比例所提供的合成方法与实施例1基本相同，区别仅在于4-(氮甲基酰氯) -1-甲基咪唑-5-酰氯和氨基-5-己酮的摩尔比为1:0.6。在监测反应过程中，原料氨基-5-己酮的吸收峰虽然消失，但出现的新峰与己酮可可碱的吸收峰出峰位置不同，分子量为513.1，经分析，其分子式为：The synthetic method provided by this comparative example is basically the same as that of Example 1, except that the molar ratio of 4-(nitromethylacyl chloride)-1-methylimidazolium-5-acid chloride and amino-5-hexanone is 1:0.6 . During the monitoring reaction process, although the absorption peak of the raw material amino-5-hexanone disappeared, the new peak that appeared was different from the peak position of the absorption peak of pentoxifylline, and the molecular weight was 513.1. After analysis, its molecular formula was:
对比例4 己酮可可碱的合成原料对比②Comparative example 4 The synthetic raw material comparison of pentoxifylline②
本对比例所提供的合成方法与实施例1基本相同，区别仅在于4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基-5-己酮的摩尔比为1:1.1。在监测反应过程中，原料氨基-5-己酮的吸收峰虽然消失，但出现的新峰与己酮可可碱的吸收峰出峰位置不同，分子量为393.4，经分析，其分子式为：The synthetic method provided by this comparative example is basically the same as that of Example 1, except that the molar ratio of 4-(nitromethylacyl chloride)-1-methylimidazolium-5-acid chloride and amino-5-hexanone is 1:1.1 . During the monitoring reaction process, although the absorption peak of raw material amino-5-hexanone disappeared, the new peak that appeared was different from the absorption peak of pentoxifylline, and its molecular weight was 393.4. After analysis, its molecular formula was:
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。It should be noted that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still understand The technical solutions described in the above embodiments are modified, or some of the technical features are equivalently replaced. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.
Claims (4)
- 一种己酮可可碱的合成方法，其特征在于：所述合成方法为分别取4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基-5-己酮溶于有机溶剂中，加入缚酸剂进行缩合反应，反应结束后，即得己酮可可碱，其反应式为：A kind of synthetic method of pentoxifylline, it is characterized in that: described synthetic method is to get 4-(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone to be dissolved in organic solvent respectively In, add acid-binding agent and carry out condensation reaction, after reaction finishes, obtain pentoxifylline, and its reaction formula is:
- 根据权利要求1所述的己酮可可碱的合成方法，其特征在于：所述4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基-5-己酮的摩尔比为1:0.8～1.02；所述缚酸剂与4-(氮甲基酰氯)-1-甲基咪唑-5-酰氯和氨基己酮总用量的摩尔比为1.8～3.3:1。The synthetic method of pentoxifylline according to claim 1, is characterized in that: the mol ratio of described 4-(nitromethyl acid chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone is 1:0.8～1.02; the molar ratio of the acid binding agent to the total amount of 4-(nitromethylimidazolium chloride)-1-methylimidazole-5-acid chloride and aminohexanone is 1.8～3.3:1.
- 根据权利要求1或2所述的己酮可可碱的合成方法，其特征在于：所述有机溶剂为四氢呋喃、1,4-二氧六环或N,N-二甲基甲酰胺；所述缚酸剂为三乙胺和/或N,N-二异丙基乙胺。The synthetic method of pentoxifylline according to claim 1 or 2, is characterized in that: the organic solvent is THF, 1,4-dioxane or N,N-dimethylformamide; The acid agent is triethylamine and/or N,N-diisopropylethylamine.
- 根据权利要求1或2所述的己酮可可碱的合成方法，其特征在于：所述缩合反应的反应温度为-15～5℃、反应时间为20～75min。The method for synthesizing pentoxifylline according to claim 1 or 2, characterized in that: the reaction temperature of the condensation reaction is -15-5° C., and the reaction time is 20-75 minutes.
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| JPS53149997A (en) * | 1977-06-03 | 1978-12-27 | Asahi Chem Ind Co Ltd | Preparation of xanthine derivatives |
| JPS5412397A (en) * | 1977-06-30 | 1979-01-30 | Shin Nippon Yakugiyou Kk | Preparation of oxoalkylxanthine |
| CN101648951A (en) * | 2009-08-11 | 2010-02-17 | 徐奎 | pentoxifylline derivative |
| CN113214259A (en) * | 2021-05-25 | 2021-08-06 | 海南通用康力制药有限公司 | Synthesis method of pentoxifylline |
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| JPS53149997A (en) * | 1977-06-03 | 1978-12-27 | Asahi Chem Ind Co Ltd | Preparation of xanthine derivatives |
| JPS5412397A (en) * | 1977-06-30 | 1979-01-30 | Shin Nippon Yakugiyou Kk | Preparation of oxoalkylxanthine |
| CN101648951A (en) * | 2009-08-11 | 2010-02-17 | 徐奎 | pentoxifylline derivative |
| CN113214259A (en) * | 2021-05-25 | 2021-08-06 | 海南通用康力制药有限公司 | Synthesis method of pentoxifylline |
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