CN106349246B - The preparation method of Olprinone and 9- azaindole -5- boric acid - Google Patents
The preparation method of Olprinone and 9- azaindole -5- boric acid Download PDFInfo
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- CN106349246B CN106349246B CN201610742071.8A CN201610742071A CN106349246B CN 106349246 B CN106349246 B CN 106349246B CN 201610742071 A CN201610742071 A CN 201610742071A CN 106349246 B CN106349246 B CN 106349246B
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- boric acid
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- olprinone
- azaindole
- bromo
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- 229950005421 olprinone Drugs 0.000 title claims abstract description 42
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 239000004327 boric acid Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000009413 insulation Methods 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- PJCCSZUMZMCWSX-UHFFFAOYSA-N 4,4-Dimethoxy-2-butanone Chemical compound COC(OC)CC(C)=O PJCCSZUMZMCWSX-UHFFFAOYSA-N 0.000 description 2
- BFZDXWYVGHGCMK-UHFFFAOYSA-N 5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-1h-pyridine-3-carbonitrile;hydrate;hydrochloride Chemical compound O.Cl.N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C BFZDXWYVGHGCMK-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- CHXARDKIHSVFDK-UHFFFAOYSA-N hexylphosphane Chemical compound CCCCCCP CHXARDKIHSVFDK-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- -1 pinacol borates Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- VRDBIJCCXDEZJN-UHFFFAOYSA-N 2-piperidin-1-ylacetic acid Chemical class OC(=O)CN1CCCCC1 VRDBIJCCXDEZJN-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
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical class O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000007858 starting material Substances 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to the preparation methods of Olprinone and 9- azaindole -5- boric acid.The invention particularly relates to the methods for obtaining Olprinone by Suzuki couplings.The preparation method of Olprinone and 9- azaindole -5- boric acid of the present invention, initiative design the synthetic route of convergence type, and relative to the synthesis technology of existing three kinds of tandems, atom utilization is high, and whole reaction yield is better than existing synthetic route；The synthetic reaction condition of the present invention is mild, easy to operate, is advantageously implemented industrialization and generates.The Olprinone of acquisition can be further through obtaining Olprinone HCl at salt, and hydrochloric acid Ao Puli obtained has many advantages, such as that impurity is low, purity is high, high income, reaction condition are mild.
Description
Technical field
The invention belongs to chemical medicines, are related to a kind of preparation method of medicinal chemicals, and in particular to Olprinone
And the preparation method of 9- azaindole -5- boric acid.
Background technology
Olprinone HCl（Olprinone Hydrochloride）It is that Japan defends material（Eisai）Co., Ltd.'s exploitation
III inhibitor of phosphodiesterase (PDE), was succeeded in developing in 1984, started within 1986 clinical test, in April, 1996 is Japanese first
Secondary listing, dosage form are ampoule injection, specification 5ml:5mg, trade name Coretec note 5mg, for other drugs treatment effect
When fruit is bad, acute heart failure is treated.In December, 2004, Japan defend material and have listed Olprinone HCl glucose in Japan again
Injection, specification 150ml:Olprinone HCl 9mg and glucose 7.05g, trade name Coretec note SB9mg, the note
Penetrate liquid can avoid medical institutions issuable miss and foreign matter when small needle is prepared be mixed into, microbial contamination, suitable first aid
In do not have to prepare rapid medication.
Olprinone HCl is usually made by Olprinone at salt, and chemistry is entitled：1,2- dihydro -5- Mi Zuobings [1,2-α]
Pyridine -6- base -6- methyl -2- oxo -3- pyridine carbon cyanogen hydrochloride monohydrates, molecular formula are：C14H10N4O·HCl·H2O,
Molecular weight is：304.73 CAS registration numbers are：119615-63-3, structural formula are
Wen Xian [Chem.Pharm.Bull.,39(6),1556-1567(1991)]Report two Olprinone HCls
Synthetic route, specific as follows, route A：
First step reaction temperature is -60 DEG C in this route, and reaction condition is too harsh, yield 17.2%, second step reaction,
Reaction time is 30 hours and yield is only 11.9%, and yield is too low.
Route B:
Raw material acetylacetone,2,4-pentanedione potassium cost is higher in this route, is more toxic, and need matching while using, is unfavorable for amplification life
Production, the yield of first two steps is relatively low, and only 36%, reaction efficiency is too low.
The route of a synthetic hydrochloric acid Olprinone, route C are reported in CN86102812 and CN20108001811：
First step yield is relatively low in this route, only 57.4%, second step prepare Grignard Reagent very exothermic than relatively hazardous,
4th step ozone oxidation, ozone utilization rate is relatively low, and discharge ozone harm is larger, and third step and the 4th step obtain grease, pure
Spending relatively low causes the 5th step yield relatively low.
Invention content
The present invention is directed to disadvantages mentioned above existing in the prior art, and research and development are a kind of difficult to understand general via the preparation of Suzuki coupling reactions
The method of power agriculture, it is specifically anti-through being coupled by 9- azaindole -5- boric acid and bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5-
Olprinone should be prepared.
The present invention is further directed to one kind by 6- bromo Mi Zuobings [1,2a]Pyridine obtains 9- azepines Yin through coupling reaction
The method of diindyl -5- boric acid.
The concrete scheme of the present invention is as follows：
A kind of preparation method of Olprinone, it is characterised in that：By bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5- with
9- azaindole -5- boric acid is made by coupling reaction, and reaction equation is：
The preparation method of the Olprinone, reaction temperature are 80~100 DEG C；
The preparation method of the Olprinone, the reaction time be 14~for 24 hours.
The preparation method of the Olprinone, reaction dissolvent are Isosorbide-5-Nitrae-dioxane or toluene；
The preparation method of the Olprinone, needs catalyst to exist, and catalyst is bi triphenyl phosphorus palladium chloride；
The preparation method of the Olprinone, bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of raw material 5-, 9- azepines Yin
Diindyl -5- boric acid and the molar ratio of bi triphenyl phosphorus palladium chloride are 1:（1~1.2）:0.1.
The preparation method of the Olprinone, the refined solvent used is in t-butyl methyl ether, petroleum ether, normal heptane
One or more mixing.
The preparation method of the Olprinone, specific method are：By bromo- -2 (the 1H)-pyridines of 3- cyano -6- methyl of 5-
The solution of potassium carbonate of ketone, 9- azaindole -5- boric acid, bi triphenyl phosphorus palladium chloride and 1.0mol/L adds under protection of argon gas
Enter into Isosorbide-5-Nitrae-dioxane, 80~90 DEG C of insulation reactions 14~for 24 hours, it is down to room temperature, reaction solution is poured into purified water,
After ethyl acetate extraction, the drying of saturated common salt water washing, anhydrous magnesium sulfate, light gray solid is concentrated under reduced pressure to obtain, petroleum ether is beaten
Slurry, obtains Olprinone.
9- azaindole -5- boric acid described in above-mentioned coupling reaction can directly be bought also to be made by the method for the invention
It is standby.
A kind of preparation method of 9- azaindoles -5- boric acid, it is characterised in that：Pass through 6- bromo Mi Zuobings [1,2a]Pyridine
It is made with the coupling of duplex pinacol borate, reaction equation is：
The preparation method of above-mentioned 9- azaindoles -5- boric acid, reaction temperature are 100~120 DEG C.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, reaction time are 24~36h.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, catalyst are tricyclohexyl phosphine and three (dibenzalacetones)
Two palladiums.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, reaction dissolvent are Isosorbide-5-Nitrae-dioxane or toluene.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, wherein 6- bromos Mi Zuobing [1,2a]Pyridine, duplex pinacol
The molar ratio of borate, tricyclohexyl phosphine and tris(dibenzylideneacetone) dipalladium is 1: 1.5: 0.1: 0.05.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, extractant is ethyl acetate.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, refining solvent are t-butyl methyl ether, petroleum ether, normal heptane
In one or more mixing.
The preparation method of above-mentioned 9- azaindoles -5- boric acid, specific method are：By 6- bromo Mi Zuobings [1,2a]Pyridine,
Duplex pinacol borate, tricyclohexyl phosphine, tris(dibenzylideneacetone) dipalladium, sodium acetate are added in Isosorbide-5-Nitrae-dioxane,
100~120 DEG C are heated to, 24~36h of insulation reaction is down to room temperature, is added in purified water, is extracted with ethyl acetate, anhydrous
Magnesium sulfate is dried, and red brown solid is concentrated under reduced pressure to obtain, and solid is added in solvent and is refined, stirring to pulp 2h filters yellowish
Color solid, i.e. 9- azaindoles -5- boric acid.
The preparation method of Olprinone and 9- azaindole -5- boric acid of the present invention, initiative design the synthesis of convergence type
Route, relative to the synthesis technology of existing three kinds of tandems, atom utilization is high, and whole reaction yield is better than existing conjunction
At route；The synthetic reaction condition of the present invention is mild, easy to operate, avoids -60 DEG C of ultralow temperature and road in prior art route A
The special consersion unit etc. such as ozone in the harshness reaction condition such as anhydrous and oxygen-free in line C required by grignard reaction and route C
Disadvantage is advantageously implemented industrialization and generates.The Olprinone of acquisition can be obtained further through obtaining Olprinone HCl at salt
Hydrochloric acid Ao Puli has many advantages, such as that impurity is low, purity is high, high income, reaction condition are mild.
Specific implementation method
With reference to embodiment, the present invention is further illustrated, but this shall not be construed as any limit to the present invention
System.Various raw materials of the present invention, reagent etc. are purchased in market.
Following is to do starting material with acetyl acetaldehyde dimethylacetal and cyanoacetamide, passes through cyclization, bromo, Suzuki idols
Connection, salt-forming reaction step obtain the embodiment of Olprinone HCl, and wherein 9- azaindoles -5- boric acid and Olprinone are using this
Invention preparation method, specific synthesis route are as follows：
Wherein：Compound vii indicates 6- bromo Mi Zuobings [1,2a]Pyridine；
Compound vi indicates 9- azaindole -5- boric acid；
Compound v indicates acetyl acetaldehyde dimethylacetal；
Compound iv indicates -2 (1H)-pyridone of 3- cyano -6- methyl；
Compound iii indicates bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5-；
Compound ii indicates Olprinone；
Compound i indicates Olprinone HCl.
Embodiment 1：Cyclization prepares -2 (1H)-pyridone of 3- cyano -6- methyl
By 40.0g compounds v（0.303mol）, 28.0g cyanoacetamides（0.333mol）, 17.5g Piperidineacetic acid salt adds
Enter in 160ml purified waters, solution clarification, heating stirring maintains the reflux for stirring for 24 hours, be cooled to 10 DEG C of stirring and crystallizings, mistake to flowing back
Filter light red solid drying is weighed to obtain 35.5g, yield 87.4%.
Embodiment 2：Bromo-reaction prepares bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5-
By 30.0g compounds iv（0.224mol）,83.6gNBS（0.470mol）It is added to 600ml dichloroethane solutions
In, it is heated to flowing back, maintains the reflux for being stirred to react 18h, be cooled to room temperature, filter to obtain off-white powder, be added to 450ml purifying
Stirring to pulp 2h in water filters to obtain off-white powder, i.e. bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5-（Compound iii）,
The dry 36.8g that weighs to obtain, yield 77.5%.
Embodiment 3：Coupling reaction prepares 9- azaindole -5- boric acid
By 20.0g compounds vii（0.102mol）, 38.7g duplex pinacol borates（0.152mol）, 2.85g tricyclics
Hexyl phosphine（0.010mol）, 4.65g tris(dibenzylideneacetone) dipalladiums（0.005mol）, 25.0 sodium acetate be added to 200ml
In Isosorbide-5-Nitrae-dioxane, 115~120 DEG C are heated to, insulation reaction for 24 hours, is cooled to room temperature, and purified water 200ml is added, and uses
200ml ethyl acetate is extracted twice, anhydrous magnesium sulfate drying, and red brown solid is concentrated under reduced pressure to obtain, and the tertiary fourths of 30ml are added in solid
In ylmethyl ether, stirring to pulp 2h filters to obtain faint yellow solid, i.e. 9- azaindoles -5- boric acid（Compound vi）, dry to weigh
Obtain 11.8g, yield 72.0%.
Embodiment 4：Coupling reaction prepares 9- azaindole -5- boric acid
By 20.0g compounds vii（0.102mol）, 38.7g duplex pinacol borates（0.152mol）, 2.85g tricyclics
Hexyl phosphine（0.010mol）, 4.65g tris(dibenzylideneacetone) dipalladiums（0.005mol）, 25.0 sodium acetate be added to
In 200ml1,4- dioxane, 100~105 DEG C, insulation reaction 36h are heated to, is cooled to room temperature, purified water 200ml is added,
It is extracted twice with 200ml ethyl acetate, red brown solid is concentrated under reduced pressure to obtain in anhydrous magnesium sulfate drying, and uncle 30ml is added in solid
In butyl methyl ether, stirring to pulp 2h filters to obtain faint yellow solid, i.e. 9- azaindoles -5- boric acid（Compound vi）, dry to claim
Heavy 11.1g, yield 67.7%.
Embodiment 5：Suzuki reactions prepare Olprinone
By 13.3g compounds iii（0.062mol）, 11.0g compounds vi（0.068mol）, 4.5g bi triphenyl phosphorus dichloros
Change palladium（0.006mol）, 1.0mol/L solution of potassium carbonate 64ml be added to 133ml1 under protection of argon gas, in 4- dioxane,
80~90 DEG C are heated to, insulation reaction 14h is down to room temperature, and reaction solution is poured into 200ml purified waters, 70ml ethyl acetate
Extraction 3 times, 100ml saturated common salts water washing 2 times, anhydrous magnesium sulfate drying are concentrated under reduced pressure dry that light gray solid, petroleum ether are beaten
Slurry 1 hour, obtains off-white powder, i.e. Olprinone（Compound ii）, the dry 10.6g that weighs to obtain, yield 67.9%.
Embodiment 6：Suzuki reactions prepare Olprinone
By 13.3g compounds iii（0.062mol）, 12.1g compounds vi（0.075mol）, 4.5g bi triphenyl phosphorus dichloros
Change palladium（0.006mol）, 1.0mol/L solution of potassium carbonate 64ml be added under protection of argon gas in 133ml toluene, be heated to
90~100 DEG C, insulation reaction for 24 hours, is down to room temperature, and reaction solution is poured into 200ml purified waters, 70ml ethyl acetate extraction 3
Secondary, 100ml saturated common salts water washing 2 times, anhydrous magnesium sulfate drying is concentrated under reduced pressure dry that light gray solid, petroleum ether mashing 1 are small
When, obtain off-white powder, i.e. Olprinone（Compound ii）, the dry 11.2g that weighs to obtain, yield 71.7%.
Embodiment 7：Olprinone HCl is prepared at salt
By 11.0g compounds ii（0.044mol）It is added in 110mlDMF, is heated to 80 DEG C, then be added dropwise into reaction bulb
The mixed solution of 9ml concentrated hydrochloric acids and ethyl alcohol（Concentrated hydrochloric acid: ethyl alcohol=1: 1）, 1h is stirred to react for 80 DEG C after adding.Stop heating, it is cooling
Crystallization filters out crystal, and 165ml methanol-waters are added（2：1）In, it is heated to flowing back, activated carbon stirring decoloration, hot leaching is added
Mother liquor cooling stirring recrystallization, filters to obtain white solid, i.e. Olprinone HCl（Compound i）, the dry 8.4g that weighs to obtain, yield
It is 62.5%.
Claims (5)
1. a kind of preparation method of Olprinone, it is characterised in that：By bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5- and 9-
Azaindole -5- boric acid is made by coupling reaction, and reaction equation is：
Specific method is：By bromo- -2 (the 1H)-pyridones of 3- cyano -6- methyl of 5-, 9- azaindole -5- boric acid, bi triphenyl phosphorus
The solution of potassium carbonate of palladium chloride and 1.0mol/L is added in Isosorbide-5-Nitrae-dioxane or toluene, 80~90 under protection of argon gas
DEG C insulation reaction 14~for 24 hours, obtain Olprinone；
Wherein, the preparation method of the 9- azaindoles -5- boric acid is：By 6- bromo Mi Zuobings [1,2a]Where are pyridine, duplex frequency
Alcohol borate, tricyclohexyl phosphine, tris(dibenzylideneacetone) dipalladium, sodium acetate are added in Isosorbide-5-Nitrae-dioxane, are heated to 100
~120 DEG C, 24~36h of insulation reaction is down to room temperature, is added in purified water, is extracted with ethyl acetate, and anhydrous magnesium sulfate is dry
It is dry, red brown solid is concentrated under reduced pressure to obtain, solid is added in solvent and is refined, stirring to pulp 2h filters to obtain faint yellow solid, i.e.,
9- azaindole -5- boric acid, reaction equation are：
。
2. preparation method according to claim 1, it is characterised in that：The coupling reaction, the bromo- 3- cyano-of raw material 5-
6- methyl -2 (1H)-pyridone, 9- azaindole -5- boric acid and the molar ratio of bi triphenyl phosphorus palladium chloride are 1: 1~1.2:
0.1。
3. preparation method according to claim 1, which is characterized in that specific method is：By the bromo- 3- cyano -6- methyl-of 5-
The solution of potassium carbonate of 2 (1H)-pyridones, 9- azaindole -5- boric acid, bi triphenyl phosphorus palladium chloride and 1.0mol/L, in argon
It is added under gas shielded in Isosorbide-5-Nitrae-dioxane, 80~90 DEG C of insulation reactions 14~for 24 hours, it is down to room temperature, reaction solution is poured into
In purified water, after ethyl acetate extraction, the drying of saturated common salt water washing, anhydrous magnesium sulfate, light gray solid is concentrated under reduced pressure to obtain,
Petroleum ether is beaten, and obtains Olprinone.
4. preparation method according to claim 1, it is characterised in that：The preparation method of the 9- azaindoles -5- boric acid,
Raw material 6- bromo Mi Zuobings [1,2a]Pyridine, duplex pinacol borate, tricyclohexyl phosphine and tris(dibenzylideneacetone) dipalladium
Molar ratio be 1: 1.5: 0.1: 0.05.
5. preparation method according to claim 1, it is characterised in that：The preparation method of the 9- azaindoles -5- boric acid,
Refining solvent is one or more mixing in t-butyl methyl ether, petroleum ether, normal heptane.
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| CN102558171A (en) * | 2010-12-21 | 2012-07-11 | 北京德众万全药物技术开发有限公司 | Preparation method of intermediate of olprinone hydrochloride |
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