CN114716434B - Nicergoline bulk drug and synthesis process thereof - Google Patents
Nicergoline bulk drug and synthesis process thereof Download PDFInfo
- Publication number
- CN114716434B CN114716434B CN202210521581.8A CN202210521581A CN114716434B CN 114716434 B CN114716434 B CN 114716434B CN 202210521581 A CN202210521581 A CN 202210521581A CN 114716434 B CN114716434 B CN 114716434B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methoxy
- ergol
- alpha
- nicergoline
- 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.)
- Active
Links
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 title claims abstract description 32
- 229960003642 nicergoline Drugs 0.000 title claims abstract description 32
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000008569 process Effects 0.000 title claims abstract description 17
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- FQIUCPGDKPXSLL-UHFFFAOYSA-N 5-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(Br)=C1 FQIUCPGDKPXSLL-UHFFFAOYSA-N 0.000 claims abstract description 11
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 10
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims abstract description 8
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims abstract description 8
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims abstract description 8
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims abstract description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 230000001678 irradiating effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000005457 ice water Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 7
- 229940088679 drug related substance Drugs 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000008034 disappearance Effects 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 5
- -1 lithium aluminum hydride Chemical compound 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- NLPHAZLCNNDGPS-UHFFFAOYSA-N 3-bromo-5-(chloromethyl)pyridine Chemical compound ClCC1=CN=CC(Br)=C1 NLPHAZLCNNDGPS-UHFFFAOYSA-N 0.000 description 1
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 239000012629 purifying agent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a synthesis process of nicergoline bulk drug, which relates to the technical field of chemical products, and comprises the following steps: step one: dropwise adding methanol into concentrated sulfuric acid, adding ergot alcohol, and irradiating the reaction solution by using an ultraviolet lamp; adding the mixture into a micro-channel reactor and adding ammonia water; recrystallizing with acetonitrile to obtain 10α -methoxy ergol; step two: potassium hydroxide and dimethyl sulfoxide are added into a micro-channel reactor, and 10 alpha-methoxy ergosterol and methyl iodide are added for reaction; drying to obtain 1-N-methyl-10 alpha-methoxy ergol; step three: and (3) sequentially adding 1-N-methyl-10 alpha-methoxy ergol, 5-bromonicotinic acid, tetrahydrofuran and dicyclohexylcarbodiimide into a microchannel reactor for reaction, and cooling the reaction liquid after the reaction is finished to obtain nicergoline. The preparation method adopts the optimized production process of the bulk drug, and has the advantages of short period, low cost and great improvement of production efficiency and yield.
Description
Technical Field
The invention relates to the technical field of chemical products, in particular to a nicergoline bulk drug and a synthesis process thereof.
Background
Nicergoline, which has the chemical name of 10α -methoxy-1, 6-dimethylergoline-8β -methanol-5' -bromonicotinic acid ester, is a semisynthetic ergoline derivative, and has the effects of blocking an α receptor and dilating blood vessels. Can strengthen metabolism of brain cell energy, increase oxygen and glucose utilization, promote transformation of neurotransmitter dopamine to enhance nerve conduction, strengthen brain protein biosynthesis, and improve brain function. Can be rapidly absorbed after oral administration, and has absolute bioavailability of less than 5%.
The nicergoline synthesis method has four methods:
route 1: under the condition of ultraviolet irradiation, lysergic acid is taken as an initial raw material, methyl 10 alpha-methoxy lysergic acid is obtained by addition in a methanol-concentrated sulfuric acid solution, 10 alpha-methoxy lysergic alcohol is obtained by reduction by lithium aluminum hydride, and nicergoline product is obtained by esterification with 5-bromonicotinyl chloride and methylation by methyl iodide;
route 2: 1-N-methyl-10 alpha-methoxy ergoline is taken as a starting material, and chloridized by phosphorus oxychloride and the like to obtain a compound, and condensed with 5-bromosodium nicotinate to obtain nicergoline products;
route 3: the ergot alcohol is taken as a starting material, 10 alpha-methoxy-ergot alcohol is obtained after ultraviolet synthesis, methyl iodide is methylated to obtain 1-N-methyl-10 alpha-methoxy ergot alcohol, and the 1-N-methyl-10 alpha-methoxy-ergot alcohol is esterified with 5-bromonicotinic acid to obtain nicergoline products; route 4: the ergot alcohol-8-methanesulfonate is taken as a starting material, and N-methyl-10 alpha-methoxy optical ergot alcohol-8-methanesulfonate is obtained after methyl iodide and ultraviolet addition, and then condensed with 5-bromonicotinic acid to obtain the nicergoline product.
Wherein, route 1: the use of lysergic acid as a starting material may result in the influence of optical isomers due to the reduction of lysergic acid ester C-8 ester groups to lysergic alcohol with lithium aluminum hydride, and lysergic acid is not readily available. Route 2: 1-N-methyl-10 alpha-methoxy ergol is used as a starting material, phosphorus oxychloride is used during chlorination, and 5-bromonicotinic acid acyl chloride have the possibility of side reaction with a chlorinating reagent during 5-bromonicotinic acid acyl chlorination, so that the product is not easy to purify. Scheme 3 and scheme 4 are not easily controlled and are less efficient during the synthesis reaction.
Disclosure of Invention
The invention aims to provide a nicergoline bulk drug and a synthesis process thereof, which are used for solving the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the nicergoline bulk drug comprises the following raw materials: ergol, 5-bromonicotinic acid, dimethyl sulfoxide, methyl iodide, dicyclohexyl carbodiimide, anhydrous methanol, concentrated sulfuric acid, ammonia water, chloroform, anhydrous magnesium sulfate, diethyl ether, acetonitrile, potassium hydroxide, acetone, tetrahydrofuran, dichloromethane and sodium bisulphite.
Based on the technical scheme, the invention also provides the following optional technical schemes:
the synthesis process of the nicergoline bulk drug comprises the following steps:
step one preparation of 10 α -methoxy ergol: dropwise adding methanol into concentrated sulfuric acid, adding ergot alcohol, and irradiating the reaction solution by using an ultraviolet lamp; placing the reaction product in ice water after reaction, adding the reaction product into a micro-channel reactor, and adding ammonia water; vacuum concentrating to obtain crude product, recrystallizing with acetonitrile to obtain 10α -methoxy ergol;
step two, preparation of 1-N-methyl-10 alpha-methoxy ergol: mixing potassium hydroxide and dimethyl sulfoxide, adding the mixture into a micro-channel reactor, and adding 10 alpha-methoxy ergosterol and methyl iodide for reaction; after the reaction is finished, pouring the reaction solution into ice water, and drying to obtain 1-N-methyl-10 alpha-methoxy ergol;
step three preparation of the tenergoline: and (3) sequentially adding 1-N-methyl-10 alpha-methoxy ergol, 5-bromonicotinic acid, tetrahydrofuran and dicyclohexylcarbodiimide into a microchannel reactor for reaction, cooling the reaction liquid after the reaction is finished, filtering insoluble substances, drying and concentrating under reduced pressure to obtain nicergoline.
In one alternative: the specific operation steps of the first step are as follows:
step D1: adding methanol into a three-mouth bottle, slowly dropwise adding concentrated sulfuric acid under stirring, and stirring at room temperature for 1 hour;
step D2: adding ergol into a three-mouth bottle, starting an ultraviolet lamp to irradiate the reaction liquid, reacting for 8 hours, and detecting the basic disappearance of the raw material ergol by TLC as a reaction end point;
step D3: pouring the reaction solution into ice water after the reaction is finished, adding the ice water into a micro-channel reactor, stirring for half an hour, slowly adding concentrated ammonia water, cooling to 10-15 ℃, extracting with chloroform, washing with water, drying with anhydrous magnesium sulfate, concentrating in vacuum to obtain a crude product, and recrystallizing with acetonitrile to obtain 10 alpha-methoxy ergosterol.
In one alternative: and D2, when the ultraviolet lamp irradiates the reaction liquid, slowly heating the reaction liquid to 35-40 ℃.
In one alternative: the specific operation steps of the second step are as follows:
step S1: adding potassium hydroxide and dimethyl sulfoxide into a three-mouth bottle, stirring and dissolving, cooling to room temperature, and then adding the mixture into a microchannel reactor;
step S2: adding 10 alpha-methoxy ergol, stirring for 1 hour, and slowly dropwise adding methyl iodide; after the addition, the reaction is carried out for 2 hours at room temperature, and TLC detects that the 10 alpha-methoxy ergol serving as a raw material basically disappears to be a reaction end point;
step S3: after the reaction is finished, pouring the reaction solution into ice water, precipitating solid, filtering, vacuum drying to obtain crude product, and recrystallizing with acetone to obtain 1-N-methyl-10 alpha-methoxy ergol.
In one alternative: the drying in step S3 is performed at a temperature of 60 ℃.
In one alternative: the specific operation steps of the third step are as follows:
step A1: sequentially adding 1-N-methyl-10 alpha-methoxy ergol, 5-bromonicotinic acid and tetrahydrofuran into a microchannel reactor, cooling, stirring and dissolving, and stirring for 30 minutes at room temperature;
step A2: adding dicyclohexylcarbodiimide into a micro-channel reactor in batches, and detecting the substantial disappearance of the raw material 1-N-methyl-10 alpha-methoxy ergol by TLC as a reaction end point;
step A3: after the reaction is finished, the reaction solution is cooled, insoluble matters are filtered, the filtrate is extracted by methylene dichloride, saturated sodium bisulphite aqueous solution is washed, water is washed, anhydrous magnesium sulfate is dried, the crude product is obtained by decompression concentration, and nicergoline is obtained by ether recrystallization.
In one alternative: the cooling temperature in the step A3 is 0-5 ℃, and the temperature is kept for stirring for 2 hours after cooling.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention adopts the micro-channel reactor in the synthesis process, can be applied to the chemical reaction process of rapid mixing, strong heat release, inflammability and explosiveness, and can obviously improve the process safety and realize the continuous operation process;
2. the preparation method adopts the optimized production process of the bulk drug, and the nicergoline prepared by the method has short period and low cost, and greatly improves the production efficiency and the yield.
Drawings
FIG. 1 is a flow chart of a process for preparing 10 alpha-methoxy ergol according to the invention.
FIG. 2 is a flow chart of a process for preparing 1-N-methyl-10 alpha-methoxy ergol according to the invention.
Fig. 3 is a flow chart of a process for preparing nicergoline according to the invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. The examples set forth herein are intended to be illustrative of the invention and are not intended to limit the scope of the invention. Any obvious modifications or alterations to the invention, as would be apparent, are made without departing from the spirit and scope of the present invention.
The components of the nicergoline drug substance are shown in the following table:
| material composition | Proportioning of |
| Ergot alcohol | 127g（0.5mol） |
| 5-Bromonicotinic acid | 87.2g |
| Dimethyl sulfoxide | 600ml |
| Methyl iodide | 30ml |
| Dicyclohexyl carbodiimide (DCC) | 24g |
| Anhydrous methanol | 1000ml |
| Concentrated sulfuric acid | 180ml |
| Ammonia water | 1000ml |
| Chloroform (chloroform) | 600ml |
| Anhydrous magnesium sulfate | Proper amount of |
| Diethyl ether | Proper amount of |
| Acetonitrile | Proper amount of |
| Potassium hydroxide | 90g |
| Acetone (acetone) | Proper amount of |
| Tetrahydrofuran (THF) | 600ml |
| Dichloromethane (dichloromethane) | 200ml |
| Sodium bisulfite | Proper amount of |
Wherein, ergot alcohol is a synthetic starting material; 5-bromonicotinic acid is a reagent for synthesis; dimethyl sulfoxide is a reagent for synthesis; methyl iodide is a reagent for synthesis. Dicyclohexylcarbodiimide (DCC) is a reagent for synthesis; anhydrous methanol is a reagent for synthesis; concentrated sulfuric acid is a reagent for synthesis; ammonia water is a reagent for synthesis; chloroform is a reagent for synthesis; anhydrous magnesium sulfate is a desiccant; diethyl ether is a crystallization reagent; acetonitrile is used for crystallization of 10 alpha-methoxy ergot alcohol; potassium hydroxide is a reagent for synthesis; acetone is a reagent for crystallizing 1-N-methyl-10 alpha-methoxy ergol; tetrahydrofuran is 1-N-methyl-10 alpha-methoxy ergot alcohol dichloromethane which is used as an extraction purifying agent; sodium bisulphite is an antioxidant.
The synthesis process of the nicergoline bulk drug comprises the following steps:
1. preparation of 10α -methoxy ergol
1000mL of methanol is added into a 2000mL three-necked flask, 180mL of concentrated sulfuric acid is slowly added dropwise under stirring, stirring is carried out at room temperature for 1 hour, 127g (0.5 mol) of ergol is added, an ultraviolet light lamp is started to irradiate the reaction liquid, the temperature is slowly increased to 35-40 ℃, the temperature is kept for 8 hours, and TLC (thin layer chromatography) detects that the raw material ergol basically disappears to be the reaction end point (developing agent is methanol: dichloromethane: ammonia water=20:80:0.5).
Pouring the reaction solution into 4L ice water after the reaction is finished, adding the ice water into a micro-channel reactor, stirring for half an hour, slowly adding 1L of concentrated ammonia water, cooling to 10-15 ℃, extracting with 300ml of chloroform and x2, washing with water, drying with anhydrous magnesium sulfate, concentrating in vacuum to obtain a crude product, and recrystallizing with acetonitrile to obtain 100.5g of 10 alpha-methoxy ergol with the yield of 70.3%, and M.P.183-185 ℃.
2. Preparation of 1-N-methyl-10 alpha-methoxy ergol
90g of potassium hydroxide and 600m of dimethyl sulfoxide are added into a 1000mL three-port bottle, stirred and dissolved, cooled to room temperature, then added into a micro-channel reactor, 103g (0.36 mol) of 10 alpha-methoxy ergosterol is added, stirred for 1 hour, and 30mL of methyl iodide is slowly added dropwise;
after the addition, the reaction is carried out for 2 hours at room temperature, and TLC (thin layer chromatography) detects that the 10 alpha-methoxy ergosterol of the raw material basically disappears to be the reaction end point (developing agent is methanol and dichloromethane and ammonia water=20:80:0.5);
after the reaction is finished, pouring the reaction solution into 3L of ice water to separate out solid; vacuum filtering, vacuum drying at 60deg.C to obtain crude 1-N-methyl-10α -methoxy ergosterol, and recrystallizing with acetone to obtain white solid 53.5g with yield of 49.5%, M.P.212-215 ℃.
3. Preparation of nicergoline
30g (0.1 mol) of 1-N-methyl-10 alpha-methoxy ergol 87.2g (0.4 mol) of 5-bromonicotinic acid and 600ml of tetrahydrofuran are added into a micro-channel reactor in sequence, stirred and dissolved under cooling, and stirred for 30 minutes at room temperature;
after this time, 24g of dicyclohexylcarbodiimide was added in portions, and TLC examined the substantial disappearance of 1-N-methyl-10α -methoxyergol as starting material (developing reagent: methanol: dichloromethane: ammonia water=20:80:0.5).
Cooling the reaction solution to 0-5 ℃ after the reaction is finished, keeping the temperature and stirring for 2 hours, filtering insoluble substances, extracting the filtrate with dichloromethane (100 ml multiplied by 2), washing with saturated sodium bisulphite aqueous solution, washing with water, drying with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain nicergoline crude product, recrystallizing with diethyl ether to obtain off-white solid 35.5g, and obtaining the yield of 71%; M.P.135-136℃and 99.2% by HPLC.
The detection of nicergoline prepared as described above is as follows:
the foregoing is merely specific embodiments of the disclosure, but the protection scope of the disclosure is not limited thereto, and any person skilled in the art can easily think about changes or substitutions within the technical scope of the disclosure, and it is intended to cover the scope of the disclosure. Therefore, the protection scope of the present disclosure shall be subject to the protection scope of the claims.
Claims (7)
1. The synthesis process of the nicergoline bulk drug is characterized by comprising the following steps:
step one preparation of 10 α -methoxy ergol: dropwise adding methanol into concentrated sulfuric acid, adding ergot alcohol, and irradiating the reaction solution by using an ultraviolet lamp; placing the reaction product in ice water after reaction, adding the reaction product into a micro-channel reactor, and adding ammonia water; vacuum concentrating to obtain crude product, recrystallizing with acetonitrile to obtain 10α -methoxy ergol;
step two, preparation of 1-N-methyl-10 alpha-methoxy ergol: mixing potassium hydroxide and dimethyl sulfoxide, adding the mixture into a micro-channel reactor, and adding 10 alpha-methoxy ergosterol and methyl iodide for reaction; after the reaction is finished, pouring the reaction solution into ice water, and drying to obtain 1-N-methyl-10 alpha-methoxy ergol;
step three preparation of the tenergoline: and (3) sequentially adding 1-N-methyl-10 alpha-methoxy ergol, 5-bromonicotinic acid, tetrahydrofuran and dicyclohexylcarbodiimide into a microchannel reactor for reaction, cooling the reaction liquid after the reaction is finished, filtering insoluble substances, drying and concentrating under reduced pressure to obtain nicergoline.
2. The process for synthesizing nicergoline drug substance according to claim 1, wherein the specific operation steps of the first step are as follows:
step D1: adding methanol into a three-mouth bottle, slowly dropwise adding concentrated sulfuric acid under stirring, and stirring at room temperature for 1 hour;
step D2: adding ergol into a three-mouth bottle, starting an ultraviolet lamp to irradiate the reaction liquid, reacting for 8 hours, and detecting the basic disappearance of the raw material ergol by TLC as a reaction end point;
step D3: pouring the reaction solution into ice water after the reaction is finished, adding the ice water into a micro-channel reactor, stirring for half an hour, slowly adding concentrated ammonia water, cooling to 10-15 ℃, extracting with chloroform, washing with water, drying with anhydrous magnesium sulfate, concentrating in vacuum to obtain a crude product, and recrystallizing with acetonitrile to obtain 10 alpha-methoxy ergosterol.
3. The process for synthesizing nicergoline drug substance according to claim 2, wherein the reaction solution is gradually heated to 35-40 ℃ when the reaction solution is irradiated by the ultraviolet light lamp in step D2.
4. The process for synthesizing nicergoline drug substance according to claim 1, wherein the specific operation steps of the second step are as follows:
step S1: adding potassium hydroxide and dimethyl sulfoxide into a three-mouth bottle, stirring and dissolving, cooling to room temperature, and then adding the mixture into a microchannel reactor;
step S2: adding 10 alpha-methoxy ergol, stirring for 1 hour, and slowly dropwise adding methyl iodide; after the addition, the reaction is carried out for 2 hours at room temperature, and TLC detects that the 10 alpha-methoxy ergol serving as a raw material basically disappears to be a reaction end point;
step S3: after the reaction is finished, pouring the reaction solution into ice water, precipitating solid, filtering, vacuum drying to obtain crude product, and recrystallizing with acetone to obtain 1-N-methyl-10 alpha-methoxy ergol.
5. The process for synthesizing nicergoline drug substance according to claim 4, wherein the drying in step S3 is performed at a temperature of 60 ℃.
6. The process for synthesizing nicergoline drug substance according to claim 1, wherein the specific operation steps of the third step are as follows:
step A1: sequentially adding 1-N-methyl-10 alpha-methoxy ergol, 5-bromonicotinic acid and tetrahydrofuran into a microchannel reactor, cooling, stirring and dissolving, and stirring for 30 minutes at room temperature;
step A2: adding dicyclohexylcarbodiimide into a micro-channel reactor in batches, and detecting the substantial disappearance of the raw material 1-N-methyl-10 alpha-methoxy ergol by TLC as a reaction end point;
step A3: after the reaction is finished, the reaction solution is cooled, insoluble matters are filtered, the filtrate is extracted by methylene dichloride, saturated sodium bisulphite aqueous solution is washed, water is washed, anhydrous magnesium sulfate is dried, the crude product is obtained by decompression concentration, and nicergoline is obtained by ether recrystallization.
7. The process for synthesizing nicergoline drug substance according to claim 6, wherein the cooling temperature in step A3 is 0-5 ℃ and the mixture is stirred for 2 hours after cooling.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210521581.8A CN114716434B (en) | 2022-05-13 | 2022-05-13 | Nicergoline bulk drug and synthesis process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210521581.8A CN114716434B (en) | 2022-05-13 | 2022-05-13 | Nicergoline bulk drug and synthesis process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114716434A CN114716434A (en) | 2022-07-08 |
| CN114716434B true CN114716434B (en) | 2023-11-17 |
Family
ID=82231626
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210521581.8A Active CN114716434B (en) | 2022-05-13 | 2022-05-13 | Nicergoline bulk drug and synthesis process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114716434B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116580A (en) * | 2019-12-27 | 2020-05-08 | 上海应用技术大学 | Improved preparation method of nicergoline |
-
2022
- 2022-05-13 CN CN202210521581.8A patent/CN114716434B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116580A (en) * | 2019-12-27 | 2020-05-08 | 上海应用技术大学 | Improved preparation method of nicergoline |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114716434A (en) | 2022-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108473524B (en) | Preparation method of tulathromycin and intermediate thereof | |
| EP3822259A1 (en) | Method for synthesizing valsartan | |
| WO2004104016A1 (en) | Process for the preparation of 4, 1', 6'-trichloro-4, 1', 6'trideoxygalactosucrose | |
| CN103554203A (en) | Amorphous crystal of tylonolide, and preparation method thereof | |
| CN114716434B (en) | Nicergoline bulk drug and synthesis process thereof | |
| CN109134581A (en) | Three water dexamethasone sodium phosphate compounds of one kind and its drug combination preparation | |
| CN109134331B (en) | Synthesis method of azithromycin genotoxic impurity | |
| CN115304526A (en) | Water-soluble florfenicol prodrug and preparation method thereof | |
| CN108840816A (en) | Acid imide midbody compound and its preparation method and application | |
| CN111362873B (en) | Synthetic method of gatifloxacin metabolite | |
| CN109575092B (en) | Synthesis method of azithromycin rearrangement impurity lactam | |
| CN110330447B (en) | Preparation method and application of nafamostat mesylate intermediate | |
| CN112724160A (en) | Preparation method of pentoxifylline impurity | |
| CN116768910B (en) | Refining method of rifabutin | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN110804022A (en) | Preparation method of dexrazoxane | |
| CN114456170B (en) | Preparation method of stable isotope labeled methotrexate internal standard reagent | |
| CN114057727B (en) | Synthesis method of zolpidem intermediate | |
| CN115785048B (en) | GL-V9 crystal form and preparation method thereof | |
| CN113683655B (en) | Preparation method of rocuronium bromide intermediate | |
| MX2013006050A (en) | Preparation of pet precursor. | |
| CN101735296A (en) | Method for preparing fludarabine | |
| CN116589422A (en) | Total synthesis and purification method of high-purity MRI (magnetic resonance imaging) contrast agent intermediate | |
| CN115141234A (en) | Synthesis process of clindamycin phosphate raw material medicine | |
| CN116462682A (en) | Synthesis method of tofacitinib demethylated impurity |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |