CN115572265A - Green synthesis process of high-purity minoxidil - Google Patents
Green synthesis process of high-purity minoxidil Download PDFInfo
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- CN115572265A CN115572265A CN202211235405.4A CN202211235405A CN115572265A CN 115572265 A CN115572265 A CN 115572265A CN 202211235405 A CN202211235405 A CN 202211235405A CN 115572265 A CN115572265 A CN 115572265A
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- minoxidil
- diamino
- chloropyrimidine
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- 229960003632 minoxidil Drugs 0.000 title claims abstract description 52
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 34
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000000047 product Substances 0.000 claims abstract description 37
- 239000012043 crude product Substances 0.000 claims abstract description 30
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000012535 impurity Substances 0.000 claims abstract description 25
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 23
- DOYINGSIUJRVKA-UHFFFAOYSA-N 6-chloro-3-hydroxy-2-iminopyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC(=N)N1O DOYINGSIUJRVKA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000002425 crystallisation Methods 0.000 claims abstract description 19
- 230000008025 crystallization Effects 0.000 claims abstract description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 18
- QJIUMVUZDYPQRT-UHFFFAOYSA-N 6-chloro-2,4-pyrimidinediamine Chemical compound NC1=CC(Cl)=NC(N)=N1 QJIUMVUZDYPQRT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 125
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- -1 minoxidil compound Chemical class 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 10
- 238000005660 chlorination reaction Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 7
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 7
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000007086 side reaction Methods 0.000 claims description 3
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 235000011118 potassium hydroxide Nutrition 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 238000004458 analytical method Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 239000007791 liquid phase Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000008213 purified water Substances 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 238000002386 leaching Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- SWELIMKTDYHAOY-UHFFFAOYSA-N 2,4-diamino-6-hydroxypyrimidine Chemical compound NC1=CC(=O)N=C(N)N1 SWELIMKTDYHAOY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 2
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000004451 qualitative analysis Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- NDEMNVPZDAFUKN-UHFFFAOYSA-N guanidine;nitric acid Chemical compound NC(N)=N.O[N+]([O-])=O.O[N+]([O-])=O NDEMNVPZDAFUKN-UHFFFAOYSA-N 0.000 description 1
- 230000009583 hair follicle growth Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000008338 local blood flow Effects 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- UHNSRFWQBVXBSK-UHFFFAOYSA-N methanol;2,2,2-trifluoroacetic acid Chemical compound OC.OC(=O)C(F)(F)F UHNSRFWQBVXBSK-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a green synthesis process of high-purity minoxidil, which comprises the following steps: 2,4-diamino-6-chloropyrimidine is used as an initial material, a crude 2,6-diamino-4-chloropyrimidine-1-oxide product is obtained through oxidation reaction, then, a refined 2,6-diamino-4-chloropyrimidine-1-oxide product is obtained through purification of water and triethylamine, the intermediate is condensed with piperidine in an aqueous solution under an alkaline condition to obtain a minoxidil crude product, and finally, the minoxidil crude product is obtained through water-ethanol decoloration and crystallization. In addition, the invention also provides a liquid phase analysis method of the key intermediate and the final finished product, and key impurities and possibly generated impurities in related steps are synthesized, so that the final finished product has high purity and less impurities, the usage amount of related reagents is greatly reduced, and the preparation method is environment-friendly.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a green synthesis process of high-purity minoxidil.
Technical Field
Minoxidil, namely a compound shown in a formula I, is clinically used as a potassium ion channel opener, can directly relax vascular smooth muscle, has a strong arteriolar expansion effect, reduces peripheral resistance and blood pressure, has certain effects of promoting local blood circulation and promoting hair follicle growth, can stimulate local atrophy hair follicles to regrow, even can generate new hair follicles, and is clinically used for treating hypertension and alopecia.
CN107857734 reports a preparation method and a synthesis energy route of a minoxidil intermediate formula V compound 2,4-diamino-6-chloropyrimidine as follows, a compound 2,4-diamino-6-hydroxypyrimidine as shown in formula IV is obtained by reacting a compound of formula II, guanidine nitrate and sodium methoxide serving as raw materials, and then phosphorus oxychloride and triethylamine are added to react to obtain a target product, namely 2,4-diamino-6-chloropyrimidine.
CN107129470 reports that compound 2,4-diamino-6-chloropyrimidine of formula v is used as starting material, peroxybenzoic acid is added, oxidation is carried out under alkaline condition to obtain compound 2,6-diamino-4-chloropyrimidine-1-oxide of formula vi, and then organic solvent is added: dioxane, acetonitrile and the like, piperidine are condensed under an alkaline condition to obtain a minoxidil crude product of a compound shown in a formula I, and finally, the minoxidil crude product is obtained by an organic solvent: and purifying the mixture to obtain a minoxidil finished product. In the method, peroxybenzoic acid is used as an oxidant, but the peroxybenzoic acid is not commercialized at present, so that industrial production is difficult to realize.
CN107235919 also reports that compound 2,4-diamino-6-chloropyrimidine of formula v is used as starting material, m-chloroperoxybenzoic acid, organic solvent: chloroform, dichloromethane, dichloroethane, ethanol, ether and the like, performing oxidation reaction under reflux, quenching, separating liquid, dripping petroleum ether into an organic phase, crystallizing and filtering to obtain a compound 2,6-diamino-4-chloropyrimidine-1-oxide shown in the formula VI, adding acetone, piperidine and alkali to perform condensation to obtain a compound minoxidil crude product shown in the formula I, and finally purifying by isopropanol to obtain a compound minoxidil finished product shown in the formula I. The method has complicated related steps, uses m-chloroperoxybenzoic acid as an oxidant, and has high price and large industrial cost.
In the 1980 edition of the national raw material medicine process compilation, the synthesis method of the minoxidil compound shown as the formula I is included, the compound shown as the formula II, the compound shown as the formula III and sodium methoxide are also used as raw materials, the compound shown as the formula IV 2,4-diamino-6-hydroxypyrimidine is obtained through condensation, then the compound shown as the formula V2,4-diamino-6-chloropyrimidine is obtained through reflux reaction in phosphorus oxychloride, the compound shown as the formula VI 2,6-diamino-4-chloropyrimidine-1-oxide is obtained through oxidation reaction, finally the compound shown as the formula I minoxidil crude product is obtained through reflux reaction in piperidine directly, and the compound shown as the formula I minoxidil crude product is decolored and crystallized through ethanol to obtain the minoxidil compound shown as the formula I finished product. The method adopts pure piperidine as a solvent for reaction, and the piperidine is expensive, seriously polluted and not suitable for large-scale production.
According to the above data combined with the results of practical verification experiments, the following disadvantages are found in the prior art:
(1) related intermediates and finished products are not subjected to quality analysis in the prior art, the key intermediate compound 2,6-diamino-4-chloropyrimidine-1-oxide in the formula VI plays an important role in the quality of the final finished product, and although a purification method is mentioned in literature reports, the effect after refining is not explained, and residual impurities are not analyzed and controlled, so that the quality of the final finished product cannot be ensured.
(2) In the condensation reaction for synthesizing the minoxidil compound shown in the formula I, the existing literature records all adopt pure organic solvents, and a large number of repeated experiments show that the problem of insufficient substrate conversion exists, so that the yield is low and the environment is not friendly.
(3) In the step of refining the minoxidil crude product of the compound shown in the formula I, most of refining modes reported in literatures are found to have unsatisfactory effects through experimental reproduction, and related substance detection is not systematically carried out on the minoxidil crude product of the compound shown in the formula I and a refined pure minoxidil product of the compound shown in the formula I, so that a finished product with high purity and controllable quality cannot be obtained.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a green synthesis process of high-purity minoxidil with simple steps, low cost, environmental protection and controllable quality, the invention also provides a liquid phase analysis method of a key intermediate compound 2,6-diamino-4-chloropyrimidine-1-oxide of a formula VI compound and a final finished product minoxidil of a formula I compound by taking 2,4-diamino-6-chloropyrimidine as a raw material and performing two-step synthesis and two-step purification, and two key impurity compounds of a formula VI-3 and a formula I-2 which are main in side reaction are synthesized and measured.
The synthesis route of the target product minoxidil, namely the compound shown in the formula I, is as follows:
the synthesis route of two key impurities generated by the side reaction of the invention is as follows:
the synthesis steps of the invention are as follows:
1) Oxidation to give the compound 2,6-diamino-4-chloropyrimidine-1-oxide of formula vi: oxidizing and hydrolyzing a raw material oxidant perbenzoic acid by benzoyl peroxide to obtain a compound 2,4-diamino-6-chloropyrimidine ethyl acetate solution in a formula V, and oxidizing by benzoyl peroxide to obtain a compound 2,6-diamino-4-chloropyrimidine-1-oxide crude product in a formula VI; refining: the crude 2,6-diamino-4-chloropyrimidine-1-oxide of the compound shown in the formula VI is recrystallized in an aqueous solution of organic alkali to obtain a 2,6-diamino-4-chloropyrimidine-1-oxide pure product of the compound shown in the formula VI.
2) On the basis of the step 1), condensing a product of the step 1), namely a compound 2,6-diamino-4-chloropyrimidine-1-oxide pure product of the formula VI, as a raw material to obtain a compound minoxidil of a formula I: adding water, inorganic base and piperidine into a 2,6-diamino-4-chloropyrimidine-1-oxide pure product of a compound shown in a formula VI for heating reaction, and directly cooling and crystallizing after the center control reaction is finished to obtain a minoxidil crude product of the compound shown in the formula I; adding a certain proportion of ethanol-water mixed solution into the minoxidil crude product of the compound shown in the formula I, heating, dissolving the minoxidil crude product of the compound shown in the formula I, adding activated carbon for decoloring, filtering and crystallizing, and finally obtaining the high-purity minoxidil compound shown in the formula I.
As a further scheme of the invention: in step 1), the molar ratio of the compound 2,4-diamino-6-chloropyrimidine of formula v to benzoyl peroxide in oxidation is 1. The oxidation reaction time is 3 to 22 hours, preferably 5 hours. The oxidation reaction temperature is 0 to 30 ℃, preferably 0 to 5 ℃. The crystallization temperature is 0-30 ℃, preferably 0-5 ℃, and the crystallization time is 2-16 h, preferably 8h.
Further, in step 1), the mass-to-volume ratio of 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI to water in the purification is 1:5-1, preferably 1. The mass volume ratio of the compound 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI to the organic base is 1.01-1:1, preferably 1. The organic base used is selected from the group consisting of organic nitrogen-containing compounds: n, N-diisopropylethylamine, triethylamine, pyridine or a combination thereof, preferably triethylamine. The dissolution temperature is from 85 ℃ to reflux temperature, preferably reflux temperature. The crystallization temperature is 0-30 ℃, preferably 15-25 ℃, and the crystallization time is 2-16 h, preferably 2h.
As a further variant of the invention, in step 2), the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine of formula vi during condensation is 1.1 to 5.0, preferably 1; the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to inorganic base of compound of formula vi is 1.1 to 1, preferably 1; the mass-to-volume ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to water of the compound of formula VI is 1:5-1, preferably 1; the reaction temperature is between 85 ℃ and reflux temperature, preferably the reflux temperature; the condensation reaction time is 2 to 10 hours, preferably 5 hours; the crystallization temperature is 0-30 ℃, preferably 15-25 ℃; the crystallization time is 2 to 16 hours, preferably 2 hours.
Furthermore, in the step 2), during the refining, the refining system is an ethanol-water mixture, and the volume ratio of the ethanol to the water mixture is 1:1-1:9, preferably 1:4; the mass volume ratio of the minoxidil crude product of the compound of the formula I to the refined system is 1; the dissolution temperature is between 80 ℃ and reflux temperature, preferably reflux temperature; the crystallization temperature is 0-30 ℃, preferably 0-5 ℃; the crystallization time is 2 to 16 hours, preferably 2 hours.
Furthermore, the main raw materials and products involved in the above steps were analyzed: liquid phase analysis is carried out on the refined product of 2,6-diamino-4-chloropyrimidine-1-oxide of the compound shown in the formula VI after the oxidation reaction in the step 1), and only the compound shown in the formula VI-3 is remained except a small amount of 2,4-diamino-6-chloropyrimidine of the compound shown in the formula V; analyzing and determining a system after the condensation reaction in the step 2), condensing the main residual impurity compound in the formula VI-3 in the previous step with the raw material piperidine to generate a key impurity compound in the formula I-2, wherein the key impurity compound in the formula I-2 and the key impurity compound in the formula VI-3 have great influence on the synthesis of high-purity minoxidil, so that the key impurity needs to be synthesized and subjected to liquid phase positioning.
By adopting the technical scheme, the target product minoxidil can be obtained through two-step reaction, the steps are simple and convenient to operate and quantitatively produce, and the alkaline mixed solution of piperidine is adopted during condensation, so that the cost can be effectively controlled, the forward reaction of the target product is not influenced, a large amount of waste water generated by condensation of a pure organic reagent is avoided, and the influence on the environment is reduced.
The key impurity synthesis steps are as follows:
3) Chlorinating a compound 2,6-diamino-4-chloropyrimidine-1-oxide of a formula VI to obtain a compound of a formula VI-1, adding ethyl acetate and water into the compound of the formula VI-1, uniformly stirring, adding m-chloroperoxybenzoic acid at a certain temperature for oxidation reaction, adding alkaline water after the reaction is finished to quench the reaction, filtering to obtain a compound VI-3 crude product, and purifying the compound VI-3 crude product with water to obtain a compound VI-3 pure product;
as a further variant of the invention, the molar ratio of the compound of the formula vi-1 to m-chloroperoxybenzoic acid during oxidation is from 1.0 to 1, preferably 1; the oxidation reaction time is 3-24 h, preferably 16h, and the oxidation reaction temperature is 0-50 ℃, preferably 20-25 ℃;
further, the oxidation reaction needs to be carried out in an ethyl acetate-water mixed solution, and the volume ratio of water to ethyl acetate is 1; the mass-to-volume ratio of the compound of formula VI-1 to ethyl acetate is 1 to 50, preferably 1.
And 4) adding N, N-dimethylformamide into the minoxidil compound shown in the formula I, fully stirring uniformly, then adding N-chlorosuccinimide to perform chlorination, decompressing and rotary steaming after the reaction is finished to obtain a crude product, and finally fully pulping by using alkaline water and ethanol to obtain the compound shown in the formula I-2.
As a further embodiment of the invention, when chlorinated, the molar ratio of the compound minoxidil of formula i to N-chlorosuccinimide is 1.0 to 1, 2.0, preferably 1; the chlorination reaction time is 3 to 24 hours, preferably 16 hours; the chlorination reaction temperature is 0-50 ℃, preferably 20-25 ℃;
further, the chlorination reaction needs to be carried out in a polar aprotic solvent, the solvent comprises N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like or a combination thereof, preferably N, N-dimethylformamide, and the mass volume ratio of the compound minoxidil with the solvent is 1:5-1, preferably 1.
By adopting the technical scheme, the controllable nodes can be visually seen from the map, and the purity of the minoxidil and the conversion rate of the substrate are effectively controlled by qualitative and quantitative analysis steps of key impurities, so that the influence on the environment is reduced.
The invention has the beneficial effects that:
according to the invention, a target product can be obtained through two-step synthesis by selecting a proper synthesis route, and the operation is simple; when the raw materials are selected, a mixed solvent with a proper proportion is adopted, so that the conversion of a substrate is promoted, and the cost of a reagent is reduced; meanwhile, all the used reagents are cheap and easy to obtain, the method has the characteristic of environmental friendliness, and meanwhile, qualitative and quantitative analysis is carried out on key impurities, so that the quality of the product can be well controlled.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention.
In the drawings:
FIG. 1 is an HPLC chromatogram of a compound of formula VI;
FIG. 2 is an HPLC chromatogram of the crude compound of formula I;
FIG. 3 is an HPLC chromatogram of a pure compound of formula I;
FIG. 4 is a drawing of a compound of formula VI-1 1 H NMR chart;
FIG. 5 is a drawing showing a scheme for preparing a compound of the formula VI-3 1 H NMR chart;
FIG. 6 is a drawing of a compound of formula VI-3 13 C NMR chart;
FIG. 7 is a drawing showing the preparation of a compound of the formula I-2 1 H NMR chart.
The specific implementation mode is as follows:
the invention is further described below by means of specific examples, without limiting the scope of the invention.
Reference example 1: synthesis of Compound of formula IV, reference is made to the national Assembly of bulk pharmaceutical technology, 1980 edition
6.3L of 30 percent sodium methoxide-methanol solution and 1.5L of methanol are added into a reaction kettle and evenly stirred, 1.5kg of compound shown in the formula III is added, and the temperature is raised to 60-65 ℃ for reaction for 1 hour. Controlling the internal temperature to be 40-50 ℃, slowly dripping 1.56kg of the compound shown in the formula II, releasing heat in the dripping process, raising the temperature to be 60-65 ℃ after finishing dripping, preserving the temperature, stirring and reacting for 4 hours. The external temperature is controlled to be 45 to 55 ℃, the mixture is decompressed and concentrated until no fraction exists basically, and 12.0L of purified water is added to be stirred and dissolved clearly. Cooling, slowly dripping concentrated hydrochloric acid at the internal temperature of below 30 ℃, adjusting the pH to 8.0-9.0, and stirring for 30min. Cooling to 0-5 ℃, stirring and crystallizing for 2h, carrying out suction filtration, and leaching a filter cake by using precooled 1.5L of purified water. The filter cake is dried for 12 hours under reduced pressure at 65-75 ℃. To obtain 1.81kg of the compound 2,4-diamino-6-hydroxypyrimidine of the formula IV.
Reference example 2: synthesis of the Compound of formula V, referred to the national bulk pharmaceutical Process compilation 1980 edition
Adding 9.0L of phosphorus oxychloride into a reaction kettle, starting stirring, adding 1.5kg of a compound 2,4-diamino-6-hydroxypyrimidine shown in the formula IV, heating to 90-100 ℃, keeping the temperature for reaction for 6 hours, controlling the external temperature to be 60-70 ℃, carrying out reduced pressure concentration until no fraction is produced, adding 4.5L of ethyl acetate, and fully stirring, dissolving or uniformly dispersing. Controlling the internal temperature not to be higher than 60 ℃, slowly dripping the reaction liquid into 9.0L of purified water, and controlling the temperature to be 50-60 ℃ after finishing dripping, stirring and reacting for 5 hours. And (3) reducing the temperature, controlling the internal temperature to be not higher than 50 ℃, and dropwise adding a 20% sodium hydroxide aqueous solution to adjust the pH of the reaction solution to 9.0-9.5. Adding 22.5L of ethyl acetate, heating to 50-60 ℃, fully stirring for 10-20 min, standing for liquid separation, adding 7.5L of ethyl acetate into the water phase, fully stirring at 50-60 ℃ for 10-20 min, standing for liquid separation, combining the organic phases, adding 9.0L of water, heating to 50-60 ℃, fully stirring for 10-20 min, and standing for liquid separation. And (3) cooling the organic phase to 20-30 ℃, adding 4.5L of saturated saline solution, fully stirring for 10-20 min, standing, separating to obtain 28.9kg of an ethyl acetate solution of 2,4-diamino-6-chloropyrimidine of the compound of the formula V, detecting the content of 2,4-diamino-6-chloropyrimidine of the compound of the formula V to be 46.9mg/ml by taking the ethyl acetate solution, and obtaining 1.355kg of 2,4-diamino-6-chloropyrimidine of the compound of the formula V after conversion.
Reference example 3: synthesis of formula VI-1
Taking 6.0g of the compound 2,4-diamino-6-chloropyrimidine of the formula V, adding 40ml of N, N-dimethylformamide, stirring for dissolving, adding 5.6g N-chlorosuccinimide, stirring for reaction at room temperature, after the reaction is finished, adding 500ml of ethyl acetate and 500ml of water, stirring for liquid separation, extracting the water layer once with 500ml of ethyl acetate, combining the ethyl acetate layers, adding 150ml of water, adjusting the pH of the water layer to 9-10 with sodium carbonate, stirring for liquid separation, washing the ethyl acetate layer once with 100ml of water, carrying out reduced pressure spin drying on the ethyl acetate layer, adding 20ml of ethanol, fully pulping, cooling, filtering and crystallizing to obtain 4.2g of the target compound. 1 H NMR(400MHz，DMSO-d6)，δ6.96(s，2H)，6.48(s，2H)。LC-MS:[M+H]＝179.09。
Example 1: synthesis of Compounds of formula VI
Adding 4.34L of purified water into the reaction kettle, sequentially adding 1125g of sodium hydroxide and 92.5g of magnesium sulfate heptahydrate under the stirring state, and cooling to 10-20 ℃. 7.05L of methanol is dripped, and the temperature is controlled to be 10-20 ℃. 12.35L of hydrogen peroxide (6.5%) is dripped, and the temperature is controlled to be 10-20 ℃. Controlling the temperature below 20 ℃, adding 3.027kg benzoyl peroxide, controlling the temperature between 18 and 22 ℃, and violently stirring and reacting for 50 to 60min. Controlling the internal temperature not higher than 20 ℃, quickly dripping the reaction liquid into 20.3L of pre-cooled 20% sulfuric acid aqueous solution, and stirring for reaction for 10-20 min after dripping. Adding 9.5L of ethyl acetate, fully stirring for 10-20 min, separating, adding 4.07L of ethyl acetate into the water phase, fully stirring for 10-20 min, separating, and combining EA layers to obtain a PBA/EA solution. Converting the ethyl acetate solution of 2,4-diamino-6-chloropyrimidine in the formula V into 1.355kg of solid, and cooling to below 5 ℃. And (3) controlling the temperature to be 0-5 ℃, dropwise adding the PBA/EA solution, and stirring and reacting for 5 hours at the temperature of 0-5 ℃ after dropwise adding. Controlling the temperature to be 0-10 ℃, and dropwise adding 16.3L7 percent of NaOH aqueous solution. Cooling to 0-5 ℃, stirring and crystallizing for 8h, carrying out suction filtration, and leaching a filter cake by using 2.7L of purified water to obtain 2.45kg of a crude wet product of the compound 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI. 15.7L of purified water is added into a reaction kettle, 2.30kg of crude wet product of 2,6-diamino-4-chloropyrimidine-1-oxide of a compound VI and 105ml of triethylamine are sequentially added under the stirring state, and the temperature is raised to 90-100 ℃. After the materials are completely dissolved, the temperature is reduced to 15 to 25 ℃, and the materials are stirred and crystallized for 2 hours. And (3) carrying out suction filtration, leaching a filter cake by using 2.1L of purified water, drying a wet product for 6h at 55 ℃ under reduced pressure to obtain 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI, wherein the purity is 98.58% by HPLC (high performance liquid chromatography) detection, and only two known impurities are remained, wherein the purity is 0.97% for the compound of the formula VI-3 and 0.44% for the compound of the formula V2,4-diamino-6-chloropyrimidine.
A liquid chromatography process for a compound of formula vi:
a Waters Symmetry Shield RP18 (250X 4.6mm,5 μm) column was used as a chromatographic column; gradient elution was performed with trifluoroacetic acid-2 g/L sodium heptanesulfonate solution (0.05) as mobile phase a and trifluoroacetic acid-methanol (0.05; the post-operation time is 15min; the flow rate is 0.8ml/min; the column temperature was 25 ℃; the detection wavelength is 245nm; the injection volume was 5. Mu.l.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 93 | 7 |
| 30 | 60 | 40 |
| 50 | 60 | 40 |
| 51 | 93 | 7 |
| 60 | 93 | 7 |
In a system applicability solution chromatogram, a compound of a formula IV, a product compound of a formula VI, an impurity compound of a formula VI-2, an impurity compound of a formula VI-3, a compound of a formula V, an impurity compound of a formula VI-1 and an impurity compound of a formula VI-2 sequentially generate peaks, and RRT sequentially comprises 0.82, 1.00, 1.12, 1.16, 1.22, 1.39 and 1.48.
List of related substances for compounds of formula VI
Example 2: synthesis of minoxidil, i.e. crude product of compound of formula I
Adding 12.75L of purified water into a reaction kettle, starting stirring, sequentially adding 850g of a compound 2,6-diamino-4-chloropyrimidine-1-oxide shown as a formula VI, 1.35kg of piperidine and 2.19kg of potassium carbonate, heating to 92-96 ℃, and reacting for 5 hours. Cooling to 15-25 ℃, stirring and crystallizing for 2-3 h, filtering, and leaching a filter cake with 850ml of purified water. Drying at 55 ℃ under reduced pressure for 6h to obtain 1.059kg of the crude compound of the formula I, the yield of the crude product is 95.6%, the purity of the crude product is 99.80% by HPLC detection, and only two known impurities are remained, namely the purity of the compound of the formula I-1 is 0.01%, and the purity of the compound of the formula VI 2,6-diamino-4-chloropyrimidine-1-oxide is 0.19%. 22.8L of purified water and 5.7L of absolute ethyl alcohol are added into a reaction kettle, 950g of crude compound of the formula I is added under the stirring state, the temperature is raised to 80-90 ℃, and the materials are completely dissolved. 47.5g of activated carbon was added thereto, and stirred for 30 mm. Filtering with double-layer qualitative filter paper while the solution is hot, and filtering the obtained filtrate with 0.22 μm water-based microporous filter membrane while the solution is hot. Cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h. And (3) carrying out suction filtration, leaching a filter cake with 950ml of purified water, and drying a wet product at 55 ℃ under reduced pressure for 8 hours to obtain 786g of the minoxidil finished product, wherein the refining yield is 82.7%, and the purity is 100% by HPLC (high performance liquid chromatography).
A liquid chromatography process for a compound of formula i:
a Waters Symmetry Shield RP18 (250X 4.6mm,5 μm) column was used as a column; gradient elution was performed with trifluoroacetic acid-2 g/L sodium heptanesulfonate solution-methanol (0.1; the post-operation time is 15min; the flow rate is 1.2ml/min; the column temperature is 50 ℃; the detection wavelength is 235nm; the injection volume was 10. Mu.l.
In a system applicability solution chromatogram, a compound of a formula IV, a compound of a formula VI, a compound of a formula V, a product compound of a formula I, an impurity compound of a formula I-1 and an impurity compound of a formula I-2 sequentially generate peaks, and RRT sequentially comprises 0.19, 0.26, 0.32, 1.00, 1.09 and 1.40.
List of related substances of Compounds of formula I
Example 3: synthesis of hetero-compounds of formula VI-3
Adding 100ml of ethyl acetate, 3.0g of impurity compound VI-1 and 2ml of purified water into a reaction bottle in sequence, stirring and cooling to 0-10 ℃, dropwise adding 6.0g of solution of m-chloroperoxybenzoic acid dissolved in 20ml of ethyl acetate, returning to 20-25 ℃ after dropwise adding, reacting, cooling to 0-10 ℃ after the reaction is finished, adding 7% sodium hydroxide aqueous solution, cooling to 0-10 ℃ for crystallization for 3 hours, performing suction filtration, adding 15ml of purified water into a filter cake, heating to 60 ℃, pulping for 1 hour, cooling to 20-30 ℃ for crystallization for 1 hour, performing suction filtration, leaching the filter cake with 5ml of water, and drying under reduced pressure at 55 ℃ to obtain 1.368g of solid. 1 H NMR(400MHz，DMSO-d6)，δ7.96(s，2H)，7.68(s，2H)。 13 C NMR(101MHz，DMSO-d6)，δ151.88，151.68，142.93，96.31。LC-MS:[M+H]＝195.16。
Example 4: synthesis of heterogeneous Compounds of formula I-2
Adding 3.0g of the compound shown in the formula I into a reaction bottle, uniformly stirring 45ml of DMF (dimethyl formamide), adding 2.1g of N-chlorosuccinimide, stirring at room temperature for reaction, concentrating under reduced pressure to dryness after the reaction is finished, adding 30ml of purified water, fully pulping 0.7g of sodium hydroxide at room temperature, performing suction filtration, leaching a filter cake with 15ml of water, adding 15ml of ethanol, heating to 70-75 ℃, pulping for 30min, cooling to room temperature, crystallizing, filtering, and drying a wet product at 50 ℃ under reduced pressure to obtain 0.756g of solid. 1 H NMR(400MHz，DMSO-d6)，δ7.27(s，2H)，7.10(s，2H)，3.24(t，J＝4.6Hz，4H)，1.57(s，6H)。LC-MS:[M+H]＝244.27。
Claims (7)
1. A green synthesis process of high-purity minoxidil is characterized in that the synthesis of the compound shown as the formula I comprises the following synthetic routes:
the synthesis steps are as follows:
1) And (3) oxidation: oxidizing an oxidant perbenzoic acid by benzoyl peroxide through an oxidation hydrolysis reaction, and oxidizing an ethyl acetate solution of 2,4-diamino-6-chloropyrimidine of a compound shown in a formula V by benzoyl peroxide to obtain a crude product of 2,6-diamino-4-chloropyrimidine-1-oxide of a compound shown in a formula VI;
and (3) refining a crude product: recrystallizing the 2,6-diamino-4-chloropyrimidine-1-oxide crude product of the compound shown in the formula VI in an aqueous solution of organic alkali to obtain a 2,6-diamino-4-chloropyrimidine-1-oxide pure product of the compound shown in the formula VI; carrying out a condensation reaction on the basis of the oxidation reaction in the step 1);
2) Condensation: adding water, inorganic base and piperidine into the 2,6-diamino-4-chloropyrimidine-1-oxide pure product of the compound shown in the formula VI for heating reaction, and directly cooling and crystallizing after the center control reaction is finished to obtain a minoxidil crude product of the compound shown in the formula I;
refining: adding a certain proportion of ethanol-water mixed solution into the minoxidil crude product of the compound shown in the formula I, heating, dissolving the compound shown in the formula I, adding activated carbon for decoloring, filtering and crystallizing to obtain the high-purity compound shown in the formula I.
2. The green synthesis process of high-purity minoxidil according to claim 1, wherein two main side reactions are generated in the synthesis process of the compound minoxidil of formula I: step 1) generating a key impurity, namely a compound shown as a formula VI-3; step 2) generating a key impurity, namely a compound of formula I-2;
the compound of the formula VI-3 and the compound of the formula I-2 comprise the following synthetic routes:
the synthesis steps are as follows:
3) Adding ethyl acetate and water into the compound of the formula VI-1, uniformly stirring, adding m-chloroperoxybenzoic acid at a certain temperature for oxidation reaction, adding alkaline water after the reaction is finished, quenching the reaction, filtering to obtain a crude compound VI-3, and purifying the crude compound VI-3 with water to obtain a pure compound VI-3;
4) Adding N, N-dimethylformamide into the minoxidil compound shown in the formula I, fully and uniformly stirring, then adding N-chlorosuccinimide for chlorination, decompressing and rotary steaming after the reaction is finished to obtain a crude product, and finally fully pulping by using alkaline water and ethanol in sequence to obtain a pure product of the compound shown in the formula I-2.
3. The green synthesis process of high-purity minoxidil according to claim 1, wherein in step 1),
when oxidized, the molar ratio of the compound 2,4-diamino-6-chloropyrimidine of formula V to benzoyl peroxide is 1; the oxidation reaction time is 3-22 h; the temperature of the oxidation reaction is 0-30 ℃; the crystallization temperature is 0-30 ℃; the crystallization time is 2 to 16 hours;
when the crude product is refined, the mass volume ratio of the 2,6-diamino-4-chloropyrimidine-1-oxide crude product of the compound shown in the formula VI to water is 1:5-1; the mass volume ratio of the crude compound 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI to the organic base is 1; the dissolving temperature is between 85 ℃ and the reflux temperature; the crystallization temperature is 0-30 ℃; the crystallization time is 2-16 h.
4. The green synthesis process of high-purity minoxidil according to claim 1, wherein in step 2),
the molar ratio of the compound 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine in formula VI during condensation is 1.1-1.0; the molar ratio of the compound 2,6-diamino-4-chloropyrimidine-1-oxide of the formula VI to the inorganic base is 1.1 to 1; the mass-to-volume ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to water of the compound of formula VI is 1:5-1; the reaction temperature is between 85 ℃ and reflux temperature; the condensation reaction time is 2-10 h; the crystallization temperature is 0-30 ℃; the crystallization time is 2 to 16 hours;
when the crude product is refined, the refining system is a mixture of ethanol and water, and the volume ratio of the ethanol to the water is 1:1-1:9; the mass-volume ratio of the minoxidil crude product of the compound shown in the formula I to the refined system is 1-20; the dissolving temperature is between 80 ℃ and the reflux temperature; the crystallization temperature is 0-30 ℃; the crystallization time is 2-16 h.
5. The green synthesis process of high-purity minoxidil according to claim 2, wherein in step 3),
the molar ratio of the compound of formula VI-1 to m-chloroperoxybenzoic acid, when oxidized, is from 1.0 to 1, preferably 1; the oxidation reaction time is 3-24 h; the temperature of the oxidation reaction is 0-50 ℃;
the oxidation reaction needs to be carried out in a mixed solution of ethyl acetate and water, and the volume ratio of water to ethyl acetate is 1; the mass volume ratio of the compound of the formula VI-1 to the ethyl acetate is 1 to 1.
6. The green synthesis process of high-purity minoxidil according to claim 2, wherein in step 4),
when chloro, the molar ratio of the minoxidil compound to the N-chlorosuccinimide is 1.0-1; the chlorination reaction time is 3-24 h; the temperature of the chlorination reaction is 0-50 ℃;
the chlorination reaction is carried out in a polar aprotic solvent, wherein the solvent comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like; the mass-volume ratio of the compound minoxidil in the formula I to the solvent is 1:5-1.
7. The green synthesis process of high-purity minoxidil according to claim 1, wherein the organic base in step 1) comprises one or more of N, N-diisopropylethylamine, triethylamine and pyridine; the inorganic base in the step 2) comprises one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
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| US3644364A (en) * | 1970-03-31 | 1972-02-22 | Upjohn Co | Compounds and process |
| JPH03127782A (en) * | 1989-10-13 | 1991-05-30 | Daicel Chem Ind Ltd | Production of 2,4-diamino-6-substitutted-pyrimidine-3-oxide |
| CN107129470A (en) * | 2017-06-12 | 2017-09-05 | 常州市天华制药有限公司 | A kind of synthesis of minoxidil and process for purification |
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- 2022-10-10 CN CN202211235405.4A patent/CN115572265A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3644364A (en) * | 1970-03-31 | 1972-02-22 | Upjohn Co | Compounds and process |
| JPH03127782A (en) * | 1989-10-13 | 1991-05-30 | Daicel Chem Ind Ltd | Production of 2,4-diamino-6-substitutted-pyrimidine-3-oxide |
| CN107129470A (en) * | 2017-06-12 | 2017-09-05 | 常州市天华制药有限公司 | A kind of synthesis of minoxidil and process for purification |
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