CN109575017A - A kind of preparation method of Olprinone HCl compound - Google Patents
A kind of preparation method of Olprinone HCl compound Download PDFInfo
- Publication number
- CN109575017A CN109575017A CN201811293175.0A CN201811293175A CN109575017A CN 109575017 A CN109575017 A CN 109575017A CN 201811293175 A CN201811293175 A CN 201811293175A CN 109575017 A CN109575017 A CN 109575017A
- Authority
- CN
- China
- Prior art keywords
- room temperature
- reaction
- added
- temperature
- preparation
- 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
- 229950005421 olprinone Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- -1 Olprinone HCl compound Chemical class 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- FXPMFQUOGYGTAM-UHFFFAOYSA-N 6-bromoimidazo[1,2-a]pyridine Chemical compound C1=C(Br)C=CC2=NC=CN21 FXPMFQUOGYGTAM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 230000003647 oxidation Effects 0.000 claims abstract 2
- 238000007254 oxidation reaction Methods 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 239000007787 solid Substances 0.000 claims description 37
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- 239000008213 purified water Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 24
- 238000005406 washing Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 238000007605 air drying Methods 0.000 claims description 22
- 239000012065 filter cake Substances 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 18
- 238000012544 monitoring process Methods 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 17
- 238000010792 warming Methods 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 230000008034 disappearance Effects 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- OHXAOPZTJOUYKM-UHFFFAOYSA-N 3-Chloro-2-methylpropene Chemical compound CC(=C)CCl OHXAOPZTJOUYKM-UHFFFAOYSA-N 0.000 claims description 11
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000009413 insulation Methods 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 229960004756 ethanol Drugs 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims 1
- UBCJCAPLMBHKPY-UHFFFAOYSA-L magnesium;oxolane;dibromide Chemical compound [Mg+2].[Br-].[Br-].C1CCOC1 UBCJCAPLMBHKPY-UHFFFAOYSA-L 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000003747 Grignard reaction Methods 0.000 abstract 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 abstract 1
- 238000007259 addition reaction Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 230000000087 stabilizing effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 6
- QEZHSXDSWBLPKD-UHFFFAOYSA-M [Br-].CC[Mg+].C1CCOC1 Chemical compound [Br-].CC[Mg+].C1CCOC1 QEZHSXDSWBLPKD-UHFFFAOYSA-M 0.000 description 5
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009875 water degumming Methods 0.000 description 2
- IIOKDOJKJGCOEP-UHFFFAOYSA-N 3h-pyrrolo[1,2-a]imidazole Chemical compound C1=CN2CC=NC2=C1 IIOKDOJKJGCOEP-UHFFFAOYSA-N 0.000 description 1
- BLFPINRQJLTUQJ-UHFFFAOYSA-N C=1C=CC(C#N)=NC=1C(O)(C)C1=CC=CC(C#N)=N1 Chemical compound C=1C=CC(C#N)=NC=1C(O)(C)C1=CC=CC(C#N)=N1 BLFPINRQJLTUQJ-UHFFFAOYSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- PWTBMBAQRAOAFF-UHFFFAOYSA-N Olprinone hydrochloride Chemical compound Cl.N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C PWTBMBAQRAOAFF-UHFFFAOYSA-N 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of preparation method of Olprinone HCl compound, with 6- bromo imidazo [1,2-a] pyridine for starting material, through grignard reaction, ozone oxidation, addition reaction, closed loop, at salt and it is refining to obtain.Preparation process of the invention, reaction condition is mild, process stabilizing, favorable reproducibility, and product yield is high, and impurity is few, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of medicinal chemicals, and in particular to a kind of system of Olprinone HCl compound
Preparation Method belongs to technical field of pharmaceuticals.
Background technique
Olprinone HCl is that a kind of phosphodiesterase iii (PDEIII) of Japanese Eisai Co., Ltd's research and development inhibits
Agent, the special phosphodiesterase of selective obstruction adenosine cyclophosphate have the function of enhancing contractile force and expand blood vessel, be
The drug for treating heart failure was listed in Japan for the first time in 1996.Clinical test also confirms that this medicine does not increase the oxygen consumption of cardiac muscle
Amount, and increase cardiac output, it is higher than the improvement cardiac energy effective percentage of catecholamines preparation.
Olprinone HCl (Olprinone Hydrochloride), chemical name 1,2- dihydro -5- imidazo [1,
2-a] pyridine -6- base -6- methyl -2- oxo -3- pyridine carbonitrile hydrochloride monohydrate, molecular formula C14H10N4O·HCl·
H2O, molecular weight 304.73, CAS registration number are 119615-63-3, and structural formula is as follows:
Document 1 [Chem.Pharm.Bull.39 (6), 1556-1567 (1991)] reports two of Olprinone HCl
Synthetic route a, wherein route restores imidazo [1,2-a] pyridine -6- using methylene chloride as solvent, with dibutyl aluminum hydride
Carboxylate methyl ester (1) obtains corresponding aldehyde (2).It under the action of butylamine, flows back in ethanol, (2) are condensed to yield with nitroethane
6- (2- nitro -1- acrylic) imidazo [1,2-a] pyridine (3).(3) and Fe-FeCl in hot ethanol-water2- HCl reaction, it is raw
At 1- (imidazo [1,2-a] pyridine -6- base) -2- acetone (4).(4) with N,N-dimethylformamide dimethyl acetal in hot DMF
Reaction obtains 4- (dimethylamino)-3- (imidazo [1,2-a] pyridine-6- base)-3- butene-2 -one (5), then in hot DMF
(5) and cyanoacetamide is in sodium methoxide catalyzed lower cyclization, generates Olprinone (6).The severe reaction conditions, the first step need
It is reacted 3 hours for subzero 60 degree under nitrogen protection, the reaction of second step needs 30 hours or more, and the yield reacted is too low.It is another
Route are as follows: under the catalytic action of KI and CuI, during 6- bromine imidazo [1,2-a] pyridine (1) and acetylacetone,2,4-pentanedione potassium are condensed to yield
Mesosome (2), (2) and sodium hydroxide hydrolysis, hydrochloric acid are acidified to obtain 1- (imidazo [1,2-a] pyridine -6- base) -2- acetone (3).
(3) it reacts to obtain 4- (dimethylamino) -3- (imidazo [1,2-a] pyrrole in hot DMF with N,N-dimethylformamide dimethyl acetal
Pyridine-6- base)-3- butene-2 -one (4), then (4) and cyanoacetamide generate difficult to understand in sodium methoxide catalyzed lower cyclization in hot DMF
Pu Linong (5).The reaction condition of the route is mild, but raw materials used acetylacetone,2,4-pentanedione potassium higher cost, is more toxic, and needs existing
With now matching, the yield of first two steps is lower, and only 36%.
Existing Olprinone HCl synthesis route has severe reaction conditions, and cost of material is high, and low wait of yield lacks
Point；Therefore, exploitation reaction condition is mild, simple controllable, and raw material is easy to get, and at low cost, the process route of high income is to need at present
The technical issues of solution.
Summary of the invention
It is an object of the invention to be directed to the deficiency of the above synthesis route, a kind of Olprinone HCl compound is provided
Preparation method, this method reaction condition is mild, and Olprinone HCl compound obtained has that impurity is low, with high purity, yield
The advantages that high.
The present invention provides a kind of preparation method of Olprinone HCl compound, synthetic routes are as follows:
Specific preparation process is as follows:
(1) into there-necked flask, 6- bromo imidazo [1,2-a] pyridine, tetrahydrofuran is added, stirring and dissolving is dripped at room temperature
Enter ethylmagnesium bromide tetrahydrofuran solution, control temperature is no more than 30 DEG C, and drop finishes, and is warming up to reflux (65-70 DEG C), reacts
1.5h is down to room temperature, instills the solution of methallyl chloride and tetrahydrofuran configuration, and temperature control is no more than 40 DEG C, and drop finishes, and is heated to
It flowing back (65-70 DEG C), reacts 1-3h, be down to room temperature, control temperature is no more than 30 DEG C, instills saturated aqueous ammonium chloride, and drop finishes,
It filters, filtrate rotates tetrahydrofuran, and surplus solution is extracted with ethyl acetate, and merges organic layer, filter cake ethyl acetate room temperature
Lower mashing 1h is filtered, and obtains filtrate, merges the organic phase obtained twice, purifying washing, organic phase is dry with anhydrous sodium sulfate, takes out
Filter, rotates solvent, obtains brown oil intermediate compound I；
(2) into another there-necked flask, intermediate I, methanol, purified water, concentrated hydrochloric acid, stirring cooling, temperature control -20 are sequentially added
DEG C~0 DEG C, it is slowly introducing O3/O2, TLC monitoring reaction, the spot disappearance of intermediate I, which is considered as reaction, terminates (solvent=dichloromethane
Alkane: methanol=20:1), temperature control is no more than 30 DEG C, saturated aqueous sodium sulfite is instilled, until starch potassium iodide paper is non-discolouring；
30% sodium hydrate aqueous solution is instilled again to pH=8~9, methylene chloride extracts reaction solution, merges organic layer, water washing is purified,
Organic phase is dry with anhydrous sodium sulfate, filters, solvent is evaporated off, obtains brown oil intermediate II；
(3) into another there-necked flask, intermediate II, isopropanol, n,N-Dimethylformamide dimethyl acetal, stirring liter is added
Temperature, reacts 0.5-2h, TLC monitoring reaction, the spot disappearance of intermediate II, which is considered as reaction, terminates (solvent by 70~90 DEG C of temperature control
=methylene chloride: methanol=15:1), system is down to room temperature, and solvent is evaporated off, and ethyl acetate is added in residue, and room temperature is beaten 2h,
It filters, 45 DEG C of forced air drying 1h obtain intermediate III；
(4) into another there-necked flask, intermediate III, dehydrated alcohol, cyanoacetamide, sodium methoxide, stirring liter are sequentially added
Temperature is to flowing back, insulation reaction 0.5~2h, TLC monitoring reaction, the spot disappearance of intermediate III be considered as reaction terminate (solvent=
Methylene chloride: methanol=10:1), it is down to room temperature, purified water is added, is slowly added to glacial acetic acid, adjusts pH=7-8, solid is precipitated,
1h is stirred at room temperature, filters, a small amount of ethanol washing, 45 DEG C of forced air drying 1h of filter cake obtain yellow solid, are intermediate IV；
(5) into another there-necked flask, intermediate IV, methanol, purified water, stirring heating is added.It 65-85 DEG C of temperature control, instills
Concentrated hydrochloric acid, solid all dissolve, and keep the temperature 10min, are down to room temperature, and solid is precipitated, and filter, and wash filter cake on a small quantity, and 45 DEG C of air blast are dry
Dry 1h, obtains light yellow solid, is Olprinone HCl crude product；
(6) into another there-necked flask, Olprinone HCl crude product, purified water is added, stirring is warming up to 75~95 DEG C, entirely
It is molten, 10min is kept the temperature, room temperature is down to, is filtered, a small amount of to purify water washing filter cake, 40 DEG C of forced air drying 1h obtain off-white powder salt
Sour Olprinone.
Preferably, after wherein instilling methallyl chloride tetrahydrofuran solution in step (1), reaction time 2h；
Preferably, wherein step (2) reacts -10 DEG C of temperature control~0 DEG C；
Preferably, wherein step (3) reaction time be 1h, 80~85 DEG C of temperature control；
Preferably, wherein in step (4) reaction, stirring is warming up to reflux, 1~1.5h of insulation reaction；
Preferably, wherein step (5) salt-forming reaction, 70-80 DEG C of temperature control；
Preferably, wherein step (6) purification stirring is warming up to 80-90 DEG C.
The main distinction of the invention for (document 1) is that third class is not used in 1. reaction process compared with the existing technology
Hazardous chemical acetylacetone,2,4-pentanedione potassium；2. using mild reaction condition instead.It the advantage is that the time 1. optimized in reaction condition
And temperature, reaction time is reduced, is reduced costs；2. purified water refining crude replaces preparing column, production technology is greatly simplified.
As a preferred embodiment of the invention, preparation step is as follows:
(1) into there-necked flask, 6- bromo imidazo [1,2-a] pyridine, tetrahydrofuran, stirring and dissolving is added.At room temperature, it drips
Enter ethylmagnesium bromide tetrahydrofuran solution, control temperature is no more than 30 DEG C.Drop finishes, and is warming up to reflux (65-70 DEG C).Reaction
1.5h is down to room temperature, instills the solution of methallyl chloride and tetrahydrofuran configuration, and temperature control is no more than 40 DEG C.Drop finishes, and is heated to
It flows back (65-70 DEG C), reacts 2h, be down to room temperature.It controls temperature and is no more than 30 DEG C, instill saturated aqueous ammonium chloride.Drop finishes, and takes out
Filter, filtrate rotate tetrahydrofuran, and surplus solution is extracted with ethyl acetate, and merge organic layer；Filter cake with ethyl acetate at room temperature
It is beaten 1h, filters, obtains filtrate.Merging the organic phase obtained twice, purifying washing, organic phase is dry with anhydrous sodium sulfate, it filters,
Solvent is rotated, brown oil intermediate compound I is obtained；
(2) into another there-necked flask, intermediate I, methanol, purified water, concentrated hydrochloric acid, stirring cooling, temperature control -10 are sequentially added
DEG C~0 DEG C, it is slowly introducing O3/O2.TLC monitoring reaction, the spot disappearance of intermediate I, which is considered as reaction, terminates (solvent=dichloromethane
Alkane: methanol=20:1), temperature control is no more than 30 DEG C, saturated aqueous sodium sulfite is instilled, until starch potassium iodide paper is non-discolouring；
30% sodium hydrate aqueous solution is instilled again to pH=8~9, methylene chloride extracts reaction solution, merges organic layer, water washing is purified,
Organic phase is dry with anhydrous sodium sulfate, filters, solvent is evaporated off, obtains brown oil intermediate II；
(3) into another there-necked flask, intermediate II, isopropanol, n,N-Dimethylformamide dimethyl acetal, stirring liter is added
Temperature.80~85 DEG C of temperature control, react 1h.TLC monitoring reaction, the spot disappearance of intermediate II, which is considered as reaction, terminates (solvent=bis-
Chloromethanes: methanol=15:1).System is down to room temperature, and solvent is evaporated off, and ethyl acetate is added in residue, and room temperature is beaten 2h, takes out
Filter, 45 DEG C of forced air drying 1h obtain brown solid intermediate III；
(4) into another there-necked flask, intermediate III, dehydrated alcohol, cyanoacetamide, sodium methoxide, stirring liter are sequentially added
Temperature extremely flows back, 1~1.5h of insulation reaction.TLC monitoring reaction, intermediate III spot disappearance be considered as reaction terminate (solvent=
Methylene chloride: methanol=10:1), it is down to room temperature, purified water is added, is slowly added to glacial acetic acid, adjusts pH=7-8, solid is precipitated,
1h is stirred at room temperature, filters, a small amount of ethanol washing, 45 DEG C of forced air drying 1h of filter cake obtain yellow solid, are intermediate IV；
(5) into another there-necked flask, intermediate IV, methanol is added, purified water stirs heating, 70-80 DEG C of temperature control, instills
Concentrated hydrochloric acid, solid all dissolve, and keep the temperature 10min, are down to room temperature, and solid is precipitated, and filter, and wash filter cake on a small quantity, and 45 DEG C of air blast are dry
Dry 1h, obtains light yellow solid, is Olprinone HCl crude product；
(6) into another there-necked flask, Olprinone HCl crude product, purified water is added, stirring is warming up to 80~90 DEG C, entirely
It is molten, 10min is kept the temperature, room temperature is down to.It filters, a small amount of to purify water washing filter cake, 40 DEG C of forced air drying 1h obtain off-white powder salt
Sour Olprinone.
The preparation method of Olprinone HCl compound of the present invention, reaction condition is mild, and Olprinone HCl obtained contains
For amount 99.5% or more, impurity content is low, has many advantages, such as that impurity is low, purity is good, high income.The beneficial effect that the present invention obtains
Fruit also resides in: starting material is 6- bromo imidazo [1,2-a] pyridine, and raw material sources are easy to get extensively；The reaction time is optimized, is contracted
It short reaction time, reduces costs；It is safe and non-toxic using purified water refining crude, simplify production technology.Generally, originally
The synthesis technology reaction condition of invention is mild, favorable reproducibility, is suitble to industrialized production.
Detailed description of the invention
Fig. 1 Olprinone HCl1H-NMR
Fig. 2 Olprinone HCl13C-NMR
Specific embodiment
It is further explained and described the content of present invention by the following examples.But provided embodiment is not understood that
To be construed as limiting to the scope of the present invention.Various raw materials of the present invention, reagent etc. are commercially available.
The preparation of 1 Olprinone HCl of embodiment
(1) preparation of intermediate I
Into 1000mL there-necked flask, 6- bromo imidazo [1,2-a] pyridine (SM1) 50.00g, tetrahydrofuran is added
200mL, stirring and dissolving.At room temperature, 2M ethylmagnesium bromide tetrahydrofuran solution is instilled, control temperature is no more than 30 DEG C.Drop finishes, and rises
Temperature extremely reflux (65-70 DEG C).1.5h is reacted, room temperature is down to, instills methallyl chloride (SM2) 99.95g and tetrahydrofuran
The solution of 200mL configuration, temperature control are no more than 40 DEG C.Drop finishes, and is heated to reflux (65-70 DEG C), reacts 2h, is down to room temperature.Control
Temperature is no more than 30 DEG C, instills saturated aqueous ammonium chloride 335mL.Drop finishes, and filters, and filtrate rotates tetrahydrofuran, remaining molten
Liquid is extracted with ethyl acetate (200mL × 3), merges organic layer；Filter cake is beaten 1h with ethyl acetate 400mL at room temperature, filters, obtains
Filtrate.Merge the organic phase obtained twice, purifying washing (200mL × 3), organic phase is dry with anhydrous sodium sulfate, filters, revolving
Fall solvent, obtains 42.56g brown oil intermediate compound I, crude product yield 97.4%.
(2) preparation of intermediate II
Into 500mL there-necked flask, intermediate I 40.00g, methanol 91mL, purified water 91mL, concentrated hydrochloric acid 91mL are sequentially added,
Stirring cooling.- 10 DEG C of temperature control, it is slowly introducing O3/O2.TLC monitoring reaction, the spot disappearance of intermediate I, which is considered as reaction, terminates (exhibition
Open agent=methylene chloride: methanol=20:1).Temperature control is no more than 30 DEG C, instills saturated aqueous sodium sulfite about 120mL, until forming sediment
Powder potassium iodide starch paper is non-discolouring；30% sodium hydrate aqueous solution is instilled again to pH=8~9.Methylene chloride extracts reaction solution
(200mL × 3) merge organic layer, purify water washing (200mL × 3), and organic phase is dry with anhydrous sodium sulfate, filter, are evaporated off molten
Agent, obtains 35.98g brown oil intermediate II, and crude product yield is 88.9%.
(3) preparation of intermediate III
Into 500mL there-necked flask, intermediate II 29.31g, isopropanol 205mL, n,N-Dimethylformamide contracting diformazan is added
Alcohol (SM3) 10.50g, stirring heating.80~85 DEG C of temperature control, react 1h.The spot disappearance of TLC monitoring reaction, intermediate II is considered as
Reaction terminates (solvent=methylene chloride: methanol=15:1).System is down to room temperature, and solvent is evaporated off, and 150mL is added in residue
Ethyl acetate, room temperature are beaten 2h, filter, 45 DEG C of forced air drying 1h, and obtaining intermediate III is brown solid 24.11g, yield
62.5%.
(4) preparation of intermediate IV
Into 500mL there-necked flask, III 12.78g of intermediate, dehydrated alcohol 166mL, cyanoacetamide (SM4) are sequentially added
6.98g, sodium methoxide 6.02g, stirring are warming up to reflux, insulation reaction 1h.TLC monitoring reaction, the spot of intermediate III, which disappears, to be regarded
Terminate (solvent=methylene chloride: methanol=10:1) for reaction.It is down to room temperature, purified water 64mL is added, is slowly added to about 7mL
Glacial acetic acid adjusts pH=7-8, and solid is precipitated, 1h is stirred at room temperature, and filters, a small amount of ethanol washing, 45 DEG C of forced air drying 1h of filter cake,
Yellow solid 12.26g is obtained, is intermediate IV, yield 87.9%.
(5) Olprinone HCl at salt, purification
Into 250mL there-necked flask, IV 9.82g of intermediate, methanol 39mL, purified water 118mL, stirring heating is added.Temperature control
70-80 DEG C, concentrated hydrochloric acid 6.5mL is instilled, solid all dissolves, and keeps the temperature 10min, is down to room temperature, and solid is precipitated, and filters, Shao Liangshui
Filter wash cake, 45 DEG C of forced air drying 1h, obtains light yellow solid 11.32g, is Olprinone HCl crude product, yield 94.7%.
Into 250mL there-necked flask, Olprinone HCl crude product 10.00g, purified water 110mL is added, stirring is warming up to 85
DEG C, Quan Rong keeps the temperature 10min, is down to room temperature.It filters, a small amount of to purify water washing filter cake, 40 DEG C of forced air drying 1h obtain off-white color
Solid 8.46g.Yield 84.6%.
The preparation of 2 Olprinone HCl of embodiment
(1) preparation of intermediate I
Into 1000mL there-necked flask, 6- bromo imidazo [1,2-a] pyridine (SM1) 50.00g, tetrahydrofuran is added
200mL, stirring and dissolving.At room temperature, 2M ethylmagnesium bromide tetrahydrofuran solution is instilled, control temperature is no more than 30 DEG C.Drop finishes, and rises
Temperature extremely reflux (65-70 DEG C).1.5h is reacted, room temperature is down to, instills methallyl chloride (SM2) 99.95g and tetrahydrofuran
The solution of 200mL configuration, temperature control are no more than 40 DEG C.Drop finishes, and is heated to reflux (65-70 DEG C), reacts 1h, is down to room temperature.Control
Temperature is no more than 30 DEG C, instills saturated aqueous ammonium chloride 335mL.Drop finishes, and filters, and filtrate rotates tetrahydrofuran, remaining molten
Liquid is extracted with ethyl acetate (200mL × 3), merges organic layer；Filter cake is beaten 1h with ethyl acetate 400mL at room temperature, filters, obtains
Filtrate.Merge the organic phase obtained twice, purifying washing (200mL × 3), organic phase is dry with anhydrous sodium sulfate, filters, revolving
Fall solvent, obtains 37.27g brown oil intermediate compound I, crude product yield 85.3%.
(2) preparation of intermediate II
Into 500mL there-necked flask, intermediate I 35.00g, methanol 91mL, purified water 91mL, concentrated hydrochloric acid 91mL are sequentially added,
Stirring cooling.0 DEG C of temperature control, it is slowly introducing O3/O2.TLC monitoring reaction, the spot disappearance of intermediate I, which is considered as reaction, terminates (expansion
Agent=methylene chloride: methanol=20:1).Temperature control is no more than 30 DEG C, saturated aqueous sodium sulfite about 120mL is instilled, until starch
Potassium iodide starch paper is non-discolouring；30% sodium hydrate aqueous solution is instilled again to pH=8~9.Methylene chloride extracts reaction solution (200mL
× 3), merge organic layer, purify water washing (200mL × 3), organic phase is dry with anhydrous sodium sulfate, filters, solvent is evaporated off, obtains
To 30.24g brown oil intermediate II, crude product yield is 85.4%.
(3) preparation of intermediate III
Into 500mL there-necked flask, intermediate II 28.00g, isopropanol 205mL, n,N-Dimethylformamide contracting diformazan is added
Alcohol (SM3) 10.50g, stirring heating.80~85 DEG C of temperature control, react 0.5h.TLC monitoring reaction, the spot of intermediate II, which disappears, to be regarded
Terminate (solvent=methylene chloride: methanol=15:1) for reaction.System is down to room temperature, and solvent is evaporated off, and residue is added
150mL ethyl acetate, room temperature are beaten 2h, filter, 45 DEG C of forced air drying 1h, and obtaining intermediate III is brown solid 20.08g, receive
Rate 54.5%.
(4) preparation of intermediate IV
Into 500mL there-necked flask, III 12.78g of intermediate, dehydrated alcohol 166mL, cyanoacetamide (SM4) are sequentially added
6.98g, sodium methoxide 6.02g, stirring are warming up to reflux, insulation reaction 0.5h.TLC monitoring reaction, the spot of intermediate III disappear
Being considered as reaction terminates (solvent=methylene chloride: methanol=10:1).It is down to room temperature, purified water 64mL is added, is slowly added to about
7mL glacial acetic acid adjusts pH=7-8, and solid is precipitated, 1h is stirred at room temperature, and filters, a small amount of ethanol washing, 45 DEG C of forced air dryings of filter cake
1h obtains yellow solid 10.06g, is intermediate IV, yield 72.1%.
(5) Olprinone HCl at salt, purification
Into 250mL there-necked flask, IV 9.82g of intermediate, methanol 39mL, purified water 118mL, stirring heating is added.Temperature control
70-80 DEG C, concentrated hydrochloric acid 6.5mL is instilled, solid all dissolves, and keeps the temperature 10min, is down to room temperature, and solid is precipitated, and filters, Shao Liangshui
Filter wash cake, 45 DEG C of forced air drying 1h, obtains light yellow solid 10.55g, is Olprinone HCl crude product, yield 93.2%.
Into 250mL there-necked flask, Olprinone HCl crude product 10.00g, purified water 110mL is added, stirring is warming up to 85
DEG C, Quan Rong keeps the temperature 10min, is down to room temperature.It filters, a small amount of to purify water washing filter cake, 40 DEG C of forced air drying 1h obtain off-white color
Solid 8.33g.Yield 83.3%.
The preparation of 3 Olprinone HCl of embodiment
(1) preparation of intermediate I
Into 1000mL there-necked flask, 6- bromo imidazo [1,2-a] pyridine (SM1) 50.00g, tetrahydrofuran is added
200mL, stirring and dissolving.At room temperature, 2M ethylmagnesium bromide tetrahydrofuran solution is instilled, control temperature is no more than 30 DEG C.Drop finishes, and rises
Temperature extremely reflux (65-70 DEG C).1.5h is reacted, room temperature is down to, instills methallyl chloride (SM2) 99.95g and tetrahydrofuran
The solution of 200mL configuration, temperature control are no more than 40 DEG C.Drop finishes, and is heated to reflux (65-70 DEG C), reacts 3h, is down to room temperature.Control
Temperature is no more than 30 DEG C, instills saturated aqueous ammonium chloride 335mL.Drop finishes, and filters, and filtrate rotates tetrahydrofuran, remaining molten
Liquid is extracted with ethyl acetate (200mL × 3), merges organic layer；Filter cake is beaten 1h with ethyl acetate 400mL at room temperature, filters, obtains
Filtrate.Merge the organic phase obtained twice, purifying washing (200mL × 3), organic phase is dry with anhydrous sodium sulfate, filters, revolving
Fall solvent, obtains 39.15g brown oil intermediate compound I, crude product yield 89.6%.
(2) preparation of intermediate II
Into 500mL there-necked flask, intermediate I 35.00g, methanol 91mL, purified water 91mL, concentrated hydrochloric acid 91mL are sequentially added,
Stirring cooling.- 20 DEG C of temperature control, it is slowly introducing O3/O2.TLC monitoring reaction, the spot disappearance of intermediate I, which is considered as reaction, terminates (exhibition
Open agent=methylene chloride: methanol=20:1).Temperature control is no more than 30 DEG C, instills saturated aqueous sodium sulfite about 120mL, until forming sediment
Powder potassium iodide starch paper is non-discolouring；30% sodium hydrate aqueous solution is instilled again to pH=8~9.Methylene chloride extracts reaction solution
(200mL × 3) merge organic layer, purify water washing (200mL × 3), and organic phase is dry with anhydrous sodium sulfate, filter, are evaporated off molten
Agent, obtains 29.43g brown oil intermediate II, and crude product yield is 83.1%.
(3) preparation of intermediate III
Into 500mL there-necked flask, intermediate II 28.00g, isopropanol 205mL, n,N-Dimethylformamide contracting diformazan is added
Alcohol (SM3) 10.50g, stirring heating.80~85 DEG C of temperature control, react 2h.The spot disappearance of TLC monitoring reaction, intermediate II is considered as
Reaction terminates (solvent=methylene chloride: methanol=15:1).System is down to room temperature, and solvent is evaporated off, and 150mL is added in residue
Ethyl acetate, room temperature are beaten 2h, filter, 45 DEG C of forced air drying 1h, and obtaining intermediate III is brown solid 21.04g, yield
57.1%.
(4) preparation of intermediate IV
Into 500mL there-necked flask, III 12.78g of intermediate, dehydrated alcohol 166mL, cyanoacetamide (SM4) are sequentially added
6.98g, sodium methoxide 6.02g, stirring are warming up to reflux, insulation reaction 2h.TLC monitoring reaction, the spot of intermediate III, which disappears, to be regarded
Terminate (solvent=methylene chloride: methanol=10:1) for reaction.It is down to room temperature, purified water 64mL is added, is slowly added to about 7mL
Glacial acetic acid adjusts pH=7-8, and solid is precipitated, 1h is stirred at room temperature, and filters, a small amount of ethanol washing, 45 DEG C of forced air drying 1h of filter cake,
Yellow solid 10.80g is obtained, is intermediate IV, yield 77.4%.
(5) Olprinone HCl at salt, purification
Into 250mL there-necked flask, IV 9.82g of intermediate, methanol 39mL, purified water 118mL, stirring heating is added.Temperature control
70-80 DEG C, concentrated hydrochloric acid 6.5mL is instilled, solid all dissolves, and keeps the temperature 10min, is down to room temperature, and solid is precipitated, and filters, Shao Liangshui
Filter wash cake, 45 DEG C of forced air drying 1h, obtains light yellow solid 10.64g, is Olprinone HCl crude product, yield 94.0%.
Into 250mL there-necked flask, Olprinone HCl crude product 10.00g, purified water 110mL is added, stirring is warming up to 85
DEG C, Quan Rong keeps the temperature 10min, is down to room temperature.It filters, a small amount of to purify water washing filter cake, 40 DEG C of forced air drying 1h obtain off-white color
Solid 8.27g.Yield 82.7%.
The Olprinone HCl compound structure that the present invention obtains confirms data:
1H-NMR: δ=1.71 (3H), 7.07 (1H), 7.46 (1H), 7.48 (1H), 7.48 (1H), 7.70 (1H), 8.00
(1H), 8.13 (1H)；
13C-NMR: δ=18.0,106.7,116.2,117.2,122.3,122.3,123.6,128.7,131.6,132.7,
136.2,148.8,156.9,162.9.
Claims (7)
1. a kind of preparation method of Olprinone HCl compound, which is characterized in that synthetic route are as follows:
Specific step is as follows:
(1) into there-necked flask, 6- bromo imidazo [1,2-a] pyridine, tetrahydrofuran is added, stirring and dissolving instills second at room temperature
Base magnesium bromide tetrahydrofuran solution, control temperature are no more than 30 DEG C, and drop finishes, and is warming up to reflux (65-70 DEG C), react 1.5h, drop
To room temperature, the solution of methallyl chloride and tetrahydrofuran configuration is instilled, temperature control is no more than 40 DEG C, and drop finishes, and is heated to flowing back
(65-70 DEG C) reacts 1-3h, is down to room temperature, and control temperature is no more than 30 DEG C, instills saturated aqueous ammonium chloride, and drop finishes, and takes out
Filter, filtrate rotate tetrahydrofuran, and surplus solution is extracted with ethyl acetate, and merge organic layer；Filter cake with ethyl acetate at room temperature
It is beaten 1h, is filtered, filtrate is obtained, merges the organic phase obtained twice, purifying washing, organic phase is dry with anhydrous sodium sulfate, it filters,
Solvent is rotated, brown oil intermediate compound I is obtained；
(2) into another there-necked flask, intermediate I is sequentially added, methanol, purified water, concentrated hydrochloric acid, stirring cooling, -20 DEG C of temperature control~
0 DEG C, it is slowly introducing O3/O2, TLC monitoring reaction, intermediate I spot disappearance be considered as reaction terminate (solvent=methylene chloride:
Methanol=20:1)；Temperature control is no more than 30 DEG C, saturated aqueous sodium sulfite is instilled, until starch potassium iodide paper is non-discolouring；It drips again
Enter 30% sodium hydrate aqueous solution to pH=8~9, methylene chloride extracts reaction solution, merges organic layer, purifies water washing, organic
It is mutually dry with anhydrous sodium sulfate, it filters, solvent is evaporated off, obtains brown oil intermediate II；
(3) into another there-necked flask, intermediate II, isopropanol is added, n,N-Dimethylformamide dimethyl acetal stirs heating,
70~90 DEG C of temperature control, 0.5-2h is reacted, TLC monitoring reaction, the spot disappearance of intermediate II, which is considered as reaction, terminates (solvent=bis-
Chloromethanes: methanol=15:1), system is down to room temperature, and solvent is evaporated off, and ethyl acetate is added in residue, and room temperature is beaten 2h, takes out
Filter, 45 DEG C of forced air drying 1h obtain intermediate III；
(4) into another there-necked flask, intermediate III is sequentially added, dehydrated alcohol, cyanoacetamide, sodium methoxide, stirring is warming up to
Reflux, insulation reaction 0.5~2h, TLC monitoring reaction, the spot disappearance of intermediate III, which is considered as reaction, terminates (solvent=dichloro
Methane: methanol=10:1), it is down to room temperature, purified water is added, is slowly added to glacial acetic acid, adjusts pH=7-8, solid, room temperature is precipitated
1h is stirred, is filtered, a small amount of ethanol washing, 45 DEG C of forced air drying 1h of filter cake obtain yellow solid, are intermediate IV；
(5) into another there-necked flask, intermediate IV, methanol is added, purified water stirs heating, 65-85 DEG C of temperature control, instills dense salt
Acid, solid all dissolve, and keep the temperature 10min, are down to room temperature, and solid is precipitated, and filter, and wash filter cake on a small quantity, 45 DEG C of forced air drying 1h,
Light yellow solid is obtained, is Olprinone HCl crude product；
(6) into another there-necked flask, Olprinone HCl crude product, purified water is added, stirring is warming up to 75~95 DEG C, Quan Rong, protects
Warm 10min is down to room temperature, filters, a small amount of to purify water washing filter cake, and it is difficult to understand to obtain off-white powder hydrochloric acid by 40 DEG C of forced air drying 1h
Pu Linong.
2. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that in step (1), drop
After entering methallyl chloride tetrahydrofuran solution, 1-3h is reacted；Preferably 2h.
3. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that step (2) oxidation is anti-
It answers, needs -20 DEG C of temperature control~0 DEG C；Preferably -10 DEG C~0 DEG C.
4. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that when step (3) is reacted
Between be 0.5-2h, 70~90 DEG C of temperature control；Preferably reaction time 1h, 80~85 DEG C of temperature control.
5. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that in step (4), stir
It mixes and is warming up to reflux, 0.5~2h of insulation reaction；Preferably 1~1.5h.
6. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that step (5) is anti-at salt
It answers, needs 65-85 DEG C of temperature control；Preferably 70-80 DEG C.
7. the preparation method of Olprinone HCl compound according to claim 1, it is characterised in that step (6) purification,
It need to stir and be warming up to 75~95 DEG C, Quan Rong, keep the temperature 10min；Preferably 80-90 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811293175.0A CN109575017A (en) | 2018-11-01 | 2018-11-01 | A kind of preparation method of Olprinone HCl compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811293175.0A CN109575017A (en) | 2018-11-01 | 2018-11-01 | A kind of preparation method of Olprinone HCl compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109575017A true CN109575017A (en) | 2019-04-05 |
Family
ID=65921059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811293175.0A Pending CN109575017A (en) | 2018-11-01 | 2018-11-01 | A kind of preparation method of Olprinone HCl compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109575017A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499631A (en) * | 2020-06-02 | 2020-08-07 | 山东美泰医药有限公司 | Preparation method of olprinone hydrochloride key intermediate |
| CN112194657A (en) * | 2020-10-16 | 2021-01-08 | 济川(上海)医学科技有限公司 | Heterocyclic compound, preparation method and application thereof |
| CN114773341A (en) * | 2022-05-10 | 2022-07-22 | 河北爱尔海泰制药有限公司 | Preparation method of olprinone hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86102812A (en) * | 1985-03-26 | 1986-11-26 | 卫材株式会社 | Preparation of 5- (6-imidazo [1, 2-a ] pyridinyl) pyridine derivatives |
| GB2374074A (en) * | 2001-03-01 | 2002-10-09 | Pfizer Ltd | Thiazolyl-benzyl-piperazines for treating gastrointestinal disorders |
| CN103087059A (en) * | 2011-10-27 | 2013-05-08 | 河北智同医药控股集团有限公司 | Preparation method for high-purity olprinone hydrochloride |
-
2018
- 2018-11-01 CN CN201811293175.0A patent/CN109575017A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86102812A (en) * | 1985-03-26 | 1986-11-26 | 卫材株式会社 | Preparation of 5- (6-imidazo [1, 2-a ] pyridinyl) pyridine derivatives |
| GB2374074A (en) * | 2001-03-01 | 2002-10-09 | Pfizer Ltd | Thiazolyl-benzyl-piperazines for treating gastrointestinal disorders |
| CN103087059A (en) * | 2011-10-27 | 2013-05-08 | 河北智同医药控股集团有限公司 | Preparation method for high-purity olprinone hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 叶从发: "奥普力农合成工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499631A (en) * | 2020-06-02 | 2020-08-07 | 山东美泰医药有限公司 | Preparation method of olprinone hydrochloride key intermediate |
| CN111499631B (en) * | 2020-06-02 | 2021-07-30 | 济南康桥医药科技有限公司 | Preparation method of olprinone hydrochloride key intermediate 1-imidazo [1,2-a ] pyridin-6-yl-2-acetone |
| CN112194657A (en) * | 2020-10-16 | 2021-01-08 | 济川(上海)医学科技有限公司 | Heterocyclic compound, preparation method and application thereof |
| CN114773341A (en) * | 2022-05-10 | 2022-07-22 | 河北爱尔海泰制药有限公司 | Preparation method of olprinone hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109575017A (en) | A kind of preparation method of Olprinone HCl compound | |
| CN108299294A (en) | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity | |
| WO2020000832A1 (en) | Method for synthesizing potassium oxonate | |
| CN102746211B (en) | Method for preparing substituted indole-3-methanal compound | |
| CN104086545A (en) | Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride | |
| CN103980280A (en) | Method for synthesizing quinazolino indazole derivatives under acidic condition | |
| CN101973932B (en) | Preparation method of bisacodyl | |
| CN105440014B (en) | A kind of preparation method of lenalidomide | |
| CN106188040A (en) | A kind of Fevipiprant and the preparation method of intermediate thereof | |
| CN107118215A (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediates | |
| CN106946880A (en) | A kind of method for preparing Rui Boxini intermediates | |
| CN111825678A (en) | Preparation method of carbamatinib | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN105272921A (en) | Method for preparing Ceritinib and intermediate compound of Ceritinib | |
| CN103664940A (en) | Preparation method of moxifloxacin impurity | |
| CN106478531A (en) | 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -4H-1,2,4- triazole -3- base sulfenyls) acid intermediates | |
| CN106588888A (en) | High-purity L-sunitinib malate preparation method | |
| CN105130886A (en) | Preparation method for 4-fluoro-3-methyl-methyl pyridine-2-carboxylate | |
| CN100376546C (en) | Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use | |
| CN105777743A (en) | Preparation method and application of pyrazolo[3, 4-b]pyridine compound intermediate | |
| WO2013149364A1 (en) | Method for synthesizing 1-hydroxymethyl cyclopropyl acetonitrile | |
| US6861525B2 (en) | Process for the preparation imidazo[1,2-A]pyridine-3-acetamides | |
| CN104211705B (en) | A kind of preparation method of sldenafil | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof | |
| CN106083839A (en) | A kind of preparation method of Dasatinib compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhang Zhiyong Inventor after: Zhao Yongmei Inventor before: Zhang Zhiyong |
|
| CB03 | Change of inventor or designer information | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190405 |
|
| RJ01 | Rejection of invention patent application after publication |