CN113801069A - Alfuzosin hydrochloride intermediate compound - Google Patents
Alfuzosin hydrochloride intermediate compound Download PDFInfo
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- CN113801069A CN113801069A CN202010542304.6A CN202010542304A CN113801069A CN 113801069 A CN113801069 A CN 113801069A CN 202010542304 A CN202010542304 A CN 202010542304A CN 113801069 A CN113801069 A CN 113801069A
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- intermediate compound
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- alfuzosin
- temperature
- hydrochloride
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 67
- YTNKWDJILNVLGX-UHFFFAOYSA-N alfuzosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 YTNKWDJILNVLGX-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960003103 alfuzosin hydrochloride Drugs 0.000 title claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 84
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 229960004607 alfuzosin Drugs 0.000 claims description 28
- WNMJYKCGWZFFKR-UHFFFAOYSA-N alfuzosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 WNMJYKCGWZFFKR-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 claims description 16
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229960000485 methotrexate Drugs 0.000 abstract 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 description 49
- 239000007787 solid Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000001816 cooling Methods 0.000 description 35
- 238000010438 heat treatment Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- 238000002425 crystallisation Methods 0.000 description 27
- 230000008025 crystallization Effects 0.000 description 27
- 238000004809 thin layer chromatography Methods 0.000 description 23
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000008213 purified water Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 238000002386 leaching Methods 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- -1 4-amino-6, 7-dimethoxy-2-quinazolinyl Chemical group 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- CCOVXHZDHACRNQ-UHFFFAOYSA-N 3-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-methylamino]propanenitrile Chemical compound N#CCCN(C)C1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 CCOVXHZDHACRNQ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- QHJABUZHRJTCAR-UHFFFAOYSA-N n'-methylpropane-1,3-diamine Chemical compound CNCCCN QHJABUZHRJTCAR-UHFFFAOYSA-N 0.000 description 2
- AUXJTEANWWFSRR-UHFFFAOYSA-N n-[3-(methylamino)propyl]oxolane-2-carboxamide Chemical compound CNCCCNC(=O)C1CCCO1 AUXJTEANWWFSRR-UHFFFAOYSA-N 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- UNIJBMUBHBAUET-UHFFFAOYSA-N 3-(methylamino)propanenitrile Chemical compound CNCCC#N UNIJBMUBHBAUET-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000021891 Micturition disease Diseases 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- GXHAENUAJYZNOA-UHFFFAOYSA-N oxolane-2-carboxamide Chemical compound NC(=O)C1CCCO1 GXHAENUAJYZNOA-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis 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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to an alfuzosin hydrochloride intermediate compound I and a preparation method thereof, wherein 1, 3-propane diamine is used for replacing 3-methotrexate propionitrile commonly used in the alfuzosin hydrochloride synthesis process, the two amino groups have consistent activity, the selectivity problem is avoided, the side reaction is less, and the high-temperature high-pressure reaction of cyano reduction is avoided; the alfuzosin hydrochloride prepared by utilizing the intermediate has simple and convenient operation, low cost, high yield and purity and suitability for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to an alfuzosin hydrochloride intermediate compound.
Background
Alfuzosin hydrochloride (alfuzosin hydrochloride), namely N- [3- (4-amino-6, 7-dimethoxy-2-quinazolinyl) methylamino ] propyl-tetrahydro-2-furancarboxamide hydrochloride, is a quinazoline derivative, belongs to an alpha 1-adrenergic receptor antagonist, can be competitively combined with alpha 1-receptors of prostate, prostatic capsule and the like with high selectivity, influences the smooth muscle contraction mediated by the alpha 1-receptors, relieves the micturition disorder of patients with benign prostatic hyperplasia, and improves the life quality of the patients. Alfuzosin hydrochloride was developed by saint delaburg corporation of sunofil france, first marketed in france in 1988 and is now widely used worldwide for the treatment of benign prostatic hyperplasia and hypertension. The structural formula is as follows:
the synthesis method of alfuzosin hydrochloride is firstly disclosed in US4315007, veratric acid is taken as a raw material, and is subjected to nitration, reduction, cyclization, chlorination and ammonolysis to obtain an intermediate 2-chloro-4-amino-6, 7-dimethoxy quinazoline, the intermediate reacts with 3-methylaminopropionitrile in isoamyl alcohol to generate N- (4-amino-6, 7-dimethoxy quinazoline-2-yl) -N-methyl-2-cyanoethylamine, the N- (4-amino-6, 7-dimethoxy quinazoline-2-yl) -N-methyl-2-cyanoethylamine is hydrogenated and reduced into amine in the presence of a catalyst raney nickel, the amine is then reacted with tetrahydrofurfurazine to generate alfuzosin hydrochloride, and the alfuzosin hydrochloride is obtained by treatment with hydrochloric acid. In the method, 80Kg of pressure needs to be applied at 70 ℃ when Raney nickel is subjected to catalytic hydrogenation reduction, so that the method is not suitable for industrial amplification; the alfuzosin hydrochloride is recrystallized in a mixture of ethanol and ether, and the ether solvent has low boiling point, is inflammable and explosive and has low safety, so the alfuzosin hydrochloride is not suitable for industrial scale-up production; the use of highly toxic potassium cyanate has adverse effects on both the environment and personnel. The reaction route is as follows:
subsequent patents such as US2007105880, WO2008114272, WO2007074364 and the like all include a cyano reduction process, and are catalyzed by metal (such as rhodium and nickel) under high temperature and high pressure conditions, so that the reaction conditions are severe, the requirements on equipment are high, and the large-scale industrial production is difficult to realize.
A synthesis of[14C]The key intermediate 6, 7-dimethoxy-quinazoline-2, 4-diketone is synthesized by using virulent potassium cyanate, so that the operation risk is high, and certain influence is caused on both environment and people. The reaction route is as follows:
an improved and commercially viable process for the preparation of Alfuzosin hydrochloride, Journal of Arkivoc,2007,13:41-46. the synthetic route for Alfuzosin is also reported, as follows: firstly, under the catalysis of sulfuric acid, 2-tetrahydrofuran formic acid and methanol are subjected to esterification reaction to obtain 2-tetrahydrofuran methyl formate, then the 2-tetrahydrofuran methyl formate reacts with 3-methylaminopropylamine to obtain N- (3-methylaminopropyl) tetrahydrofuran-2-formamide, then the N- (3-methylaminopropyl) tetrahydrofuran-2-formamide reacts with 2-chloro-4-amino-6, 7-dimethoxyquinazoline, and finally alfuzosin hydrochloride is obtained after acidification. In the method, although the 3-methylaminopropylamine is respectively primary amine and secondary amine, the steric hindrance of the secondary amine (methylamino) is not large, so that the activity of the secondary amine (methylamino) is almost the same, the reaction selectivity in the step is poor, side reactions are generated, and the product quality and the yield are influenced. The reaction route is as follows:
CN101687859A takes alfuzosin as a raw material, reacts with an activating reagent to prepare a diamine compound N- [3- [ (4-acyl/aroyl substituted amino-6, 7-dimethoxy-2-quinazolinyl) methylamino ] propyl ] tetrahydro-2-furancarboxamide, then reacts with 2-tetrahydrofuran formic acid in the presence of N, N-carbonyl diimidazole to obtain free alkali of alfuzosin, then reacts with an acylating reagent to obtain N-acyl alfuzosin, and is hydrolyzed to obtain alfuzosin hydrochloride. The process takes alfuzosin as a raw material, but in the process of synthesizing the alfuzosin, a step of reducing cyano groups into amino groups still exists, and meanwhile, a flammable Raney nickel catalyst is used and is carried out under the conditions of high temperature and high pressure, so that the process has high requirements on equipment and high danger, and is not suitable for industrial production.
In conclusion, it is necessary to improve the synthesis process and conditions of alfuzosin hydrochloride and to explore a preparation method of alfuzosin hydrochloride with simple operation, high purity and high yield.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an alfuzosin hydrochloride intermediate compound I and a new route for synthesizing alfuzosin hydrochloride by using the same, which has the advantages of simple and safe operation, low cost, high yield and high purity, and is suitable for large-scale industrial production.
The specific technical scheme of the invention is as follows:
an alfuzosin hydrochloride intermediate compound represented by formula I:
a preparation method of an alfuzosin hydrochloride intermediate compound shown in a formula I comprises the following steps: sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline and 1, 3-propane diamine into an organic solvent, controlling the temperature to react, obtaining hydrochloride of an intermediate compound I after the reaction is finished, and carrying out alkali treatment to obtain the intermediate compound I, wherein the reaction route is as follows:
preferably, the organic solvent is selected from one or more of isopropanol, diglyme, N-dimethylformamide, N-dimethylacetamide, tert-butanol and hexamethylphosphoramide; further preferred is N, N-dimethylacetamide.
Preferably, the temperature-controlled reaction temperature is 80-120 ℃; further preferably 100 ℃.
Preferably, the feeding molar ratio of the 2-chloro-4-amino-6, 7-dimethoxyquinazoline to the 1, 3-propanediamine is 1: 1.1 to 1.5; more preferably 1: 1.2.
preferably, the mass volume ratio of the 2-chloro-4-amino-6, 7-dimethoxyquinazoline to the organic solvent is 1: 4-7, wherein the mass is in g and the volume is in ml.
In a preferable scheme, after the 2-chloro-4-amino-6, 7-dimethoxyquinazoline and 1, 3-propane diamine are reacted, the temperature is reduced to room temperature, and the intermediate compound I hydrochloride is obtained by suction filtration.
In a preferred embodiment, the alkali treatment process is as follows: adding the intermediate compound I hydrochloride into water, heating to 70-80 ℃, stirring until the solid is completely dissolved, dropwise adding a 30% sodium hydroxide solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring for 2-3 h for crystallization, starting suction filtration, leaching a filter cake with purified water until the pH value of filtrate is equal to 7, and drying the filter cake to obtain the intermediate compound I.
The application of the alfuzosin hydrochloride intermediate compound I in preparing alfuzosin hydrochloride.
A method for preparing alfuzosin hydrochloride by an alfuzosin hydrochloride intermediate compound I comprises the following steps: 1) under the alkaline condition, adding the intermediate compound I into an organic solvent, then dropwise adding 2-tetrahydrofuran formyl chloride, controlling the temperature to react, and obtaining an intermediate compound II after the reaction is finished; 2) under the alkaline condition, sequentially adding the intermediate II and methyl iodide into an organic solvent, controlling the temperature to react, and obtaining alfuzosin after the reaction is finished; 3) dissolving alfuzosin in an organic solvent, dropwise adding a hydrochloric acid-alcohol solution, and obtaining alfuzosin hydrochloride after the reaction is finished, wherein the reaction route is as follows:
preferably, the method for preparing alfuzosin hydrochloride from the alfuzosin hydrochloride intermediate compound I comprises the following steps: 1) under the alkaline condition, adding the intermediate compound I into an organic solvent, stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride, controlling the temperature to react, and obtaining an intermediate compound II after the reaction is finished; 2) under the alkaline condition, sequentially adding the intermediate compound II and methyl iodide into an organic solvent, controlling the temperature to react, and obtaining alfuzosin after the reaction is finished; 3) adding alfuzosin into an organic solvent, heating until the alfuzosin is completely dissolved, dropwise adding a hydrochloric acid-alcohol solution at a controlled temperature, carrying out heat preservation reaction, cooling and crystallizing after the reaction is finished, carrying out suction filtration, and drying to obtain the alfuzosin hydrochloride.
Preferably, the alkaline condition in step 1) is the addition of an organic base or an inorganic base.
Further preferably, the organic base is selected from one or more of triethylamine, DIPEA, imidazole, DBU, piperazine and DMAP; the inorganic base is one or more selected from potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide; further preferred is triethylamine.
Preferably, the organic solvent in step 1) is selected from one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide; more preferably dichloromethane or tetrahydrofuran.
Preferably, the feeding molar ratio of the intermediate compound I to the 2-tetrahydrofuran formyl chloride and the alkali in the step 1) is 1: 1.1-1.5: 1.2 to 1.8; more preferably 1: 1.2:1.5.
Preferably, the mass-to-volume ratio of the intermediate compound I to the organic solvent in the step 1) is 1: 3-6, wherein the mass is in g and the volume is in ml.
Preferably, the temperature-controlled reaction temperature in the step 1) is 20-30 ℃; further preferably 25 ℃.
In a preferred embodiment, the post-treatment step in step 1) is: and after the reaction is finished, carrying out suction filtration and rotary evaporation, then adding ethanol for crystallization, and after the crystallization is finished, carrying out suction filtration to obtain a white solid intermediate compound II.
Preferably, the organic solvent in step 2) is selected from one or more of diglyme, N-dimethylformamide, N-dimethylacetamide and tetrahydrofuran; further preferred is tetrahydrofuran.
Preferably, the alkaline condition in step 2) is the addition of an organic base or an inorganic base.
Further preferably, the organic base is selected from one or more of DIPEA, imidazole, DBU, piperazine, DMAP; the inorganic base is one or more selected from potassium carbonate, sodium carbonate and sodium bicarbonate.
Preferably, the feeding molar ratio of the intermediate compound II, methyl iodide and the base in the step 2) is 1: 1.1-1.5: 1.1 to 1.5; further preferably 1:1.2: 1.2.
Preferably, the mass-to-volume ratio of the intermediate compound II to the organic solvent in the step 2) is 1: 3-6, wherein the mass is in g and the volume is in ml.
Preferably, the temperature-controlled reaction temperature in the step 2) is 40-45 ℃.
In a preferred embodiment, the post-treatment step in step 2) is: and after the reaction is finished, filtering, distilling under reduced pressure, then adding a saturated sodium carbonate solution for washing, extracting by using dichloromethane, carrying out rotary evaporation, adding methanol for crystallization, filtering after crystallization is finished, and drying to obtain the alfuzosin.
Preferably, the organic solvent in step 3) is selected from one or more of methanol and ethanol.
Preferably, the hydrochloric acid-alcohol solution in the step 3) is selected from one or a combination of hydrochloric acid methanol and hydrochloric acid ethanol solution; further preferably a hydrochloric acid ethanol solution; the concentration of the hydrochloric acid alcohol solution is preferably 30%.
Preferably, the mass-to-volume ratio of alfuzosin to organic solvent in step 3) is 1: 8-12, wherein the mass is in g and the volume is in ml.
Preferably, the mass ratio of alfuzosin to the hydrochloric acid-alcohol solution in step 3) is 1: 0.4 to 0.8.
In a preferable scheme, the heating and dissolving temperature in the step 3) is a temperature for completely dissolving the alfuzosin in the organic solvent, and the heating and dissolving temperature can be up to reflux for the purpose of dissolving.
Preferably, the temperature of dropwise adding the hydrochloric acid-alcohol solution is controlled to be 40-50 ℃.
Compared with the prior art, the invention provides a novel alfuzosin hydrochloride intermediate compound I and a route for synthesizing alfuzosin hydrochloride by using the intermediate. The intermediate compound is simple and easy to synthesize and control, 1, 3-propane diamine is used for replacing 3-methyl propionitrile commonly used in the alfuzosin hydrochloride synthesis process, the activity of two amino groups is consistent, the selectivity problem is avoided, side reactions are few, and the high-temperature high-pressure reaction of cyano reduction is avoided; the alfuzosin hydrochloride prepared by utilizing the intermediate is simple and convenient to operate, safe, low in cost, high in yield and purity and suitable for large-scale industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of an alfuzosin hydrochloride intermediate compound I is confirmed as follows:
ESI-MS m/z：278.1[M+H]+；
1H NMR(CDCl3)：δ7.69(s,1H,Ar-H),7.58(s,1H,Ar-H),7.03(t,1H,CNH),4.01(s,3H, OCH3),3.98(s,3H,OCH3),3.40(m,2H,NHCH2),2.70(m,2H,NH2CH2),1.86(m,2H,CH2) 1.60(m,2H,NH2)；
13C NMR(CDCl3)：δ176.3,161.9,157.6,146.5,146.3,105.9,104.7,98.0,56.1(2C)39.4 (2C),31.5。
preparation of alfuzosin hydrochloride intermediate compound I
Example 1
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mmol) and 1, 3-propanediamine (8.89g, 0.12mol) into N, N-dimethylformamide (120ml), heating to 100 ℃ for reaction, completely detecting by TLC, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the filtrate is equal to 7, drying the filter cake after leaching is finished, and obtaining 26.60g of the white solid intermediate compound I with the yield of 95.91% and the purity of 99.63%.
Example 2
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (8.15g, 0.11mol) into isopropanol (120ml), heating to 80 ℃ for reaction, detecting by TLC (thin layer chromatography) for complete reaction, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 25.72g of the white solid intermediate compound I, wherein the yield is 92.74% and the purity is 99.34%.
Example 3
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (11.12g, 0.15mol) into diglyme (120ml), heating to 120 ℃ for reaction, detecting by TLC (thin layer chromatography) for complete reaction, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake to obtain 25.49g of the white solid intermediate compound I, wherein the yield is 91.91% and the purity is 99.12%.
Example 4
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (9.64g, 0.13mol) into N, N-dimethylformamide (100ml), heating to 90 ℃ for reaction, completely detecting by TLC, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 26.21g of the white solid intermediate compound I, wherein the yield is 94.51% and the purity is 99.50%.
Example 5
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (10.38g, 0.14mol) into N, N-dimethylacetamide (120ml), heating to 100 ℃ for reaction, detecting by TLC (thin layer chromatography) to complete the reaction, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 2 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 26.09g of the white solid intermediate compound I, wherein the yield is 94.08% and the purity is 99.17%.
Example 6
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (11.12g, 0.15mol) into hexamethylphosphoramide (150ml), heating to 110 ℃ for reaction, detecting by TLC for complete reaction, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 26.02g of the white solid intermediate compound I, wherein the yield is 93.82% and the purity is 99.24%.
Example 7
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (12.60g, 0.17mol) into N, N-dimethylacetamide (120ml), heating to 100 ℃ for reaction, detecting by TLC (thin layer chromatography) to complete reaction, cooling to room temperature, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 25.25g of white solid intermediate compound I, wherein the yield is 91.05% and the purity is 99.01%.
Example 8
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (8.89g, 0.12mol) into tert-butyl alcohol (120ml), heating to 80 ℃ for reaction, detecting by TLC (thin layer chromatography) to completely react, and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 3 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake after the suction filtration to obtain 25.31g of the white solid intermediate compound I, wherein the yield is 91.26%, and the purity is 98.95%.
Example 9
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline (24.00g, 0.10mol) and 1, 3-propanediamine (8.89g, 0.12mol) into N, N-dimethylformamide (120ml), heating to 130 ℃ for reaction, completely detecting by TLC (thin layer chromatography), and performing suction filtration to obtain a solid intermediate compound I hydrochloride; and then transferring the intermediate compound I hydrochloride into a reaction bottle, adding purified water (100ml), heating to 70-80 ℃, keeping the temperature and stirring until the solid is completely dissolved, dropwise adding a 30% NaOH solution, adjusting the pH value to 12-14, gradually separating out the solid, then closing the heating, cooling to 20-30 ℃, stirring and crystallizing for 2 hours, starting suction filtration, leaching the filter cake with the purified water until the pH value of the solution is 7, and drying the filter cake to obtain 25.05g of the white solid intermediate compound I with the yield of 90.33% and the purity of 99.18%.
Preparation of intermediate compound II
Example 10
Adding the intermediate compound I (27.73g, 0.10mol) and triethylamine (15.18g, 0.15mol) into dichloromethane (100ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (16.15g, 0.12mol), dropwise closing, carrying out temperature control reaction at 25 ℃, carrying out TLC detection reaction completely, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying, thus obtaining 35.05g of white solid intermediate compound II, wherein the yield is 93.36%.
Example 11
Adding the intermediate compound I (27.73g, 0.10mol) and DIPEA (15.51g, 0.12mol) into tetrahydrofuran (100ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (14.80g, 0.11mol), dropwise adding, controlling the temperature to react at 20 ℃, detecting by TLC to completely react, performing suction filtration and rotary evaporation, then adding ethanol (70ml) to perform crystallization, performing suction filtration and drying after the crystallization is finished, and obtaining 34.39g of white solid intermediate compound II with the yield of 91.60%.
Example 12
Adding the intermediate compound I (27.73g, 0.10mol) and DMAP (21.99g, 0.18mol) into N, N-dimethylformamide (150ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (20.18g, 0.15mol), dropwise closing, reacting at the temperature controlled at 30 ℃, completely reacting by TLC detection, performing suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, performing suction filtration and drying after crystallization is finished, thus obtaining 34.14g of a white solid intermediate compound II, wherein the yield is 90.94%.
Example 13
Adding the intermediate compound I (27.73g, 0.10mol) and potassium carbonate (24.88g, 0.18mol) into N, N-dimethylacetamide (100ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (16.15g, 0.12mol), dropwise closing, carrying out temperature control reaction at 25 ℃, carrying out TLC detection reaction to complete reaction, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying after crystallization is finished, thus obtaining 34.78g of a white solid intermediate compound II, wherein the yield is 92.64%.
Example 14
Adding the intermediate compound I (27.73g, 0.10mol) and sodium hydroxide (6.40g, 0.16mol) into dichloromethane (130ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (18.84g, 0.14mol), dropwise closing, carrying out temperature control reaction at 30 ℃, carrying out TLC detection reaction completely, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying, thus obtaining 34.36g of a white solid intermediate compound II with the yield of 91.52%.
Example 15
Adding the intermediate compound I (27.73g, 0.10mol) and potassium hydroxide (8.42g, 0.15mol) into dichloromethane (100ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (17.49g, 0.13mol), dropwise closing, carrying out temperature control reaction at 25 ℃, carrying out TLC detection reaction completely, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying, thus obtaining 34.19g of a white solid intermediate compound II with the yield of 91.07%.
Example 16
Adding the intermediate compound I (27.73g, 0.10mol) and triethylamine (10.12g, 0.10mol) into tetrahydrofuran (120ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (13.46g, 0.10mol), dropwise closing, carrying out temperature control reaction at 25 ℃, carrying out TLC detection reaction completely, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying to obtain 33.25g of white solid intermediate compound II, wherein the yield is 88.56%.
Example 17
Adding the intermediate compound I (27.73g, 0.10mol) and pyridine (11.86g, 0.15mol) into tetrahydrofuran (100ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (16.15g, 0.12mol), dropwise closing, carrying out temperature control reaction at 35 ℃, carrying out TLC detection reaction completely, carrying out suction filtration and rotary evaporation, then adding ethanol (70ml) for crystallization, carrying out suction filtration and drying to obtain 33.56g of white solid intermediate compound II, wherein the yield is 89.39%.
Preparation of alfuzosin
Example 18
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (8.52g, 0.06mol) and potassium carbonate (8.29g, 0.06mol) into tetrahydrofuran (70ml), controlling the temperature at 40 ℃ to react, detecting by TLC that the reaction is complete, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution to wash, extracting by dichloromethane (100ml multiplied by 3), rotary steaming, adding methanol (110ml) to crystallize, filtering, drying to obtain 17.75g alfuzosin, wherein the yield is 91.15%.
Example 19
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (7.81g, 0.055mol) and sodium carbonate (10.37g, 0.075mol) into diglyme (70ml), controlling the temperature at 45 ℃ to react, detecting the reaction by TLC to be complete, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution to wash, extracting by dichloromethane (100ml multiplied by 3), carrying out rotary evaporation, adding methanol (110ml) to crystallize, completing crystallization, filtering, drying, obtaining 17.40g alfuzosin, the yield is 89.36%.
Example 20
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (10.65g, 0.075mol) and DIPEA (7.11g, 0.055mol) into N, N-dimethylformamide (70ml), controlling the temperature at 45 ℃ for reaction, detecting the reaction by TLC to be complete, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution for washing, extracting by dichloromethane (100ml multiplied by 3), carrying out rotary evaporation, adding methanol (110ml) for crystallization, completing crystallization, filtering and drying to obtain 17.32g of alfuzosin, wherein the yield is 88.95%.
Example 21
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (9.94g, 0.07mol) and imidazole (4.42g, 0.065mol) into N, N-dimethylacetamide (90ml), controlling the temperature at 40 ℃ for reaction, detecting the reaction by TLC completely, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution for washing, extracting by dichloromethane (100ml multiplied by 3), carrying out rotary evaporation, adding methanol (110ml) for crystallization, carrying out crystallization, filtering, drying, obtaining 17.67g alfuzosin, wherein the yield is 90.74%.
Example 22
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (8.52g, 0.06mol) and potassium carbonate (8.29g, 0.06mol) into tetrahydrofuran (110ml), controlling the temperature at 55 ℃ to react, detecting by TLC that the reaction is complete, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution to wash, extracting by dichloromethane (100ml multiplied by 3), rotary steaming, adding methanol (110ml) to crystallize, filtering, drying to obtain 16.82g alfuzosin with the yield of 86.38%.
Example 23
Adding the intermediate compound II (18.77g, 0.05mol), methyl iodide (12.06g, 0.085mol) and piperazine (5.17g, 0.06mol) into tetrahydrofuran (90ml), carrying out temperature-controlled reaction at 40 ℃, detecting complete reaction by TLC, filtering, carrying out reduced pressure distillation, then adding saturated sodium carbonate solution for washing, extracting dichloromethane (100ml multiplied by 3), carrying out rotary evaporation, adding methanol (110ml) for crystallization, carrying out crystallization, filtering, drying, obtaining 17.14g alfuzosin, wherein the yield is 88.02%.
Preparation of alfuzosin hydrochloride
Example 24
Adding alfuzosin (21.45g, 0.05mol) into ethanol (200ml), controlling the temperature and refluxing, cooling to 45 ℃ after dissolution is finished, dropwise adding a hydrochloric acid-ethanol solution (8.58g) with the concentration of 30%, carrying out heat preservation reaction, cooling and crystallizing after TCL detection reaction is finished, carrying out crystallization, carrying out suction filtration and drying to obtain 20.30g of alfuzosin hydrochloride, wherein the yield is 95.33%, and the purity is 99.98%.
Example 25
Adding alfuzosin (21.45g, 0.05mol) into methanol (200ml), controlling the temperature and refluxing, cooling to 50 ℃ after dissolution is finished, dropwise adding a hydrochloric acid-methanol solution (17.16g) with the concentration of 30%, carrying out heat preservation reaction, cooling and crystallizing after TCL detection reaction is finished, carrying out crystallization, carrying out suction filtration and drying to obtain 20.18g of alfuzosin hydrochloride, wherein the yield is 94.76%, and the purity is 99.97%.
Example 26
Adding alfuzosin (21.45g, 0.05mol) into ethanol (200ml), controlling the temperature and refluxing, cooling to 40 ℃ after dissolution is finished, dropwise adding a hydrochloric acid-ethanol solution (12.87g) with the concentration of 30%, carrying out heat preservation reaction, cooling and crystallizing after TCL detection reaction is finished, carrying out crystallization, carrying out suction filtration and drying to obtain 20.25g of alfuzosin hydrochloride, wherein the yield is 95.09%, and the purity is 99.95%.
Example 27
Adding alfuzosin (21.45g, 0.05mol) into ethanol (250ml), controlling the temperature and refluxing, cooling to 45 ℃ after dissolution is finished, dropwise adding a hydrochloric acid-ethanol solution (6.44g) with the concentration of 30%, carrying out heat preservation reaction, cooling and crystallizing after TCL detection reaction is finished, carrying out crystallization, carrying out suction filtration and drying to obtain 20.07g of alfuzosin hydrochloride, wherein the yield is 94.25%, and the purity is 99.97%.
Claims (10)
1. An alfuzosin hydrochloride intermediate compound represented by the formula I:
2. a process for the preparation of alfuzosin hydrochloride intermediate compound i according to claim 1, characterized in that it comprises the following steps: sequentially adding 2-chloro-4-amino-6, 7-dimethoxyquinazoline and 1, 3-propane diamine into an organic solvent, controlling the temperature to react, obtaining hydrochloride of an intermediate compound I after the reaction is finished, and carrying out alkali treatment to obtain the intermediate compound I, wherein the reaction route is as follows:
3. the method for preparing the alfuzosin hydrochloride intermediate compound I as claimed in claim 2, wherein the temperature-controlled reaction temperature is 80-120 ℃.
4. The process for the preparation of alfuzosin hydrochloride intermediate compound i according to claim 3 wherein said organic solvent is selected from one or more of the group consisting of isopropanol, diglyme, N-dimethylformamide, N-dimethylacetamide, t-butanol, hexamethylphosphoramide.
5. Use of the alfuzosin hydrochloride intermediate compound i as defined in claim 1 for the preparation of alfuzosin hydrochloride.
6. A process for the preparation of alfuzosin hydrochloride from alfuzosin hydrochloride intermediate compound i as defined in claim 1, comprising the steps of: 1) under the alkaline condition, adding the intermediate compound I into an organic solvent, then dropwise adding 2-tetrahydrofuran formyl chloride, controlling the temperature to react, and obtaining an intermediate compound II after the reaction is finished; 2) under the alkaline condition, sequentially adding the intermediate II and methyl iodide into an organic solvent, controlling the temperature to react, and obtaining alfuzosin after the reaction is finished; 3) dissolving alfuzosin in an organic solvent, dropwise adding a hydrochloric acid-alcohol solution, and obtaining alfuzosin hydrochloride after the reaction is finished, wherein the reaction route is as follows:
7. the preparation method according to claim 6, wherein the temperature-controlled reaction temperature in step 1) is 20-30 ℃.
8. The preparation method according to claim 6, wherein the temperature-controlled reaction temperature in the step 2) is 40-45 ℃.
9. The method according to claim 6, wherein the basic conditions in steps 1) and 2) are the addition of an organic base or an inorganic base.
10. The method according to claim 6, wherein the hydrochloric acid-alcohol solution in step 3) is one selected from a hydrochloric acid-methanol solution and a hydrochloric acid-ethanol solution.
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| CN114674967A (en) * | 2022-03-25 | 2022-06-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Method for detecting related substances of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate |
| WO2023179068A1 (en) * | 2022-03-21 | 2023-09-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Drug intermediate and synthetic method, and isoquinoline derivative and synthetic method therefor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023179068A1 (en) * | 2022-03-21 | 2023-09-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Drug intermediate and synthetic method, and isoquinoline derivative and synthetic method therefor |
| CN114674967A (en) * | 2022-03-25 | 2022-06-28 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Method for detecting related substances of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate |
| CN114674967B (en) * | 2022-03-25 | 2022-10-04 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Method for detecting related substances of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate |
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