CN106831575B - A kind of preparation method of 1- aminoisoquinoline -6- methanol - Google Patents
A kind of preparation method of 1- aminoisoquinoline -6- methanol Download PDFInfo
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- CN106831575B CN106831575B CN201710075876.6A CN201710075876A CN106831575B CN 106831575 B CN106831575 B CN 106831575B CN 201710075876 A CN201710075876 A CN 201710075876A CN 106831575 B CN106831575 B CN 106831575B
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- Prior art keywords
- isoquinolin
- added
- ethyl acetate
- water
- methyl formate
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- ZGQORUBXVDCOFZ-UHFFFAOYSA-N (1-aminoisoquinolin-6-yl)methanol Chemical compound OCC1=CC=C2C(N)=NC=CC2=C1 ZGQORUBXVDCOFZ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 242
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 158
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 102
- 239000000047 product Substances 0.000 claims abstract description 91
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 67
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims abstract description 65
- 238000001816 cooling Methods 0.000 claims abstract description 50
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000000741 silica gel Substances 0.000 claims abstract description 38
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000012043 crude product Substances 0.000 claims abstract description 26
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007787 solid Substances 0.000 claims abstract description 23
- 239000010813 municipal solid waste Substances 0.000 claims abstract description 21
- VACUCNDAEWCFHZ-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]isoquinolin-1-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC=CC2=CC=CC=C12 VACUCNDAEWCFHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- DCSWGUBEMVRKQO-UHFFFAOYSA-N isoquinoline-6-carbonitrile Chemical compound C1=NC=CC2=CC(C#N)=CC=C21 DCSWGUBEMVRKQO-UHFFFAOYSA-N 0.000 claims abstract description 16
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 15
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims abstract description 15
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- ADAHADRJWVCICR-UHFFFAOYSA-N isoquinoline-6-carboxylic acid Chemical compound C1=NC=CC2=CC(C(=O)O)=CC=C21 ADAHADRJWVCICR-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZTEATMVVGQUULZ-UHFFFAOYSA-N 6-bromoisoquinoline Chemical compound C1=NC=CC2=CC(Br)=CC=C21 ZTEATMVVGQUULZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 12
- 230000009467 reduction Effects 0.000 claims abstract description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims description 55
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 52
- 239000012071 phase Substances 0.000 claims description 48
- 239000012074 organic phase Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 41
- 238000005406 washing Methods 0.000 claims description 40
- 238000001035 drying Methods 0.000 claims description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 19
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 18
- 239000000908 ammonium hydroxide Substances 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000003480 eluent Substances 0.000 claims description 17
- 238000000746 purification Methods 0.000 claims description 17
- 238000000926 separation method Methods 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- -1 filters Substances 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 8
- 235000011182 sodium carbonates Nutrition 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 239000012266 salt solution Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002024 ethyl acetate extract Substances 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 9
- 150000002148 esters Chemical class 0.000 claims 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 3
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims 3
- 229910052740 iodine Inorganic materials 0.000 claims 3
- 239000011630 iodine Substances 0.000 claims 3
- 150000002978 peroxides Chemical class 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 241000254173 Coleoptera Species 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000003810 ethyl acetate extraction Methods 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 239000012467 final product Substances 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical group C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- XQRDIHPBRTXGJU-UHFFFAOYSA-N [N]=O.C(=O)OC Chemical class [N]=O.C(=O)OC XQRDIHPBRTXGJU-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XIRLIZNMBKEUDD-UHFFFAOYSA-N isoquinolin-6-ylmethanol Chemical compound C1=NC=CC2=CC(CO)=CC=C21 XIRLIZNMBKEUDD-UHFFFAOYSA-N 0.000 description 1
- ZSVHUITUMSDFCK-UHFFFAOYSA-N isoquinoline;quinoline Chemical compound C1=NC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 ZSVHUITUMSDFCK-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 208000020442 loss of weight Diseases 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- YQEJIIUSNDZIGO-UHFFFAOYSA-N quinolin-6-ylmethanol Chemical compound N1=CC=CC2=CC(CO)=CC=C21 YQEJIIUSNDZIGO-UHFFFAOYSA-N 0.000 description 1
- NIFLNJLWZZABMI-UHFFFAOYSA-N quinoline-6-carbonitrile Chemical compound N1=CC=CC2=CC(C#N)=CC=C21 NIFLNJLWZZABMI-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- 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)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
It is using 6- bromo-isoquinoline as raw material, reaction forms 6- Cyanoisoquinoline the present invention relates to a kind of synthetic method of 1- aminoisoquinoline -6- methanol；Then sulfuric acid solution is added and obtains isoquinolin -6- formic acid；Further under the action of anhydrous methanol and thionyl chloride, obtain isoquinolin -6- methyl formate, further, in methylene chloride, it is added portionwise under the action of metachloroperbenzoic acid and reacts, obtain mixture isoquinolin -6- methyl formate nitrogen oxides, it is added portionwise in phosphorus oxychloride, after fully reacting, it is cooling, it pours into trash ice, the 1- chlorine isoquinolin -6- methyl formate crude product of solid is precipitated, water phase is directly extracted with ethyl acetate, it is spin-dried for also having obtained crude product 1- chlorine isoquinolin -6- methyl formate, merge two batches crude product and crosses column with silica gel, afford 1- chlorine isoquinolin -6- methyl formate, it is added in tetrahydrofuran, then it is cooled under -30 degree, lithium aluminium hydride reduction is added portionwise and obtains product 1- (1- chlorine isoquinolin -6- base) methanol, (1- is obtained with 4-Methoxybenzylamine Hybrid Heating (4- methoxybenzylamino) isoquinolin -6- base) methanol, it is added in trifluoroacetic acid and flows back, obtain final product 1- aminoisoquinoline -6- methanol.This method route is reasonable, and waste is few, and yield is higher, saves raw material and easily operated.
Description
Technical field
The present invention relates to medicine intermediate fields, and in particular to a kind of preparation method of 1- aminoisoquinoline -6- methanol.
Background technique
Isoquinolin and its derivative are a kind of important compounds, have stronger bioactivity, be widely used in medicine,
The fields such as pesticide, therefore the synthesis of isoquinilone derivatives has received widespread attention, and especially obtains among medicine intermediate
It is widely applied.A kind of chiral aza ring carbene precursor with 3,4- dihydro-isoquinoline skeleton is given in CN104558014A
Salt, synthetic method and purposes give a kind of synthetic method of diaryl substituted isoquinoline compound in CN104529896A,
A kind of preparation method of Isosorbide-5-Nitrae-diallyl isoquinolin is given in CN104478799A, this is all isoquinoline class derivate application
Example, but the 1- aminoisoquinoline -6- methanol that refers to of the application is rarely used as the application of medicine intermediate, efficient to make
Preparation Method is not reported even more.Due to the characteristic of the molecule, this method cannot be generalized in the synthesis of other similar structure.
Summary of the invention
The present invention is mainly to provide a kind of 1- aminoisoquinoline -6- methanol and preparation method thereof.This method step is clear, wave
Take less, yield is higher, saves raw material, whole relatively inexpensive.
Above-mentioned technical problem of the invention is mainly to be addressed by following technical proposals:
A kind of medicine intermediate 1- aminoisoquinoline -6- methanol, which is characterized in that there is structure as described below:
A kind of preparation method of 1- aminoisoquinoline -6- methanol, it is characterised in that include the following steps:
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide 420-
460g, cuprous iodide 80-140g under nitrogen protection, are heated to 140-150 degrees Celsius, react 3-5h, and TLC is monitored to having reacted
Entirely, rear cooling, it pours into 1-2L water, filters, filter cake is added portionwise in the solution of 400-600mL ammonium hydroxide and 400-600mL water,
Cooperation is with ice bath to guarantee that temperature is unlikely to too high；Then it after the stirring of 0.8-1.2L ethyl acetate is added, filters, filter cake is steeped with EA
Less to product, then filter cake is then added in 400-600mL ammonium hydroxide and 400-600mL water and stirs, so by water phase liquid separation extraction
It after ethyl acetate stirring is added afterwards, filters, filter cake steeps product, water phase liquid separation extraction, rear combined ethyl acetate phase, saturated salt solution
Washing 2-4 times, dry to filter, concentrated solvent obtains S1 step products 6- Cyanoisoquinoline；Preferably, the nitrogen atmosphere protection
Under, it is to be deep into nitrogen under liquid level to be continually fed into, the cooling and ice bath are intended to carrying out in guaranteeing the stable 15min of temperature
It operates in next step.
S2, by the sulfuric acid solution of 700-800mL50% mass fraction, be added in four-hole bottle, be then added with stirring
The 6- Cyanoisoquinoline of 200-300g then heats to interior temperature 120-140 degrees centigrade, and flow back 2-3h, and TLC is monitored to raw material
It disappears, it is rear cooling, a large amount of solids are precipitated, pour into about 1.5-2.5L trash ice, filter, a small amount of washing 2-4 times, drying obtains
S2 step products isoquinolin -6- formic acid；Preferably, it is described be precipitated solid process to wait solid stop be precipitated after 10min again
Operation.
Isoquinolin -6- the formic acid of S3,250-300g by the biodiversity percentage composition of drying less than 1%, are added to 3-
In 4L anhydrous methanol, then system is cooled to 0-5 degrees Celsius, and 200-400ml thionyl chloride is added dropwise, and is added dropwise 1.5-2.5 hours, protects
Hold 0-5 degrees Celsius, drip off nature and be warmed to room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water
Then 1.5-2.5L is extracted three times every time with 0.8-1.2L ethyl acetate, is merged organic then with sodium carbonate tune PH=9-10
Phase, 20-40 minutes dry with appropriate anhydrous sodium sulfate, rear filter removes anhydrous sodium sulfate, and organic phase is concentrated under reduced pressure, and obtains thick
Product isoquinolin -6- methyl formate, then cross column with 100-200 mesh 400-600g silica gel, eluent petroleum ether than ethyl acetate=
10:1 obtains S3 step product isoquinolin -6- methyl formate；Preferably, the system is cooled to 0-5 degrees Celsius, Yao Wending 10-
It is followed the steps below again after 15min, the time being refluxed overnight is no less than 12h.
S4,200-300g isoquinolin -6- methyl formate is added in methylene chloride 1.5-2.5L, is then added portionwise
300-350g metachloroperbenzoic acid, maintains the temperature at 0-10 DEG C, and after adding metachloroperbenzoic acid, system reaction is stayed overnight, TLC
Monitoring to raw material disappears, and system is cooled to 0 DEG C, and system filters, and filter cake drying is directly used in the S4 step for obtaining mixture in next step
Rapid product isoquinolin -6- methyl formate nitrogen oxides；Preferably, system is cooled to 0 DEG C, carried out again after Yao Wending 10-15min with
Lower step, filter cake drying will be dried to substantially not until loss of weight.
S5,150-250g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 400-600ml phosphorus oxychloride,
It is warming up to 80 degrees Celsius after adding, reacts 30min-60min, TLC is monitored to fully reacting, and it is cooling, it pours into enough trash ices, analyses
A large amount of solids out filter, 400ml-600ml water washing 2-4 times, and after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate,
Water phase directly uses 1.5-2.5L ethyl acetate to extract 2-4 times, and combined ethyl acetate phase is washed till with enough saturated aqueous sodium carbonates
Neutrality, then 1.5-2.5L saturated salt solution washed once, dry with appropriate anhydrous sodium sulfate, be spin-dried for organic phase, merge two batches
Crude product crosses column with the 100-200 mesh silica gel of 400-600g, eluent petroleum ether: ethyl acetate=20:1-5:1 obtains S5 step
Product 1- chlorine isoquinolin -6- methyl formate；The step of being preferably added among phosphorus oxychloride, until TLC is monitored to fully reacting
Before, carried out in closed workbench, it is described be precipitated a large amount of solids to wait 20min or more be no longer precipitated carry out again it is next
Step.
S6, the 1- chlorine isoquinolin -6- methyl formate of 8-12g is added in 150-250ml tetrahydrofuran, is then cooled to
Subzero 10 degrees Celsius to subzero 20 degrees Celsius, 2-3g lithium aluminium hydride reduction is added portionwise, after fully reacting, instills 5-15ml water, 5-
Then plus the anhydrous sodium sulfate of 15-25g the NaOH of 15% weight percent of 15ml is filtered, filter cake 80-120ml after stirring
Ethyl acetate washing, merges organic phase, is spin-dried for obtaining S6 step product 1- (1- chlorine isoquinolin -6- base) methanol；Preferably, in tetrahydro
Reaction among furans carries out in closed workbench, and suction filtration can be repeated a number of times, and is spin-dried for subtracting in 0.15-0.05 atmospheric pressure
It is carried out under conditions of few.
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 15-25ml 4-Methoxybenzylamine of 8-12g are mixed and heated to
140-150 degrees Celsius, 1.5-2.5h is reacted, after fully reacting, system is cooling, and residue is pure with 100-200 mesh silica gel chromatographic column
Change, obtains S7 step product (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol；Preferably, needed for the cooling arrival
20min is at least placed after temperature carries out below step again.
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 50-70ml trifluoroacetic acid, is flowed back
Then plus water 80-120mL 1.5-2.5h after fully reacting, spins off trifluoroacetic acid, is 9-10 with sodium carbonate tune pH value, then often
Secondary to be extracted 2-4 times with 80-120ml ethyl acetate, organic phase is finally produced after being spin-dried for 100-200 mesh silica gel chromatograph column purification
Product 1- aminoisoquinoline -6- methanol.Preferably, described spin off carries out under conditions of 0.15-0.05 atmospheric pressure is reduced.
Compared with the prior art, the advantages of the present invention are as follows: it is using 6- bromo-isoquinoline as raw material, it is different that reaction forms 6- cyano
Quinoline；Then sulfuric acid solution is added and obtains isoquinolin -6- formic acid；Further under the action of anhydrous methanol and thionyl chloride, obtain
To isoquinolin -6- methyl formate, further, in methylene chloride, it is added portionwise under the action of metachloroperbenzoic acid and reacts,
Mixture isoquinolin -6- methyl formate nitrogen oxides is obtained, is added portionwise in phosphorus oxychloride, it is cooling after fully reacting, it pours into
In trash ice, the 1- chlorine isoquinolin -6- methyl formate crude product of solid is precipitated, water phase is directly extracted with ethyl acetate, is spin-dried for also obtaining
Crude product 1- chlorine isoquinolin -6- methyl formate merges two batches crude product with silica gel and crosses column, affords 1- chlorine isoquinolin -6- formic acid
Methyl esters is added in tetrahydrofuran, is then cooled under -30 degree, lithium aluminium hydride reduction is added portionwise and obtains product 1- (1- chlorine isoquinolin -
6- yl) methanol and 4-Methoxybenzylamine Hybrid Heating obtain (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol, it is added
It flows back into trifluoroacetic acid, obtains final product 1- aminoisoquinoline -6- methanol.4-Methoxybenzylamine is dexterously utilized herein
Under the action of-Cl changed into amino, and remove extra functional group under the action of trifluoroacetic acid, obtain final product, body
Extremely strong inventive concept and creativeness are showed, having no similar approach in currently available technology can be for reference.This method has step
Clearly, waste is few, and yield is higher, saves raw material and easily operated advantage.
Detailed description of the invention
Fig. 1 is the HNMR spectrogram of 1- aminoisoquinoline -6- methanol of the invention；
Fig. 2 is the HPLC spectrogram of 1- aminoisoquinoline -6- methanol of the invention.
Specific embodiment
The preferred embodiment of the present invention is described in detail with reference to the accompanying drawing, so that advantages and features of the invention energy
It is easier to be readily appreciated by one skilled in the art, so as to make a clearer definition of the protection scope of the present invention.This hair
It is bright to be embodied in many different forms, and should not be construed as limited to embodiment set forth herein.On the contrary, providing these
Design of the invention so that this disclosure will be thorough and complete, and will be fully conveyed to art technology by embodiment
Personnel, the present invention will only be defined by the appended claims.The preparation method of 1- aminoisoquinoline -6- methanol provided by the invention,
Process route is as follows:
Its synthetic method can be summarized as follows: using 6- bromo-isoquinoline as raw material, reaction forms 6- Cyanoisoquinoline；Then plus
Enter sulfuric acid solution and obtains isoquinolin -6- formic acid；Further under the action of anhydrous methanol and thionyl chloride, isoquinolin -6- is obtained
Methyl formate further in methylene chloride, is added portionwise under the action of metachloroperbenzoic acid and reacts, obtain mixture
Isoquinolin -6- methyl formate nitrogen oxides, is added portionwise in phosphorus oxychloride, cooling after fully reacting, pours into trash ice, analyses
The 1- chlorine isoquinolin -6- methyl formate crude product of solid, water phase are directly extracted with ethyl acetate, are spin-dried for also having obtained crude product 1- chlorine out
Isoquinolin -6- methyl formate merges two batches crude product with silica gel and crosses column, affords 1- chlorine isoquinolin -6- methyl formate, be added to
In tetrahydrofuran, then it is cooled under -30 degree, lithium aluminium hydride reduction is added portionwise and obtains product 1- (1- chlorine isoquinolin -6- base) methanol, and
4-Methoxybenzylamine Hybrid Heating obtains (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol, is added in trifluoroacetic acid
Reflux, obtains final product 1- aminoisoquinoline -6- methanol.
Embodiment 1
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide
420g, cuprous iodide 80g under nitrogen protection, are heated to 140 degrees Celsius, react 3h, and TLC is monitored to fully reacting, rear cooling,
It pours into 1L water, filters, filter cake is added portionwise in the solution of 400mL ammonium hydroxide and 400mL water, and cooperation is with ice bath to guarantee temperature
It is unlikely to too high；Then it after the stirring of 0.8L ethyl acetate is added, filtering, filter cake steeps, water phase liquid separation extraction less to product with EA,
Then filter cake is then added in 400mL ammonium hydroxide and 400mL water and is stirred, after ethyl acetate stirring is then added, filtered, filter cake bubble
Product, water phase liquid separation extraction, rear combined ethyl acetate phase, saturated common salt water washing 2 times, dry to filter, concentrated solvent obtains S1
Step products 6- Cyanoisoquinoline.
S2, by the sulfuric acid solution of 700mL50% mass fraction, be added in four-hole bottle, be then added with stirring 200g's
6- Cyanoisoquinoline then heats to interior 120 degrees centigrade of temperature, and flow back 2h, and TLC, which is monitored to raw material, to disappear, rear cooling, is precipitated
A large amount of solids pour into about 1.5L trash ice, filter, and a small amount of washing 2 times, drying obtains S2 step products isoquinolin -6- first
Acid.
Isoquinolin -6- the formic acid of S3,250g by the biodiversity percentage composition of drying less than 1%, it is anhydrous to be added to 3L
In methanol, then system is cooled to 0 degree Celsius, and 200ml thionyl chloride is added dropwise, and is added dropwise 1.5 hours, is kept for 0 degree Celsius, drips off certainly
So be warmed to room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 1.5L, then with sodium carbonate tune PH
=9, it is then extracted three times with 0.8L ethyl acetate every time, merges organic phase, it is 20 minutes dry with appropriate anhydrous sodium sulfate, it is rear to take out
Anhydrous sodium sulfate is filtered out, organic phase is concentrated under reduced pressure, obtains crude product isoquinolin -6- methyl formate, then with 100-200 mesh
400g silica gel crosses column, and eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1.
S4,200g isoquinolin -6- methyl formate is added in methylene chloride 1.5L, 300g m-chloro mistake is then added portionwise
Oxybenzoic acid maintains the temperature at 0 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear, body for system reaction
System is cooled to 0 DEG C, and system filters, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- first of mixture
Sour methyl esters nitrogen oxides.
S5,150g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 400ml phosphorus oxychloride, is risen after adding
Temperature reacts 30min-40min to 80 degrees Celsius, and TLC is monitored to fully reacting, cooling, pours into enough trash ices, is precipitated a large amount of solid
Body filters, 400ml water washing 2 times, and after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 1.5L second
Acetoacetic ester extracts 2 times, and combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, then 1.5L saturated common salt
Water washing is primary, dry with appropriate anhydrous sodium sulfate, is spin-dried for organic phase, merges the 100-200 mesh silica gel of two batches crude product 400g
Cross column, eluent petroleum ether: ethyl acetate=20:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate.
S6, the 1- chlorine isoquinolin -6- methyl formate of 8g is added in 150ml tetrahydrofuran, is then cooled to subzero 10
Degree Celsius, 2g lithium aluminium hydride reduction is added portionwise, after fully reacting, instillation 5ml water, the NaOH of 15% weight percent of 5ml, then
Add the anhydrous sodium sulfate of 15g, filtered after stirring, filter cake is washed with 80ml ethyl acetate, merges organic phase, is spin-dried for obtaining the production of S6 step
Product 1- (1- chlorine isoquinolin -6- base) methanol.
S7, that 1- (the 1- chlorine isoquinolin -6- base) methanol and 15ml 4-Methoxybenzylamine of 8g are mixed and heated to 140 is Celsius
Degree reacts 1.5h, and after fully reacting, system is cooling, residue 100-200 mesh silica gel chromatograph column purification, obtains the production of S7 step
Product (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol.
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 50ml trifluoroacetic acid, is flowed back
Then plus water 80mL 1.5h after fully reacting, spins off trifluoroacetic acid, is 9 with sodium carbonate tune pH value, then uses 80ml second every time
Acetoacetic ester extracts 2 times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- aminoisoquinoline-after being spin-dried for
6- methanol.
Embodiment 2
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide
440g, cuprous iodide 120g under nitrogen protection, are heated to 145 degrees Celsius, react 4h, and TLC is monitored to fully reacting, rear cooling,
It pours into 1.5L water, filters, filter cake is added portionwise in the solution of 500mL ammonium hydroxide and 500mL water, and cooperation is with ice bath to guarantee temperature
Degree is unlikely to too high；Then it after the stirring of 1L ethyl acetate is added, filtering, filter cake steeps, water phase liquid separation extraction less to product with EA,
Then filter cake is then added in 500mL ammonium hydroxide and 500mL water and is stirred, after ethyl acetate stirring is then added, filtered, filter cake bubble
Product, water phase liquid separation extraction, rear combined ethyl acetate phase, saturated common salt water washing 3 times, dry to filter, concentrated solvent obtains S1
Step products 6- Cyanoisoquinoline.
S2, by the sulfuric acid solution of 750mL50% mass fraction, be added in four-hole bottle, be then added with stirring 250g's
6- Cyanoisoquinoline then heats to interior 130 degrees centigrade of temperature, and flow back 2.5h, and TLC, which is monitored to raw material, to disappear, rear cooling, analysis
A large amount of solids out pour into about 2L trash ice, filter, and a small amount of washing 3 times, drying obtains S2 step products isoquinolin -6- first
Acid.
Isoquinolin -6- the formic acid of S3,280g by the biodiversity percentage composition of drying less than 1%, be added to 3.5L without
In water methanol, then system is cooled to 2 degrees Celsius, and 300ml thionyl chloride is added dropwise, and is added dropwise 2 hours, is kept for 2 degrees Celsius, drips off certainly
So be warmed to room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 2L, then with sodium carbonate tune PH=
9.5, it is then extracted three times with 1L ethyl acetate every time, merges organic phase, it is 30 minutes dry with appropriate anhydrous sodium sulfate, it is rear to filter
Anhydrous sodium sulfate is removed, organic phase is concentrated under reduced pressure, obtains crude product isoquinolin -6- methyl formate, then with 100-200 mesh 500g
Silica gel crosses column, and eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1.
S4,250g isoquinolin -6- methyl formate is added in methylene chloride 2L, 325g m-chloro peroxide is then added portionwise
Benzoic acid maintains the temperature at 5 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear, system for system reaction
It is cooled to 0 DEG C, system filters, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- formic acid of mixture
Methyl esters nitrogen oxides.
S5,200g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 500ml phosphorus oxychloride, is risen after adding
Temperature reacts 40min-50min to 80 degrees Celsius, and TLC is monitored to fully reacting, cooling, pours into enough trash ices, is precipitated a large amount of solid
Body filters, 500ml water washing 3 times, and after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 2L acetic acid
Ethyl ester extracts 3 times, and combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, and then 2L saturated common salt is washed
It washs once, it is dry with appropriate anhydrous sodium sulfate, it is spin-dried for organic phase, merges two batches crude product with the 100-200 mesh silica gel of 500g and crosses column,
Eluent petroleum ether: ethyl acetate=10:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate.
S6, the 1- chlorine isoquinolin -6- methyl formate of 10g is added in 200ml tetrahydrofuran, is then cooled to subzero 15
Degree Celsius, 2.5g lithium aluminium hydride reduction is added portionwise, after fully reacting, instillation 10ml water, the NaOH of 15% weight percent of 10ml,
Then plus the anhydrous sodium sulfate of 20g, filtered after stirring, filter cake is washed with 100ml ethyl acetate, is merged organic phase, is spin-dried for obtaining S6
Step product 1- (1- chlorine isoquinolin -6- base) methanol.
S7, that 1- (the 1- chlorine isoquinolin -6- base) methanol and 20ml 4-Methoxybenzylamine of 10g are mixed and heated to 145 is Celsius
Degree reacts 2h, and after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains S7 step product
(1- (4- methoxybenzylamino) isoquinolin -6- base) methanol.
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 60ml trifluoroacetic acid, flow back 2h,
Then plus water 100mL after fully reacting, trifluoroacetic acid is spun off, is 9.5 with sodium carbonate tune pH value, then uses 100ml acetic acid every time
Ethyl ester extracts 3 times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- aminoisoquinoline -6- after being spin-dried for
Methanol.
Embodiment 3
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide
460g, cuprous iodide 140g under nitrogen protection, are heated to 150 degrees Celsius, react 5h, and TLC is monitored to fully reacting, rear cooling,
It pours into 2L water, filters, filter cake is added portionwise in the solution of 600mL ammonium hydroxide and 600mL water, and cooperation is with ice bath to guarantee temperature
It is unlikely to too high；Then it after the stirring of 1.2L ethyl acetate is added, filtering, filter cake steeps, water phase liquid separation extraction less to product with EA,
Then filter cake is then added in 600mL ammonium hydroxide and 600mL water and is stirred, after ethyl acetate stirring is then added, filtered, filter cake bubble
Product, water phase liquid separation extraction, rear combined ethyl acetate phase, saturated common salt water washing 4 times, dry to filter, concentrated solvent obtains S1
Step products 6- Cyanoisoquinoline.
S2, by the sulfuric acid solution of 800mL50% mass fraction, be added in four-hole bottle, be then added with stirring 300g's
6- Cyanoisoquinoline then heats to interior 140 degrees centigrade of temperature, and flow back 3h, and TLC, which is monitored to raw material, to disappear, rear cooling, is precipitated
A large amount of solids pour into about 2.5L trash ice, filter, and a small amount of washing 4 times, drying obtains S2 step products isoquinolin -6- first
Acid.
Isoquinolin -6- the formic acid of S3,300g by the biodiversity percentage composition of drying less than 1%, it is anhydrous to be added to 4L
In methanol, then system is cooled to 5 degrees Celsius, and 400ml thionyl chloride is added dropwise, and is added dropwise 2.5 hours, is kept for 5 degrees Celsius, drips off certainly
So be warmed to room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 2.5L, then with sodium carbonate tune PH
=10, it is then extracted three times with 1.2L ethyl acetate every time, merges organic phase, it is 40 minutes dry with appropriate anhydrous sodium sulfate, after
It filters and removes anhydrous sodium sulfate, organic phase is concentrated under reduced pressure, obtain crude product isoquinolin -6- methyl formate, then with 100-200 mesh
600g silica gel crosses column, and eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1.
S4,300g isoquinolin -6- methyl formate is added in methylene chloride 2.5L, 350g m-chloro mistake is then added portionwise
Oxybenzoic acid maintains the temperature at 10 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear for system reaction,
System is cooled to 0 DEG C, and system filters, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- of mixture
Methyl formate nitrogen oxides.
S5,250g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 600ml phosphorus oxychloride, is risen after adding
Temperature reacts 50min-60min to 80 degrees Celsius, and TLC is monitored to fully reacting, cooling, pours into enough trash ices, is precipitated a large amount of solid
Body filters, 600ml water washing 4 times, and after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 2.5L second
Acetoacetic ester extracts 4 times, and combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, then 2.5L saturated common salt
Water washing is primary, dry with appropriate anhydrous sodium sulfate, is spin-dried for organic phase, merges the 100-200 mesh silica gel of two batches crude product 600g
Cross column, eluent petroleum ether: ethyl acetate=5:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate.
S6, the 1- chlorine isoquinolin -6- methyl formate of 12g is added in 250ml tetrahydrofuran, is then cooled to subzero 20
Degree Celsius, 3g lithium aluminium hydride reduction is added portionwise, after fully reacting, instillation 15ml water, the NaOH of 15% weight percent of 15ml, so
Afterwards plus the anhydrous sodium sulfate of 25g, it is filtered after stirring, filter cake is washed with 120ml ethyl acetate, merges organic phase, is spin-dried for obtaining S6 step
Rapid product 1- (1- chlorine isoquinolin -6- base) methanol.
S7, that 1- (the 1- chlorine isoquinolin -6- base) methanol and 25ml 4-Methoxybenzylamine of 12g are mixed and heated to 150 is Celsius
Degree reacts 2.5h, and after fully reacting, system is cooling, residue 100-200 mesh silica gel chromatograph column purification, obtains the production of S7 step
Product (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol.
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 70ml trifluoroacetic acid, is flowed back
Then plus water 120mL 2.5h after fully reacting, spins off trifluoroacetic acid, is 10 with sodium carbonate tune pH value, then uses 120ml every time
Ethyl acetate extracts 4 times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- amino isoquinoline after being spin-dried for
Quinoline -6- methanol.
Embodiment 4
S1,500g 6- bromo-isoquinoline is added in the n,N-Dimethylformamide of 2L, adds 443g cuprous cyanide,
87g cuprous iodide under nitrogen protection, is heated to 145 degree, reacts 4h, and TLC shows fully reacting.Post-processing: it is cooling, it pours into
It in 1.5L water, filters, filter cake is added portionwise in the solution of 500mL ammonium hydroxide and 500mL water, is careful not to make heat release too severe；
Then it after the stirring of 1L ethyl acetate is added, filters, filter cake steeps, water phase liquid separation extraction less to product with EA.Then again by filter cake
It is added in 500mL ammonium hydroxide and 500mL water and stirs, after ethyl acetate stirring is then added, filter, filter cake steeps product, water phase point
Liquid extraction.Combined ethyl acetate phase, saturated salt solution washed once, dry, filter, and concentrated solvent obtains 6- Cyanoisoquinoline.
S2,50% sulfuric acid solution by 750mL, are added in four-hole bottle, and the 6- cyano for being then added with stirring 250g is different
Quinoline then heats to 120 degree or so of interior temperature, reacts 2.5-3h, and TLC shows that raw material disappears.Post-processing: cooling to be precipitated largely admittedly
Body pours into about 2L trash ice, filters, and a small amount of washing 2-3 times, drying obtains isoquinolin -6- formic acid.
S3, the isoquinolin -6- formic acid by the moisture content of the drying of 270g less than 1% are added in 3.5L anhydrous methanol,
Then system is cooled to 0-5 degree, and 300mL thionyl chloride is added dropwise, and is added dropwise about 2 hours, keeps 0-5 degree, drips off nature and rise to room
Temperature, then system is refluxed overnight.Post-processing: mixture is cooling, and solvent is spin-dried for, and adds water 2L, then with sodium carbonate tune PH=9-10,
Then it is extracted three times with ethyl acetate 1L every time, is then combined with organic phase, anhydrous sodium sulfate is 30 minutes dry, then filters and removes
Desiccant, organic phase are concentrated under reduced pressure, and obtain 250g crude product isoquinolin -6- methyl formate.With 100-200 mesh 500g silica gel mistake
Column, eluent petroleum ether obtain the pure isoquinolin -6- methyl formate of product than ethyl acetate=10:1.
S4,250g raw material isoquinolin -6- methyl formate is added in methylene chloride 2L, content 85% is then added portionwise
325g metachloroperbenzoic acid, after maintaining the temperature at 10 DEG C hereinafter, adding metachloroperbenzoic acid, system reaction overnight, TLC
After showing fully reacting, system is cooled to 10 DEG C, and system filters, and filter cake drying is directly used in next step, obtains mixture isoquinoline
Quinoline -6- methyl formate nitrogen oxides.
S5,200g raw material isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 500mL phosphorus oxychloride, is added
After be warming up to 80 degree of reaction 30min-1h, system can warm naturally to 100 degree in the reaction, cold after TLC shows fully reacting
But, it pours into 5kg trash ice, a large amount of solids is precipitated, filter, 500mL is washed three times, and after washing, drying obtains 1- chlorine isoquinolin -6-
Methyl formate crude product, water phase are directly extracted three times with the ethyl acetate of 2L every time, and combined ethyl acetate mutually uses the unsaturated carbonate of 3L
Sodium water solution washing to neutrality, then washed once with the saturated salt solution of 2L and be dried with anhydrous sodium sulfate, is spin-dried for organic three times
Phase merges two batches crude product with the 100-200 mesh silica gel of 500g and crosses column, and petroleum ether in eluant, eluent: ethyl acetate=20:1-5:1 obtains
It is greater than 95% product 1- chlorine isoquinolin -6- methyl formate to purity.
S6, the 1- chlorine isoquinolin -6- methyl formate of 10g is added in the tetrahydrofuran of 200mL, is then cooled to -30
Then plus the anhydrous sulphur of 20g under degree, 2.5g lithium aluminium hydride reduction is added portionwise, after fully reacting, drip 10mL, the 15%NaOH of 10mL,
Sour sodium stirs, and filters, and filter cake wash with 100mL ethyl acetate, merging organic phase be spin-dried for 7.5g product 1- (1- chlorine isoquinoline
Quinoline -6- base) methanol.
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 20mL 4-Methoxybenzylamine of 10g are mixed and heated to 140 degree, instead
2h is answered, after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains 12g product (1- (4- first
Oxygroup benzyl amino) isoquinolin -6- base) methanol.
S8, raw material (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in the trifluoroacetic acid of 60mL and is returned
Flow 2h.Then plus water 100mL after fully reacting, trifluoroacetic acid is spun off, is 10 with sodium carbonate tune pH value, then uses 100ml every time
Ethyl acetate extracts three times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains product 1- aminoisoquinoline -6- after being spin-dried for
Methanol.
A kind of application of medicine intermediate, the 1- ammonia prepared by the preparation method of any one embodiment as previously described
Base isoquinolin -6- methanol is used as medicine intermediate to prepare drug.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, of the invention
Protection scope should be determined by the scope of protection defined in the claims.
Claims (4)
1. a kind of preparation method of 1- aminoisoquinoline -6- methanol, which comprises the steps of:
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide 420-
460g, cuprous iodide 80-140g under nitrogen protection, are heated to 140-150 degrees Celsius, react 3-5h, and TLC is monitored to having reacted
Entirely, rear cooling, it pours into 1-2L water, filters, filter cake is added portionwise in the solution of 400-600mL ammonium hydroxide and 400-600mL water,
Cooperation is with ice bath to guarantee that temperature is unlikely to too high；Then it after the stirring of 0.8-1.2L ethyl acetate is added, filters, filter cake is steeped with EA
Less to product, then filter cake is then added in 400-600mL ammonium hydroxide and 400-600mL water and stirs, so by water phase liquid separation extraction
It after ethyl acetate stirring is added afterwards, filters, filter cake steeps product, water phase liquid separation extraction, rear combined ethyl acetate phase, saturated salt solution
Washing 2-4 times, dry to filter, concentrated solvent obtains S1 step products 6- Cyanoisoquinoline；
S2, by the sulfuric acid solution of 700-800mL50% mass fraction, be added in four-hole bottle, be then added with stirring 200-
The 6- Cyanoisoquinoline of 300g then heats to interior temperature 120-140 degrees centigrade, and flow back 2-3h, and TLC, which is monitored to raw material, to disappear
It loses, it is rear cooling, a large amount of solids are precipitated, pour into about 1.5-2.5L trash ice, filter, a small amount of washing 2-4 times, drying obtains S2
Step products isoquinolin -6- formic acid；
Isoquinolin -6- the formic acid of S3,250-300g by the biodiversity percentage composition of drying less than 1%, be added to 3-4L without
In water methanol, then system is cooled to 0-5 degrees Celsius, and 200-400ml thionyl chloride is added dropwise, and is added dropwise 1.5-2.5 hours, keeps 0-
5 degrees Celsius, drip off nature and be warmed to room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 1.5-
Then 2.5L is extracted three times every time with 0.8-1.2L ethyl acetate then with sodium carbonate tune pH=9-10, merges organic phase, used
Appropriate anhydrous sodium sulfate is 20-40 minutes dry, and rear filter removes anhydrous sodium sulfate, and organic phase is concentrated under reduced pressure, crude product is obtained
Isoquinolin -6- methyl formate, then cross column with 100-200 mesh 400-600g silica gel, eluent petroleum ether than ethyl acetate=10:1,
Obtain S3 step product isoquinolin -6- methyl formate；
S4,200-300g isoquinolin -6- methyl formate is added in methylene chloride 1.5-2.5L, 300- is then added portionwise
350g metachloroperbenzoic acid, maintains the temperature at 0-10 DEG C, and after adding metachloroperbenzoic acid, overnight, TLC is monitored for system reaction
It disappears to raw material, system is cooled to 0 DEG C, and system filters, and filter cake drying is directly used in the S4 step production for obtaining mixture in next step
Product isoquinolin -6- methyl formate nitrogen oxides；
S5,150-250g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 400-600ml phosphorus oxychloride, is added
After be warming up to 80 degrees Celsius, react 30min-60min, TLC is monitored to fully reacting, cooling, is poured into enough trash ices, is precipitated big
Solid is measured, is filtered, 400ml-600ml water washing 2-4 times, after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, water phase
It is directly extracted 2-4 times with 1.5-2.5L ethyl acetate, combined ethyl acetate phase, is washed till with enough saturated aqueous sodium carbonates
Property, then 1.5-2.5L saturated salt solution washed once, and it is dry with appropriate anhydrous sodium sulfate, it is spin-dried for organic phase, it is thick to merge two batches
Product cross column with the 100-200 mesh silica gel of 400-600g, eluent petroleum ether: ethyl acetate=20:1-5:1, obtain the production of S5 step
Product 1- chlorine isoquinolin -6- methyl formate；
S6, the 1- chlorine isoquinolin -6- methyl formate of 8-12g is added in 150-250ml tetrahydrofuran, is then cooled to subzero
10 degrees Celsius to subzero 20 degrees Celsius, 2-3g lithium aluminium hydride reduction is added portionwise, after fully reacting, instills 5-15ml water, 5-15ml's
Then plus the anhydrous sodium sulfate of 15-25g the NaOH of 15% weight percent is filtered, filter cake 80-120ml acetic acid second after stirring
Ester washing, merges organic phase, is spin-dried for obtaining S6 step product 1- (1- chlorine isoquinolin -6- base) methanol；
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 15-25ml 4-Methoxybenzylamine of 8-12g are mixed and heated to 140-150
Degree Celsius, 1.5-2.5h is reacted, after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains
S7 step product (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol；
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 50-70ml trifluoroacetic acid, flow back 1.5-
Then plus water 80-120mL 2.5h after fully reacting, spins off trifluoroacetic acid, is 9-10 with sodium carbonate tune pH value, then uses every time
80-120ml ethyl acetate extracts 2-4 times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- after being spin-dried for
Aminoisoquinoline -6- methanol.
2. a kind of preparation method as described in claim 1, which is characterized in that S1-S8 step specifically:
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide 420g, iodine
Changing cuprous 80g, under nitrogen protection, be heated to 140 degrees Celsius, reacts 3h, TLC is monitored to fully reacting, and it is rear cooling, pour into 1L water
In, it filters, filter cake is added portionwise in the solution of 400mL ammonium hydroxide and 400mL water, and cooperation is with ice bath to guarantee that temperature is unlikely to too
It is high；Then it after the stirring of 0.8L ethyl acetate is added, filters, filter cake steeps, water phase liquid separation extraction less to product with EA, then will filter
Cake is then added in 400mL ammonium hydroxide and 400mL water and stirs, and after ethyl acetate stirring is then added, filters, filter cake steeps product, water
Phase liquid separation extraction, rear combined ethyl acetate phase, saturated common salt water washing 2 times, dry to filter, concentrated solvent obtains S1 step products
6- Cyanoisoquinoline；
S2, by the sulfuric acid solution of 700mL50% mass fraction, be added in four-hole bottle, be then added with stirring the 6- cyanogen of 200g
Base isoquinolin then heats to interior 120 degrees centigrade of temperature, and flow back 2h, and TLC, which is monitored to raw material, to disappear, rear cooling, is precipitated a large amount of
Solid pours into about 1.5L trash ice, filters, and a small amount of washing 2 times, drying obtains S2 step products isoquinolin -6- formic acid；
Isoquinolin -6- the formic acid of S3,250g by the biodiversity percentage composition of drying less than 1%, are added to 3L anhydrous methanol
In, then system is cooled to 0 degree Celsius, and 200ml thionyl chloride is added dropwise, and is added dropwise 1.5 hours, is kept for 0 degree Celsius, drips off nature liter
To room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 1.5L, then with sodium carbonate tune pH=9,
Then it is extracted three times with 0.8L ethyl acetate every time, merges organic phase, 20 minutes dry with appropriate anhydrous sodium sulfate, rear filter is removed
Anhydrous sodium sulfate is removed, organic phase is concentrated under reduced pressure, obtains crude product isoquinolin -6- methyl formate, then with 100-200 mesh 400g silicon
Glue crosses column, and eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1；
S4,200g isoquinolin -6- methyl formate is added in methylene chloride 1.5L, 300g m-chloro peroxide benzene is then added portionwise
Formic acid maintains the temperature at 0 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear, system drop for system reaction
To 0 DEG C, system filters temperature, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- formic acid first of mixture
Ester nitrogen oxides；
S5,150g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 400ml phosphorus oxychloride, is warming up to after adding
80 degrees Celsius, 30min-40min is reacted, TLC is monitored to fully reacting, and it is cooling, it pours into enough trash ices, a large amount of solids is precipitated,
It filters, 400ml water washing 2 times, after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 1.5L acetic acid second
Ester extracts 2 times, and combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, and then 1.5L saturated common salt is washed
It washs once, it is dry with appropriate anhydrous sodium sulfate, it is spin-dried for organic phase, merges two batches crude product with the 100-200 mesh silica gel of 400g and crosses column,
Eluent petroleum ether: ethyl acetate=20:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate；
S6, the 1- chlorine isoquinolin -6- methyl formate of 8g is added in 150ml tetrahydrofuran, it is Celsius is then cooled to subzero 10
Degree, 2g lithium aluminium hydride reduction is added portionwise, after fully reacting, instill 5ml water, the NaOH of 15% weight percent of 5ml, then plus
The anhydrous sodium sulfate of 15g filters after stirring, and filter cake is washed with 80ml ethyl acetate, merges organic phase, is spin-dried for obtaining S6 step product
1- (1- chlorine isoquinolin -6- base) methanol；
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 15ml 4-Methoxybenzylamine of 8g are mixed and heated to 140 degrees Celsius, instead
1.5h is answered, after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains S7 step product (1-
(4- methoxybenzylamino) isoquinolin -6- base) methanol；
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 50ml trifluoroacetic acid, flow back 1.5h, instead
Should completely after, then plus water 80mL spin off trifluoroacetic acid, be 9 with sodium carbonate tune pH value, then extracted every time with 80ml ethyl acetate
It takes 2 times, organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- aminoisoquinoline -6- methanol after being spin-dried for.
3. a kind of preparation method as described in claim 1, which is characterized in that S1-S8 step specifically:
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide 440g, iodine
Changing cuprous 120g, under nitrogen protection, be heated to 145 degrees Celsius, reacts 4h, TLC is monitored to fully reacting, and it is rear cooling, it pours into
It in 1.5L water, filters, filter cake is added portionwise in the solution of 500mL ammonium hydroxide and 500mL water, and cooperation is with ice bath to guarantee temperature not
As for too high；Then it after the stirring of 1L ethyl acetate is added, filters, filter cake steeps, water phase liquid separation extraction less to product with EA, then
Filter cake is then added in 500mL ammonium hydroxide and 500mL water and is stirred, after ethyl acetate stirring is then added, is filtered, filter cake bubble produces
Product, water phase liquid separation extraction, rear combined ethyl acetate phase is saturated common salt water washing 3 times, dry to filter, and concentrated solvent obtains S1 step
Rapid product 6- Cyanoisoquinoline；
S2, by the sulfuric acid solution of 750mL50% mass fraction, be added in four-hole bottle, be then added with stirring the 6- cyanogen of 250g
Base isoquinolin then heats to interior 130 degrees centigrade of temperature, and flow back 2.5h, and TLC, which is monitored to raw material, to disappear, rear cooling, is precipitated big
Solid is measured, is poured into about 2L trash ice, is filtered, a small amount of washing 3 times, drying obtains S2 step products isoquinolin -6- formic acid；
Isoquinolin -6- the formic acid of S3,280g by the biodiversity percentage composition of drying less than 1%, are added to 3.5L without water beetle
In alcohol, then system is cooled to 2 degrees Celsius, and 300ml thionyl chloride is added dropwise, and is added dropwise 2 hours, is kept for 2 degrees Celsius, drips off nature liter
To room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 2L, then with sodium carbonate tune pH=9.5,
Then it is extracted three times with 1L ethyl acetate every time, merges organic phase, it is 30 minutes dry with appropriate anhydrous sodium sulfate, it is rear to filter removing
Organic phase is concentrated under reduced pressure anhydrous sodium sulfate, obtains crude product isoquinolin -6- methyl formate, then with 100-200 mesh 500g silica gel
Column is crossed, eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1；
S4,250g isoquinolin -6- methyl formate is added in methylene chloride 2L, 325g m-chloro peroxide benzene first is then added portionwise
Acid maintains the temperature at 5 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear, system cooling for system reaction
To 0 DEG C, system is filtered, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- methyl formate of mixture
Nitrogen oxides；
S5,200g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 500ml phosphorus oxychloride, is warming up to after adding
80 degrees Celsius, 40min-50min is reacted, TLC is monitored to fully reacting, and it is cooling, it pours into enough trash ices, a large amount of solids is precipitated,
It filters, 500ml water washing 3 times, after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 2L ethyl acetate
Extraction 3 times, combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, then 2L saturated common salt water washing one
It is secondary, it is dry with appropriate anhydrous sodium sulfate, it is spin-dried for organic phase, merges two batches crude product with the 100-200 mesh silica gel of 500g and crosses column, elute
Agent petroleum ether: ethyl acetate=10:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate；
S6, the 1- chlorine isoquinolin -6- methyl formate of 10g is added in 200ml tetrahydrofuran, it is Celsius is then cooled to subzero 15
Degree, is added portionwise 2.5g lithium aluminium hydride reduction, after fully reacting, instillation 10ml water, and the NaOH of 15% weight percent of 10ml, then
Add the anhydrous sodium sulfate of 20g, filtered after stirring, filter cake is washed with 100ml ethyl acetate, is merged organic phase, is spin-dried for obtaining S6 step
Product 1- (1- chlorine isoquinolin -6- base) methanol；
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 20ml 4-Methoxybenzylamine of 10g are mixed and heated to 145 degrees Celsius, instead
2h is answered, after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains S7 step product (1- (4-
Methoxybenzylamino) isoquinolin -6- base) methanol；
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 60ml trifluoroacetic acid, flow back 2h, reaction
Then plus water 100mL after completely, trifluoroacetic acid is spun off, is 9.5 with sodium carbonate tune pH value, then uses 100ml ethyl acetate every time
Extraction 3 times, organic phase with 100-200 mesh silica gel chromatograph column purification obtain final products 1- aminoisoquinoline -6- methanol after being spin-dried for.
4. a kind of preparation method as described in claim 1, which is characterized in that S1-S8 step specifically:
S1,500g 6- bromo-isoquinoline is added among the n,N-Dimethylformamide of 2L, adds cuprous cyanide 460g, iodine
Changing cuprous 140g, under nitrogen protection, be heated to 150 degrees Celsius, reacts 5h, TLC is monitored to fully reacting, and it is rear cooling, pour into 2L
It in water, filters, filter cake is added portionwise in the solution of 600mL ammonium hydroxide and 600mL water, and cooperation is with ice bath to guarantee that temperature is unlikely to
It is too high；Then be added 1.2L ethyl acetate stirring after, filter, filter cake steeped with EA it is less to product, water phase liquid separation extraction, then will
Filter cake is then added in 600mL ammonium hydroxide and 600mL water and stirs, and after ethyl acetate stirring is then added, filters, and filter cake steeps product,
Water phase liquid separation extraction, rear combined ethyl acetate phase is saturated common salt water washing 4 times, dry to filter, and concentrated solvent obtains the production of S1 step
Object 6- Cyanoisoquinoline；
S2, by the sulfuric acid solution of 800mL50% mass fraction, be added in four-hole bottle, be then added with stirring the 6- cyanogen of 300g
Base isoquinolin then heats to interior 140 degrees centigrade of temperature, and flow back 3h, and TLC, which is monitored to raw material, to disappear, rear cooling, is precipitated a large amount of
Solid pours into about 2.5L trash ice, filters, and a small amount of washing 4 times, drying obtains S2 step products isoquinolin -6- formic acid；
Isoquinolin -6- the formic acid of S3,300g by the biodiversity percentage composition of drying less than 1%, are added to 4L anhydrous methanol
In, then system is cooled to 5 degrees Celsius, and 400ml thionyl chloride is added dropwise, and is added dropwise 2.5 hours, is kept for 5 degrees Celsius, drips off nature liter
To room temperature, then system is refluxed overnight, after mixture is cooling, be spin-dried for solvent, add water 2.5L, then with sodium carbonate tune pH=
10, it is then extracted three times with 1.2L ethyl acetate every time, merges organic phase, it is 40 minutes dry with appropriate anhydrous sodium sulfate, it is rear to take out
Anhydrous sodium sulfate is filtered out, organic phase is concentrated under reduced pressure, obtains crude product isoquinolin -6- methyl formate, then with 100-200 mesh
600g silica gel crosses column, and eluent petroleum ether obtains S3 step product isoquinolin -6- methyl formate than ethyl acetate=10:1；
S4,300g isoquinolin -6- methyl formate is added in methylene chloride 2.5L, 350g m-chloro peroxide benzene is then added portionwise
Formic acid maintains the temperature at 10 DEG C, after adding metachloroperbenzoic acid, and overnight, TLC, which is monitored to raw material, to disappear, system for system reaction
It is cooled to 0 DEG C, system filters, and filter cake drying is directly used in next step, obtains the S4 step product isoquinolin -6- formic acid of mixture
Methyl esters nitrogen oxides；
S5,250g isoquinolin -6- methyl formate nitrogen oxides is added portionwise in 600ml phosphorus oxychloride, is warming up to after adding
80 degrees Celsius, 50min-60min is reacted, TLC is monitored to fully reacting, and it is cooling, it pours into enough trash ices, a large amount of solids is precipitated,
It filters, 600ml water washing 4 times, after washing, drying obtains 1- chlorine isoquinolin -6- methyl formate, and water phase directly uses 2.5L acetic acid second
Ester extracts 4 times, and combined ethyl acetate phase is washed till neutrality with enough saturated aqueous sodium carbonates, and then 2.5L saturated common salt is washed
It washs once, it is dry with appropriate anhydrous sodium sulfate, it is spin-dried for organic phase, merges two batches crude product with the 100-200 mesh silica gel of 600g and crosses column,
Eluent petroleum ether: ethyl acetate=5:1 obtains S5 step product 1- chlorine isoquinolin -6- methyl formate；
S6, the 1- chlorine isoquinolin -6- methyl formate of 12g is added in 250ml tetrahydrofuran, it is Celsius is then cooled to subzero 20
Degree, 3g lithium aluminium hydride reduction is added portionwise, after fully reacting, instill 15ml water, the NaOH of 15% weight percent of 15ml, then plus
The anhydrous sodium sulfate of 25g filters after stirring, and filter cake is washed with 120ml ethyl acetate, merges organic phase, is spin-dried for obtaining the production of S6 step
Product 1- (1- chlorine isoquinolin -6- base) methanol；
S7,1- (the 1- chlorine isoquinolin -6- base) methanol and 25ml 4-Methoxybenzylamine of 12g are mixed and heated to 150 degrees Celsius, instead
2.5h is answered, after fully reacting, system is cooling, and residue 100-200 mesh silica gel chromatograph column purification obtains S7 step product (1-
(4- methoxybenzylamino) isoquinolin -6- base) methanol；
S8, (1- (4- methoxybenzylamino) isoquinolin -6- base) methanol is added in 70ml trifluoroacetic acid, flow back 2.5h, instead
Should completely after, then plus water 120mL spin off trifluoroacetic acid, be 10 with sodium carbonate tune pH value, then use 120ml acetic acid second every time
Ester extracts 4 times, and organic phase with 100-200 mesh silica gel chromatograph column purification obtains final products 1- aminoisoquinoline -6- first after being spin-dried for
Alcohol.
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