CN114057653A - Preparation method of urapidil - Google Patents
Preparation method of urapidil Download PDFInfo
- Publication number
- CN114057653A CN114057653A CN202111620758.1A CN202111620758A CN114057653A CN 114057653 A CN114057653 A CN 114057653A CN 202111620758 A CN202111620758 A CN 202111620758A CN 114057653 A CN114057653 A CN 114057653A
- Authority
- CN
- China
- Prior art keywords
- urapidil
- dimethyl
- chloropropylamino
- reaction
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960001130 urapidil Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- RPYBDDBZRQGARJ-UHFFFAOYSA-N 6-(3-chloropropylamino)-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(NCCCCl)=CC(=O)N(C)C1=O RPYBDDBZRQGARJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- PBIJDBVKVFZACL-UHFFFAOYSA-N 6-(3-hydroxypropylamino)-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(NCCCO)=CC(=O)N(C)C1=O PBIJDBVKVFZACL-UHFFFAOYSA-N 0.000 claims abstract description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 16
- DDMVHGULHRJOEC-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazin-1-ium;chloride Chemical compound Cl.COC1=CC=CC=C1N1CCNCC1 DDMVHGULHRJOEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 9
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- WHGYBXFWUBPSRW-FEYSZYNQSA-N β-dextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)C(O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FEYSZYNQSA-N 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 238000007086 side reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 2
- OVGGXHMQXIQOBR-UHFFFAOYSA-N 3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-amine Chemical compound COC1=CC=CC=C1N1CCN(CCCN)CC1 OVGGXHMQXIQOBR-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 102000012306 5-Hydroxytryptamine 1A receptors Human genes 0.000 description 1
- 108050002825 5-Hydroxytryptamine 1A receptors Proteins 0.000 description 1
- VATQPUHLFQHDBD-UHFFFAOYSA-N 6-chloro-1,3-dimethylpyrimidine-2,4-dione Chemical compound CN1C(Cl)=CC(=O)N(C)C1=O VATQPUHLFQHDBD-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type 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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of urapidil. The preparation method comprises the following steps: mixing 1, 3-dimethyl-6-semicarbazide pyrimidine and 3-amino-1-propanol for reaction to prepare 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil; mixing 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil and thionyl chloride for reaction to prepare 6- (3-chloropropylamino) -1, 3-dimethyl uracil; reacting 6- (3-chloropropylamino) -1, 3-dimethyluracil with 1- (2-methoxyphenyl) piperazine hydrochloride to obtain urapidil. The preparation method has the advantages of simple operation, cheap and easily obtained reagents, less side reactions, high yield, good purity of the obtained product and contribution to industrial production.
Description
Technical Field
The invention relates to a preparation method of urapidil, belonging to the technical field of chemical synthesis.
Background
Urapidil is a selective alpha 1 receptor blocker and has the double functions of peripheral and central pressure reduction. Peripheral vasodilation acts to dilate blood vessels primarily by blocking postsynaptic α 1 receptors, resulting in a significant decrease in peripheral resistance. The central action plays a role in reducing blood pressure by activating 5-hydroxytryptamine-1A receptors and reducing sympathetic feedback of the brain-extending cardiovascular regulation center. The product has effects of blocking postsynaptic alpha 1 receptor and peripheral alpha 2 receptor, but the former is the main one. The product has vasodilatation effect on vein blood vessel larger than that on artery blood vessel, can reduce resistance of renal blood vessel, has no blood pressure lowering effect on blood pressure patients, and has no obvious effect on heart rate.
The chemical name of urapidil is 6- [ [3- [4- (2-methoxyphenyl) -1-piperazinyl ] propyl ] amino ] -1, 3-dimethyluracil, and the name of English is 6- ((3- (4- (2-methoxyphenyl) piperazin-1-yl) propyl) amino) -1, 3-dimethylpyrimidine-2, 4(1H, 3H) -dione.
Two synthetic methods disclosed in the original Takeda patent US3957786 are as follows:
route one: with 3- [4- (2-methoxyphenyl) piperazin-1-yl]Propylamine (IV) with 6-chloro-1, 3-dimethyluracil (V) in Et3N，K2CO3，Na2CO3And condensing in the presence of alkali such as KOH or NaOH to obtain the target urapidil. The raw materials required by the route are all industrially produced, the reagent price is low, the reaction time and the production period are long, and the yield is low.
And a second route: condensing 6- (3-chloropropylamino) -1, 3-dimethyl uracil (II) and 1- (2-methoxyphenyl) piperazine (IIa) or hydrochloride thereof (IIb) to obtain the target urapidil. The raw materials used in the route are not produced at home, and the foreign products are expensive.
Patent CN104262264B applied and granted by Hebei Yipin pharmaceutical Co., Ltd. in 2014 selects route one, Pd/NHC is selected as a catalytic system in the synthesis of urapidil, and although the preparation process has the advantages of good selectivity, high yield and the like, the route needs a Pd catalyst and is high in cost.
Journal of chinese medical industry, 2000, 31 (7): 294, 295, selecting a second route to optimize the process, taking 6- (3-chloropropylamino) -1, 3-dimethyl uracil and 1- (2-methoxyphenyl) piperazine hydrochloride as raw materials, water as a solvent, sodium carbonate as an acid-binding agent, and preparing urapidil through heating reaction. The post-treatment comprises adding water into the reaction solution to precipitate the product, and then recrystallizing with ethanol to obtain the purified urapidil product. This process does not provide product purity. Weathered et al (CN102295607A) made a process modification to this step. In the reaction process, a phase transfer catalyst (cetyl trimethyl ammonium bromide, N-dimethyl hexadecyl tertiary amine, PEG-400, beta-cyclodextrin and the like) is added, and the method can prepare urapidil with high selectivity and high purity. However, the route only reports the one-step reaction for synthesizing urapidil, and an anti-solvent recrystallization method is selected in the process for purifying the crude urapidil, so that the yield is not mentioned, and the purification method may have poor impurity removal effect on some processes. Xu you jun et al (journal of chinese medical industry, 2000, (07): 8-10.) reported that urapidil was synthesized from cyanoacetic acid mainly by the route two method, but in the synthetic route, dichloroethane was used as a kind of solvent, and the purity of the intermediate and the product urapidil was not mentioned.
The document Arseim Forsch Drug, 1997, 10: 1895-1897 also reports a synthetic method of urapidil.
The compound 6- (3- (2- (2-methoxyanilino) ethylamino) propyl) amino) -1, 3-dimethylpyrimidine reacts with 1, 2-dibromoethane to prepare urapidil. The route has more side reactions and difficult post-treatment, so the method is only suitable for laboratory pilot scale reactions and has no significance of production amplification.
Disclosure of Invention
In order to solve the above problems of the prior art, the present invention aims to provide a method for preparing urapidil. The method has the advantages of simple operation, cheap and easily obtained reagents, less side reaction, high yield, good purity of the obtained product and contribution to industrial production.
In order to realize the technical purpose, the invention provides a preparation method of urapidil, which takes 1, 3-dimethyl-6-semicarbazide pyrimidine as a raw material and comprises the following steps:
reacting 1, 1, 3-dimethyl-6-semicarbazide pyrimidine with 3-amino-1-propanol to obtain an intermediate 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil;
and 3, reacting 6- (3-chloropropylamino) -1, 3-dimethyluracil with 1- (2-methoxyphenyl) piperazine hydrochloride to obtain urapidil.
Further, the step 1 comprises the following steps:
step 11, adding 1, 3-dimethyl-6-semicarbazide pyrimidine serving as a raw material into 3-amino-1-propanol, adding ammonium chloride, and heating to 100 ℃ and 150 ℃ for reaction for 5-6 hours;
and step 12, cooling to 80 ℃ after the reaction is finished, adding a crystallization solvent, cooling to 0-10 ℃, filtering, washing and drying a filter cake to obtain the 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil.
Wherein, the crystallization solvent adopted in the step 12 is selected from one or more of ethanol, ethyl acetate and acetone.
Further, the step 2 comprises the following steps:
step 21, dissolving 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil in solvent, adding thionyl chloride, heating to 35-55 ℃ and reacting for 0.5-1 hour;
and step 22, cooling to room temperature after the reaction is finished, filtering, washing and drying a filter cake to obtain the 6- (3-chloropropylamino) -1, 3-dimethyluracil.
Wherein, the solvent adopted in the step 21 is one or more selected from dichloromethane, toluene and ethyl acetate.
Further, the step 3 comprises the following steps:
step 31, adding 1- (2-methoxyphenyl) piperazine hydrochloride into water, adding inorganic base and a phase transfer catalyst, heating to 100 ℃, adding 6- (3-chloropropylamino) -1, 3-dimethyluracil in batches, and reacting for 1-2 hours;
and step 32, adding water after the reaction is finished, cooling to room temperature, filtering, adding a crystallization solvent into the crude product after the filter cake is washed, heating and refluxing until the product is clear, naturally cooling to 0-10 ℃, preserving heat and growing crystals for 0.5-1 hour, filtering, washing and drying the filter cake to obtain the urapidil pure product.
Wherein, the inorganic base adopted in the step 31 is one or a combination of potassium carbonate, sodium carbonate and sodium bicarbonate; the phase transfer catalyst is one or a combination of more of cetyl trimethyl ammonium bromide, N-dimethyl hexadecyl tertiary amine, beta-dextrin and PEG.
Wherein, the crystallization solvent adopted in step 32 is selected from one or a combination of several of methanol, ethanol and isopropanol.
The raw materials required by the preparation method of urapidil are industrially produced, the price is low, the operation is simple, the side reaction is less, the yield is high, and the method can be used for large-scale production.
Drawings
FIG. 1 shows LC-MS of urapidil in example 1 of the present invention.
FIG. 2 is a drawing showing the preparation of urapidil in example 1 of the present invention1H NMR。
Detailed Description
The following examples1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.
The type of the high performance liquid chromatograph: agilent 1260 and Silmer fly U3000; the type of the chromatographic column: waters xbrige C18(4.6 × 150mm, 3.5 μm); mobile phase: a: ACN, B: water (0.1% H3PO 4); flow rate: 1.0 mL/min; gradient: 5% A for 1min, increment to 20% A with 4min, increment to 80% A with 8min, 80% A for 2min, and back to 5% A with 0.1 min; wavelength: 220 nm; column oven: 35 ℃ is carried out.
TLC: thin layer chromatography. The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
The column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, the national drug group, the welfare technology limited, the schehia (shanghai) chemical development limited, the shanghai bibi medical technology limited, the shanghai meihel chemical technology limited, and the like.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed liquid chromatography (TLC), a developing agent used for the reaction, a system of eluents for column chromatography employed for purifying compounds or a developing agent system for thin layer chromatography including: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Example 1
The embodiment provides a preparation method of urapidil, which specifically comprises the following steps:
In a 500ml three-necked flask, 3-amino-1-propanol (36.3g, 483.9mmol) was added, ammonium chloride (8.6g, 161.3mmol) and 1, 3-dimethyl-6-semicarbazide pyrimidine (25.0g, 161.3mmol) were added with mechanical stirring, heated to 100 ℃ and stirred for 30min, then heated to 150 ℃, stirred for 2.5h the system clear, and the temperature was maintained for 3h, TLC showed the reaction was complete. Cooling to 80 ℃, adding 75ml of ethanol, dissolving the system clearly, then slowly cooling to 10 ℃, and separating out a large amount of white solid. Filtration, filter cake washing twice with acetone (2 x 100ml), product room temperature drying to get 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil (24.1g white solid, yield 70.2%), HPLC purity 97.1%.
LC-MS：m/z＝214.1[M+H]+
1H NMR(400MHz，CDCl3)δ5.89(s，1H)，4.81(s，1H)，3.99-3.91(m，2H)，3.86-3.81(m，2H)，3.36(s，3H)，3.33(s，1H)，3.32(s，3H)，1.98-1.92(m，2H).
EA (140ml) and 6- (3-hydroxypropylamino) -1, 3-dimethyluracil (24.1g, 113.1mmol) were added to a 500ml three-necked flask, thionyl chloride (20.2g, 169.7mmol) was added dropwise, the temperature was raised to 35-40 ℃, heated to 55 ℃ and stirred for 30min, TLC showed completion of the reaction, the temperature was lowered to room temperature, the reaction solution was filtered, the cake was washed with EA (100m1), and the solid was air-dried at room temperature to give 6- (3-chloropropylamino) -1, 3-dimethyluracil (28.1g as a white solid in 100% yield).
LC-MS：m/z＝232.1[M+H]+
Step 3, synthesis of urapidil
In a 500ml three-necked flask, water (100m1), sodium carbonate (30.0g, 282.8mmol) and beta-dextrin (1.3g, 1.1mmol) were added, after stirring at room temperature for 10min, 1- (2-methoxyphenyl) piperazine hydrochloride (25.9g, 113.1mmol) was added, heating to 100 ℃ was carried out, 6- (3-chloropropylamino) -1, 3-dimethyluracil (26.2g, 113.1mmol) was added in three portions and stirred for 2h, TLC showed completion of the reaction. 300ml of water was added to the reaction mixture and cooled to room temperature, a solid precipitated, filtered and the filter cake washed with water. Adding ethanol (50ml) into the crude product, heating to reflux, dissolving the product, slowly cooling to 10 ℃, stirring for 30min, separating out a large amount of solid, filtering, washing a filter cake twice by using ethanol (2 x 20ml), and airing the product at room temperature to obtain urapidil (25.1g of white solid, the yield of the two steps is 57.3%) with the purity of HPLC (high performance liquid chromatography) of 99.9%.
LC-MS of urapidil of the present example is shown in FIG. 1, and LC-MS:m/z＝388.3[M+H]+. As shown in figure 2 of the drawings, in which,1H NMR(400MHz，CDCl3)δ7.34(s，1H)，7.08-7.00(m，1H)，6.98-6.85(m，3H)，4.79(s，1H)，3.87(s，3H)，3.41(s，3H)，3.31(s，3H)，3.19(dd，J＝9.6，5.6Hz，2H)，3.09(s，4H)，2.75(s，4H)，2.69-2.60(m，2H)，1.99-1.84(m，2H)。
comparative example 1
The comparative example provides a preparation method of urapidil, which specifically comprises the following steps:
In a 500ml three-necked flask, 3-amino-1-propanol (36.3g, 483.9mmol) was added, ammonium chloride (8.6g, 161.3mmol) and 1, 3-dimethyl-6-semicarbazide pyrimidine (25.0g, 161.3mmol) were added with mechanical stirring, heated to 180 ℃ and stirred for 30min, then heated to 180 ℃ and stirred for 2.5h until the system cleared, and the temperature was maintained for 3h, and TLC showed the reaction to be complete. Cooling to 50 ℃, adding 75ml of ethanol, dissolving the system clearly, then slowly cooling to-10 ℃, and separating out a large amount of white solid. Filtration, filter cake washing with acetone (2 x 100ml) twice, product room temperature drying to get 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil, HPLC purity 66.1%.
LC-MS：m/z＝214.1[M+H]+
1H NMR(400MHz，CDC13)δ5.89(s，1H)，4.81(s，1H)，3.99-3.91(m，2H)，3.86-3.81(m，2H)，3.36(s，3H)，3.33(s，1H)，3.32(s，3H)，1.98-1.92(m，2H).
EA (140m1) and 6- (3-hydroxypropylamino) -1, 3-dimethyluracil (24.1g, 113.1mmol) were added to a 500ml three-necked flask, thionyl chloride (20.2g, 169.7mmol) was added dropwise, the temperature was raised to 25 ℃ and stirred for 30min, TLC showed completion of the reaction, the temperature was decreased to room temperature, the reaction solution was filtered, the filter cake was washed with EA (100ml), and the solid was dried at room temperature to give 6- (3-chloropropylamino) -1, 3-dimethyluracil.
LC-MS：m/z＝232.1[M+H]+
Step 3, synthesis of urapidil
In a 500ml three-necked flask, water (100ml), sodium carbonate (30.0g, 282.8mmol) and beta-dextrin (1.3g, 1.1mmol) were added, after stirring for 10min at room temperature, 1- (2-methoxyphenyl) piperazine hydrochloride (25.9g, 113.1mmol) was added, heating to 120 ℃ was carried out, 6- (3-chloropropylamino) -1, 3-dimethyluracil (26.2g, 113.1mmol) was added in three portions and stirred for 2h, TLC showed completion of the reaction. 300ml of water was added to the reaction mixture and cooled to room temperature, a solid precipitated, filtered and the filter cake washed with water. Adding ethanol (50ml) into the crude product, heating to reflux, dissolving the product, slowly cooling to 10 ℃, stirring for 30min, separating out a large amount of solid, filtering, washing a filter cake twice by using ethanol (2 x 20ml), and airing the product at room temperature to obtain urapidil (the yield is 32.7%) with the purity of HPLC (high performance liquid chromatography) of 99.9%.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A preparation method of urapidil comprises the following steps:
mixing 1, 3-dimethyl-6-semicarbazide pyrimidine and 3-amino-1-propanol for reaction to prepare 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil;
mixing the 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil and thionyl chloride for reaction to prepare 6- (3-chloropropylamino) -1, 3-dimethyl uracil;
and (2) reacting the 6- (3-chloropropylamino) -1, 3-dimethyluracil with 1- (2-methoxyphenyl) piperazine hydrochloride to obtain the urapidil.
2. The production method of urapidil according to claim 1, wherein the mixing ratio of 1, 3-dimethyl-6-semicarbazide pyrimidine to 3-amino-1-propanol is 150mmol to 180 mmol: 450mmol-500 mmol;
the mixing ratio of the 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil and thionyl chloride is 110mmol-130mmol, 150mmol-180 mmol;
the mixing ratio of the 6- (3-chloropropylamino) -1, 3-dimethyluracil to 1- (2-methoxyphenyl) piperazine hydrochloride is 110mmol-120mmol, 110mmol-115 mmol.
3. The method of producing urapidil according to claim 1, wherein the production of 6- (3-hydroxypropylamino) -1, 3-dimethyluracil comprises the steps of:
1, 3-dimethyl-6-semicarbazide pyrimidine is taken as a raw material, added into 3-amino-1-propanol, added with ammonium chloride, heated to 100 ℃ and reacted for 5 to 6 hours at 150 ℃;
and after the reaction is finished, cooling to 80 ℃, adding a crystallization solvent, cooling to 0-10 ℃, filtering, washing and drying a filter cake to obtain the 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil.
4. The method for preparing urapidil according to claim 3, wherein the crystallization solvent is selected from one or more of ethanol, ethyl acetate and acetone.
5. The method for preparing urapidil according to claim 1, wherein the preparation of 6- (3-chloropropylamino) -1, 3-dimethyluracil comprises the steps of:
dissolving the 6- (3-hydroxypropyl amino) -1, 3-dimethyl uracil in an organic solvent, adding thionyl chloride, heating to 35-55 ℃ and reacting for 0.5-1 hour;
and after the reaction is finished, cooling to room temperature, filtering, washing and drying a filter cake to obtain the 6- (3-chloropropylamino) -1, 3-dimethyluracil.
6. The method for preparing urapidil according to claim 5, wherein the organic solvent is selected from one or more of dichloromethane, toluene and ethyl acetate.
7. The method for preparing urapidil according to claim 1, wherein the preparation of urapidil comprises the steps of:
adding the 1- (2-methoxyphenyl) piperazine hydrochloride into water, adding inorganic base and a phase transfer catalyst, heating to 100 ℃, adding 6- (3-chloropropylamino) -1, 3-dimethyluracil in batches, and reacting for 1-2 hours;
adding water after the reaction is finished, cooling to room temperature, filtering, washing a filter cake, adding a crystallization solvent into the crude product, heating and refluxing until the product is clear, naturally cooling to 0-10 ℃, preserving heat and growing crystals for 0.5-1 hour, filtering, washing and drying the filter cake to obtain the urapidil.
8. The preparation method of urapidil according to claim 7, wherein the inorganic base is selected from one or a combination of potassium carbonate, sodium carbonate and sodium bicarbonate.
9. The method for preparing urapidil according to claim 7, wherein the phase transfer catalyst is selected from one or a combination of cetyl trimethyl ammonium bromide, N-dimethyl hexadecyl tertiary amine, beta-dextrin and PEG.
10. The production method of urapidil according to claim 7, wherein the crystallization solvent is one or a combination selected from methanol, ethanol, isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111620758.1A CN114057653A (en) | 2021-12-27 | 2021-12-27 | Preparation method of urapidil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111620758.1A CN114057653A (en) | 2021-12-27 | 2021-12-27 | Preparation method of urapidil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114057653A true CN114057653A (en) | 2022-02-18 |
Family
ID=80230519
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111620758.1A Pending CN114057653A (en) | 2021-12-27 | 2021-12-27 | Preparation method of urapidil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114057653A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295607A (en) * | 2011-06-16 | 2011-12-28 | 郑州大学 | Inverse phase transfer catalysis preparation method for urapidil |
-
2021
- 2021-12-27 CN CN202111620758.1A patent/CN114057653A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295607A (en) * | 2011-06-16 | 2011-12-28 | 郑州大学 | Inverse phase transfer catalysis preparation method for urapidil |
Non-Patent Citations (3)
| Title |
|---|
| WEN LI等: "New and efficient technique for the synthesis of Urapidil using -cyclodextrin as an inverse phase-transfer catalyst", APPLIED CATALYSIS A: GENERAL, vol. 419, pages 210 - 214, XP028402783, DOI: 10.1016/j.apcata.2012.01.030 * |
| 李雯 等: "乌拉地尔的合成改进", 高校化学工程学报, vol. 27, no. 1, pages 131 - 135 * |
| 许佑君 等: "乌拉地尔的合成", 中国医药工业杂志, vol. 31, no. 7, pages 294 - 296 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2796461B1 (en) | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof | |
| CN107973779B (en) | Preparation method of N- (2-pyridine/pyrimidine-based) indole derivative | |
| JP7539451B2 (en) | Improved process for preparing aminopyrimidine derivatives | |
| CN109485638B (en) | Preparation method of oxitinib intermediate | |
| KR101653025B1 (en) | Method for producing 2-amino-4-(trifluoromethyl)pyridine | |
| CN114057653A (en) | Preparation method of urapidil | |
| JP2023525732A (en) | Method for synthesizing antitumor compound and intermediate thereof | |
| CN112250620A (en) | Synthesis method of pirfenidone | |
| CN116041253A (en) | Method for synthesizing diphenyl-2-pyridylmethane derivative | |
| CN110204542A (en) | A kind of synthetic method of JAK1 inhibitor Filgotinib | |
| CN115611947A (en) | Chiral phosphoric acid catalyst and synthesis method thereof | |
| CN105884746B (en) | The synthetic method of fluorine imatinib | |
| CN106854200B (en) | The preparation method of Ceritinib and its intermediate | |
| CN107383097A (en) | The preparation method of the phosphonylation derivative of the ketone of 3 benzylidene iso-indoles of N phenyl 1 | |
| CN111943853B (en) | Preparation method of pezopanib impurity | |
| CN111116552B (en) | Quinazolinone compound and preparation method thereof | |
| JP3161690B2 (en) | Method for producing 2-mercaptoimidazole fused ring compound | |
| CN103201278A (en) | Method for preparing zidovudine and intermediate thereof | |
| CN115521238B (en) | Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine | |
| WO2024183094A1 (en) | Use of ligand catalyst in synthesis of indole alkaloids | |
| CN101555248A (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| JPH07242694A (en) | Triazolopurine nucleoside derivative and synthetic intermediate useful for producing the same derivative | |
| CN116410129A (en) | Nevirapine intermediate compound | |
| JP2006070001A (en) | Chiral phase transfer catalyst with spiro skeleton, its preparation method and catalytic asymmetric reaction using the same | |
| CN116813538A (en) | Nevirapine intermediate compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 9 / F, building a, 108 Yuxin Road, Suzhou Industrial Park, 215000 Jiangsu Province Applicant after: Suzhou Zhongke new drug basket Biomedical Technology Co.,Ltd. Address before: 9 / F, building a, 108 Yuxin Road, Suzhou Industrial Park, 215000 Jiangsu Province Applicant before: Suzhou New Medicine Basket Biomedical Technology Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220218 |