CN113801069B - Alfuzosin hydrochloride intermediate compound - Google Patents
Alfuzosin hydrochloride intermediate compound Download PDFInfo
- Publication number
- CN113801069B CN113801069B CN202010542304.6A CN202010542304A CN113801069B CN 113801069 B CN113801069 B CN 113801069B CN 202010542304 A CN202010542304 A CN 202010542304A CN 113801069 B CN113801069 B CN 113801069B
- Authority
- CN
- China
- Prior art keywords
- intermediate compound
- reaction
- alfuzosin
- temperature
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 47
- 229960003103 alfuzosin hydrochloride Drugs 0.000 title claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 229960004607 alfuzosin Drugs 0.000 claims description 29
- 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 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 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
- 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
- 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
- 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 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 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 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
- UNIJBMUBHBAUET-UHFFFAOYSA-N 3-(methylamino)propanenitrile Chemical compound CNCCC#N UNIJBMUBHBAUET-UHFFFAOYSA-N 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 description 51
- 239000007787 solid Substances 0.000 description 47
- 238000002425 crystallisation Methods 0.000 description 41
- 230000008025 crystallization Effects 0.000 description 41
- 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
- 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 27
- 238000001816 cooling Methods 0.000 description 24
- 238000010438 heat treatment Methods 0.000 description 24
- 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 20
- 239000012065 filter cake Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000001514 detection method Methods 0.000 description 19
- 239000008213 purified water Substances 0.000 description 19
- 238000002390 rotary evaporation Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 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
- 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
- 230000001376 precipitating effect Effects 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
- ZVAKZVDJIUFFFP-UHFFFAOYSA-N 2-chlorooxolane Chemical compound ClC1CCCO1 ZVAKZVDJIUFFFP-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- 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
- -1 4-amino-6, 7-dimethoxy-2-quinazolinyl Chemical group 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 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
- 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
- 238000000605 extraction Methods 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 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
- 239000002585 base Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- QHJABUZHRJTCAR-UHFFFAOYSA-N n'-methylpropane-1,3-diamine Chemical compound CNCCCN QHJABUZHRJTCAR-UHFFFAOYSA-N 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- 150000003141 primary amines Chemical group 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 2
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KWNQIIMVPSMYEM-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinazoline-2,4-dione Chemical compound N1C(=O)NC(=O)C2=C1C=C(OC)C(OC)=C2 KWNQIIMVPSMYEM-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension 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
- 208000028938 Urination disease Diseases 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
- 239000002253 acid Substances 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
- 238000009835 boiling Methods 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
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007547 defect Effects 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
- 239000012458 free base Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011031 large-scale 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
- IXHZGHPQQTXOKV-UHFFFAOYSA-N methyl oxolane-2-carboxylate Chemical compound COC(=O)C1CCCO1 IXHZGHPQQTXOKV-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- AUXJTEANWWFSRR-UHFFFAOYSA-N n-[3-(methylamino)propyl]oxolane-2-carboxamide Chemical compound CNCCCNC(=O)C1CCCO1 AUXJTEANWWFSRR-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- GXHAENUAJYZNOA-UHFFFAOYSA-N oxolane-2-carboxamide Chemical compound NC(=O)C1CCCO1 GXHAENUAJYZNOA-UHFFFAOYSA-N 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
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 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
- 238000010025 steaming Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000004809 thin layer chromatography 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
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-propanediamine is used for replacing 3-methyl aminopropionitrile commonly used in the alfuzosin hydrochloride synthesis process, the activity of two amino groups is consistent, the selectivity problem is avoided, the side reaction is less, and the high-temperature high-pressure reaction of cyano reduction is avoided; the preparation of the alfuzosin hydrochloride by using the intermediate has the advantages of 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 (N- [3- (4-amino-6, 7-dimethoxy-2-quinazolinyl) methylamino ] propyl-tetrahydro-2-furancarboxamide hydrochloride), which is a quinazoline derivative, belongs to an alpha 1-adrenergic receptor antagonist, can be highly selectively combined with alpha 1-receptors such as prostate and prostatic capsule in a competitive manner, affects alpha 1-receptor mediated smooth muscle contraction, reduces urination disorder in benign prostatic hyperplasia patients, and improves the life quality of the patients. Alfuzosin hydrochloride was developed by the company san france, sonafil, 1988, and was first marketed in france, 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 disclosed in U.S. Pat. No. 3,182 at the earliest, veratric acid is used 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, which is reacted with 3-methylaminopropionitrile in isoamyl alcohol to generate N- (4-amino-6, 7-dimethoxy quinazoline-2-yl) -N-methyl-2-cyanoethylamine, then hydrogenation reduction is carried out to obtain amine in the presence of Raney nickel as a catalyst, and then the amine reacts with tetrahydrofurfuryl acid to generate alfuzosin, and hydrochloric acid is treated to obtain alfuzosin hydrochloride. In the method, 80Kg of pressure is required to be applied at 70 ℃ during Raney nickel catalytic hydrogenation reduction, so that the method is not suitable for industrial scale-up; the alfuzosin hydrochloride is recrystallized in a mixture of ethanol and ether, and the ether solvent has low multiple boiling points, is flammable and explosive and has low safety, so that the alfuzosin hydrochloride is not suitable for industrial large-scale production; the use of highly toxic potassium cyanate has adverse effects on the environment and personnel. The reaction route is as follows:
in the following patents, such as US2007105880, WO2008114272, WO2007074364, etc., the cyano reduction process is carried out under high temperature and high pressure conditions by metal (such as rhodium and nickel) catalysis, the reaction conditions are severe, the equipment requirements are high, and the large-scale industrial production is difficult to realize.
A synthesis of[ 14 C]The key intermediate 6, 7-dimethoxy-quinazoline-2, 4-dione is synthesized by using virulent potassium cyanate, and the method has great operational risk and has certain influence on the 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. Synthetic routes to alfuzosin are also reported, specifically as follows: firstly, under the catalysis of sulfuric acid, 2-tetrahydrofuranic acid and methanol undergo esterification reaction to obtain 2-tetrahydrofuranic acid methyl ester, then react with 3-methylaminopropylamine to obtain N- (3-methylaminopropyl) tetrahydrofuran-2-formamide, then react with 2-chloro-4-amino-6, 7-dimethoxy quinazoline, and acidify to obtain alfuzosin hydrochloride. In the method, although the 3-methylaminopropylamine is primary amine and secondary amine respectively, the steric hindrance of the secondary amine (methylamino) is small, so that the activities of the primary amine and the secondary amine are almost the same, the reaction selectivity is poor in the step, and side reactions occur mostly, so that the product quality and the yield are affected. The reaction route is as follows:
CN101687859A is prepared from alfuzosin by reacting 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 reacting with 2-tetrahydrofurancarboxylic acid in the presence of N, N-carbonyldiimidazole to obtain the free base of alfuzosin, then reacting with an acylating reagent to obtain N-acyl alfuzosin, and hydrolyzing to obtain alfuzosin hydrochloride. The process takes alfuzosin as a raw material, but in the process of synthesizing alfuzosin, the step of reducing cyano into amino is still carried out, meanwhile, a flammable Raney nickel catalyst is used, and the process is carried out under high-temperature and high-pressure conditions, so that the requirement on equipment is high, the danger is high, and the industrial production is not suitable.
In summary, 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 novel route for synthesizing alfuzosin hydrochloride by utilizing the intermediate, and the method has the advantages of simple and convenient operation, safety, low cost, high yield and purity, and is suitable for large-scale industrial production.
The specific technical scheme of the invention is as follows:
an alfuzosin hydrochloride intermediate compound shown in a formula I:
a process for the preparation of an alfuzosin hydrochloride intermediate compound of formula I comprising the steps of: sequentially adding 2-chloro-4-amino-6, 7-dimethoxy quinazoline and 1, 3-propane diamine into an organic solvent, controlling the temperature to react, and obtaining an intermediate compound I after the reaction is completed and the hydrochloride of the intermediate compound I is subjected to alkali treatment, wherein the reaction route is as follows:
preferably, the organic solvent is selected from one or more of isopropanol, diglyme, N-dimethylformamide, N-dimethylacetamide, tertiary butanol and hexamethylphosphoramide; n, N-dimethylacetamide is more preferable.
Preferably, the temperature-controlled reaction temperature is 80-120 ℃; further preferably 100 ℃.
Preferably, the feeding mole ratio of the 2-chloro-4-amino-6, 7-dimethoxy quinazoline to the 1, 3-propane diamine is 1:1.1 to 1.5; further preferably 1:1.2.
preferably, the mass volume ratio of the 2-chloro-4-amino-6, 7-dimethoxy quinazoline to the organic solvent is 1: 4-7, wherein the mass is in g and the volume is in ml.
In a preferred embodiment, the hydrochloride of intermediate compound I is obtained by cooling the reaction of 2-chloro-4-amino-6, 7-dimethoxyquinazoline and 1, 3-propanediamine to room temperature and suction filtration.
In a preferred embodiment, the alkali treatment process is: adding the hydrochloride of the intermediate compound I into water, heating to 70-80 ℃, stirring until the solid is completely dissolved, dripping a sodium hydroxide solution with the concentration of 30%, regulating the pH value to 12-14, gradually precipitating the solid, closing heating, cooling to 20-30 ℃, stirring for crystallizing for 2-3 hours, starting suction filtration, leaching a filter cake with purified water until the pH value of the filtrate is equal to 7, and drying the filter cake after leaching to obtain the intermediate compound I.
The application of the alfuzosin hydrochloride intermediate compound I in preparing alfuzosin hydrochloride is provided.
A method for preparing alfuzosin hydrochloride by using an alfuzosin hydrochloride intermediate compound I comprises the following steps: 1) Under alkaline condition, adding the intermediate compound I into an organic solvent, then dropwise adding 2-tetrahydrofuran formyl chloride, and performing temperature control reaction to obtain an intermediate compound II; 2) Under alkaline condition, sequentially adding the intermediate II and methyl iodide into an organic solvent, and performing temperature control reaction to obtain alfuzosin after the reaction is finished; 3) The alfuzosin is dissolved in an organic solvent, hydrochloric acid-alcohol solution is added dropwise, and the alfuzosin hydrochloride is obtained after the reaction is finished, wherein the reaction route is as follows:
preferably, the method for preparing the alfuzosin hydrochloride by using the alfuzosin hydrochloride intermediate compound I specifically comprises the following steps: 1) Under alkaline condition, adding the intermediate compound I into an organic solvent, stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride, performing temperature control reaction, and obtaining an intermediate compound II after the reaction is completed; 2) Under alkaline conditions, sequentially adding an intermediate compound II and methyl iodide into an organic solvent, and carrying out temperature control reaction to obtain alfuzosin after the reaction is finished; 3) Adding alfuzosin into an organic solvent, heating until the alfuzosin is completely dissolved, controlling Wen Dijia hydrochloric acid-alcohol solution, performing heat preservation reaction, cooling for crystallization after the reaction is finished, performing suction filtration, and drying to obtain alfuzosin hydrochloride.
Preferably, the alkaline condition in step 1) is the addition of an organic or inorganic base.
Further preferably, the organic base is selected from one or more of triethylamine, DIPEA, imidazole, DBU, piperazine, DMAP; the inorganic base is selected from one or more of 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, N-dimethylacetamide; further preferred is dichloromethane and tetrahydrofuran.
Preferably, the molar ratio of the intermediate compound I to the 2-tetrahydrofuranyl chloride to the base in step 1) is 1:1.1 to 1.5:1.2 to 1.8; further 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, rotary steaming, adding ethanol for crystallization, and carrying out suction filtration after the crystallization is finished to obtain the white solid intermediate compound II.
Preferably, the organic solvent in the step 2) is selected from one or more of diglyme, N-dimethylformamide, N-dimethylacetamide and tetrahydrofuran; tetrahydrofuran is further preferred.
Preferably, the alkaline condition in step 2) is the addition of an organic or inorganic base.
Further preferably, the organic base is selected from one or more of DIPEA, imidazole, DBU, piperazine, DMAP; the inorganic base is selected from one or more of potassium carbonate, sodium carbonate and sodium bicarbonate.
Preferably, the molar ratio of the intermediate compound ii, methyl iodide and base in step 2) is 1:1.1 to 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 step 2) is 40-45 ℃.
In a preferred embodiment, the post-treatment step in step 2) is: after the reaction is finished, filtering, distilling under reduced pressure, then adding saturated sodium carbonate solution for washing, extracting with dichloromethane, performing rotary evaporation, adding methanol for crystallization, filtering after crystallization is finished, and drying to obtain 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 step 3) is selected from one or a combination of hydrochloric acid methanol, hydrochloric acid ethanol solution; further preferred is ethanol hydrochloride solution; the concentration of the hydrochloric acid alcohol solution is preferably 30%.
Preferably, the mass-volume ratio of the alfuzosin to the organic solvent in the step 3) is 1: 8-12, wherein the mass is in g and the volume is in ml.
Preferably, in the step 3), the mass ratio of the alfuzosin to the hydrochloric acid-alcohol solution is 1:0.4 to 0.8.
In a preferred embodiment, the heating and dissolving temperature in step 3) is a temperature at which alfuzosin is completely dissolved in an organic solvent, and the heating and dissolving can be performed to reflux for the purpose of dissolution.
Preferably, the temperature of the Wen Dijia 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 control in synthesis, 1, 3-propanediamine is used for replacing 3-methyl aminopropionitrile commonly used in the alfuzosin hydrochloride synthesis process, two amino activities are consistent, the selectivity problem is avoided, the side reaction is less, and the high-temperature high-pressure reaction of cyano reduction is avoided; the preparation of the alfuzosin hydrochloride by using the intermediate has the advantages of simple and convenient operation, safety, low cost, high yield and purity, and suitability for large-scale industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The structure of the alfuzosin hydrochloride intermediate compound I is confirmed:
ESI-MS m/z：278.1[M+H] + ；
1 H NMR(CDCl 3 )：δ7.69(s,1H,Ar-H),7.58(s,1H,Ar-H),7.03(t,1H,CNH),4.01(s,3H, OCH 3 ),3.98(s,3H,OCH 3 ),3.40(m,2H,NHCH 2 ),2.70(m,2H,NH 2 CH 2 ),1.86(m,2H,CH 2 ) 1.60(m,2H,NH 2 )；
13 C NMR(CDCl 3 )：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
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mmol) and 1, 3-propane diamine (8.89 g,0.12 mol) are sequentially added into N, N-dimethyl formamide (120 ml), the temperature is raised to 100 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out, thus obtaining a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching a filter cake with the purified water until the pH value of the filtrate is 7, and drying the filter cake to obtain 26.60g of white solid intermediate compound I with the yield of 95.91% and the purity of 99.63%.
Example 2
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (8.15 g,0.11 mol) are sequentially added into isopropanol (120 ml), the temperature is raised to 80 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out to obtain a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 25.72g of white solid intermediate compound I with the yield of 92.74% and the purity of 99.34%.
Example 3
Sequentially adding 2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (11.12 g,0.15 mol) into diglyme (120 ml), heating to 120 ℃ for reaction, cooling to room temperature after TLC detection reaction is complete, and carrying out suction filtration to obtain a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 25.49g of white solid intermediate compound I with the yield of 91.91% and the purity of 99.12%.
Example 4
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (9.64 g,0.13 mol) are sequentially added into N, N-dimethyl formamide (100 ml), the temperature is increased to 90 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out, thus obtaining a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 26.21g of white solid intermediate compound I with the yield of 94.51% and the purity of 99.50%.
Example 5
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (10.38 g,0.14 mol) are sequentially added into N, N-dimethyl acetamide (120 ml), the temperature is raised to 100 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out, thus obtaining a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 2h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 26.09g of white solid intermediate compound I with the yield of 94.08% and the purity of 99.17%.
Example 6
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (11.12 g,0.15 mol) are sequentially added into hexamethylphosphoramide (150 ml), the temperature is raised to 110 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out to obtain a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 26.02g of white solid intermediate compound I with the yield of 93.82% and the purity of 99.24%.
Example 7
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (12.60 g,0.17 mol) are sequentially added into N, N-dimethyl acetamide (120 ml), the temperature is raised to 100 ℃ for reaction, TLC detection reaction is complete, the temperature is reduced to room temperature, and suction filtration is carried out, thus obtaining solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, 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 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
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (8.89 g,0.12 mol) are sequentially added into tertiary butanol (120 ml), the temperature is raised to 80 ℃ for reaction, TLC detection reaction is complete, and suction filtration is carried out to obtain a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 3h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 25.31g of white solid intermediate compound I, wherein the yield is 91.26% and the purity is 98.95%.
Example 9
2-chloro-4-amino-6, 7-dimethoxy quinazoline (24.00 g,0.10 mol) and 1, 3-propane diamine (8.89 g,0.12 mol) are sequentially added into N, N-dimethyl formamide (120 ml), the temperature is raised to 130 ℃ for reaction, TLC detection reaction is complete, and suction filtration is carried out to obtain a solid intermediate compound I hydrochloride; transferring the hydrochloride of the intermediate compound I into a reaction bottle, adding purified water (100 ml), heating to 70-80 ℃, keeping the temperature, stirring until the solid is completely dissolved, dripping 30% NaOH solution, adjusting the pH value to 12-14, gradually precipitating the solid, closing the heating, cooling to 20-30 ℃, stirring for crystallization for 2h, starting suction filtration, leaching the pH value of the filter cake with the purified water to 7, and drying the filter cake after suction filtration to obtain 25.05g of white solid intermediate compound I, wherein the yield is 90.33% and the purity is 99.18%.
Preparation of intermediate Compound II
Example 10
Intermediate compound I (27.73 g,0.10 mol) and triethylamine (15.18 g,0.15 mol) are added into dichloromethane (100 ml), stirred, cooled to-10-0 ℃, then 2-tetrahydrofuranyl chloride (16.15 g,0.12 mol) is added dropwise, the mixture is closed dropwise, the temperature is controlled at 25 ℃, TLC detection reaction is complete, suction filtration and rotary evaporation are carried out, ethanol (70 ml) is added for crystallization, after crystallization is completed, suction filtration and drying are carried out, and 35.05g of white solid intermediate compound II is obtained, and the yield is 93.36%.
Example 11
Adding an intermediate compound I (27.73 g,0.10 mol) and DIPEA (15.51 g,0.12 mol) into tetrahydrofuran (100 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuranyl chloride (14.80 g,0.11 mol), dropwise closing, performing temperature control reaction at 20 ℃, completely detecting by TLC, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration after crystallization, and drying to obtain 34.39g of white solid intermediate compound II, wherein the yield is 91.60%.
Example 12
Intermediate compound I (27.73 g,0.10 mol) and DMAP (21.99 g,0.18 mol) are added into N, N-dimethylformamide (150 ml), stirred, cooled to-10-0 ℃, then 2-tetrahydrofuranyl chloride (20.18 g,0.15 mol) is added dropwise, the mixture is closed dropwise, the temperature is controlled at 30 ℃, TLC detection reaction is complete, suction filtration and rotary evaporation are carried out, ethanol (70 ml) is added for crystallization, suction filtration and drying are carried out after crystallization is completed, and 34.14g of white solid intermediate compound II is obtained, and the yield is 90.94%.
Example 13
Adding an intermediate compound I (27.73 g,0.10 mol) and potassium carbonate (24.88 g,0.18 mol) into N, N-dimethylacetamide (100 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuranyl chloride (16.15 g,0.12 mol), dropwise closing, performing temperature control reaction at 25 ℃, performing TLC detection, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration after crystallization, and drying to obtain 34.78g of a white solid intermediate compound II, wherein the yield is 92.64%.
Example 14
Adding an intermediate compound I (27.73 g,0.10 mol) and sodium hydroxide (6.40 g,0.16 mol) into dichloromethane (130 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuranyl chloride (18.84 g,0.14 mol), dropwise closing, performing temperature control reaction at 30 ℃, completely detecting by TLC, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration after crystallization, and drying to obtain 34.36g of white solid intermediate compound II, wherein the yield is 91.52%.
Example 15
Adding an intermediate compound I (27.73 g,0.10 mol) and potassium hydroxide (8.42 g,0.15 mol) into dichloromethane (100 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuran formyl chloride (17.49 g,0.13 mol), dropwise closing, performing temperature control reaction at 25 ℃, completely detecting by TLC, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration after crystallization, and drying to obtain 34.19g of white solid intermediate compound II, wherein the yield is 91.07%.
Example 16
Adding an intermediate compound I (27.73 g,0.10 mol) and triethylamine (10.12 g,0.10 mol) into tetrahydrofuran (120 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuranyl chloride (13.46 g,0.10 mol), dropwise closing, performing temperature control reaction at 25 ℃, completely detecting by TLC, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration, and drying to obtain 33.25g of white solid intermediate compound II, wherein the yield is 88.56%.
Example 17
Adding an intermediate compound I (27.73 g,0.10 mol) and pyridine (11.86 g,0.15 mol) into tetrahydrofuran (100 ml), stirring, cooling to-10-0 ℃, then dropwise adding 2-tetrahydrofuranyl chloride (16.15 g,0.12 mol), dropwise closing, performing temperature control reaction at 35 ℃, detecting that the reaction is complete by TLC, performing suction filtration, performing rotary evaporation, adding ethanol (70 ml) for crystallization, performing suction filtration and drying after crystallization is finished, and obtaining 33.56g of white solid intermediate compound II, wherein the yield is 89.39%.
Preparation of alfuzosin
Example 18
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (8.52 g,0.06 mol) and potassium carbonate (8.29 g,0.06 mol) were added to tetrahydrofuran (70 ml), the reaction was controlled at 40℃and completed by TLC detection, filtration and distillation under reduced pressure, followed by washing with saturated sodium carbonate solution, extraction with methylene chloride (100 ml. Times.3), rotary evaporation, crystallization with methanol (110 ml) was completed, filtration and drying to give 17.75g of alfuzosin, yield 91.15%.
Example 19
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (7.81 g,0.055 mol) and sodium carbonate (10.37 g,0.075 mol) were added to diglyme (70 ml), the reaction was controlled at 45℃and completed, filtration and distillation under reduced pressure were performed, then saturated sodium carbonate solution was added for washing, dichloromethane (100 ml. Times.3) was extracted, rotary evaporation was performed, methanol (110 ml) was added for crystallization, and after completion of crystallization, filtration and drying were performed, 17.40g of alfuzosin was obtained, and the yield was 89.36%.
Example 20
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (10.65 g,0.075 mol) and DIPEA (7.11 g,0.055 mol) were added to N, N-dimethylformamide (70 ml), the reaction was controlled at 45℃and complete by TLC detection, filtration and distillation under reduced pressure, then washing with saturated sodium carbonate solution, extraction with methylene chloride (100 ml. Times.3), rotary evaporation, crystallization with methanol (110 ml) was carried out, filtration and drying were carried out to obtain 17.32g of alfuzosin, and the yield was 88.95%.
Example 21
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (9.94 g,0.07 mol) and imidazole (4.42 g,0.065 mol) were added to N, N-dimethylacetamide (90 ml), the reaction was controlled at 40℃and completed, the reaction was filtered and distilled under reduced pressure, then saturated sodium carbonate solution was added for washing, methylene chloride (100 ml. Times.3) was extracted, rotary distilled, methanol (110 ml) was added for crystallization, and after completion of crystallization, filtration and drying, 17.67g of alfuzosin was obtained, and the yield was 90.74%.
Example 22
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (8.52 g,0.06 mol) and potassium carbonate (8.29 g,0.06 mol) were added to tetrahydrofuran (110 ml), the reaction was controlled at 55℃and completed by TLC detection, filtration and distillation under reduced pressure, followed by washing with saturated sodium carbonate solution, extraction with methylene chloride (100 ml. Times.3), rotary evaporation, crystallization with methanol (110 ml) was completed, filtration and drying to give 16.82g of alfuzosin, yield 86.38%.
Example 23
Intermediate compound II (18.77 g,0.05 mol), methyl iodide (12.06 g,0.085 mol) and piperazine (5.17 g,0.06 mol) were added to tetrahydrofuran (90 ml), the reaction was controlled at 40℃and completed, the reaction was checked by TLC, filtration and distillation under reduced pressure, then washing with saturated sodium carbonate solution, extraction with methylene chloride (100 ml. Times.3), rotary evaporation, crystallization with methanol (110 ml) was completed, filtration and drying to give 17.14g of alfuzosin, yield 88.02%.
Preparation of alfuzosin hydrochloride
Example 24
Alfuzosin (21.45 g,0.05 mol) is added into ethanol (200 ml), temperature is controlled for reflux, the temperature is reduced to 45 ℃ after dissolution, 30% hydrochloric acid-ethanol solution (8.58 g) is added dropwise, the temperature is kept for reaction, TCL detection reaction is finished, cooling crystallization is finished, suction filtration is carried out, and drying is carried out, thus 20.30g of alfuzosin hydrochloride is obtained, the yield is 95.33%, and the purity is 99.98%.
Example 25
Alfuzosin (21.45 g,0.05 mol) is added into methanol (200 ml), temperature is controlled for reflux, the temperature is reduced to 50 ℃ after dissolution, 30% hydrochloric acid-methanol solution (17.16 g) is added dropwise for heat preservation reaction, TCL detection reaction is completed, cooling crystallization is completed, suction filtration is carried out, and drying is carried out, thus 20.18g of alfuzosin hydrochloride is obtained, the yield is 94.76%, and the purity is 99.97%.
Example 26
Alfuzosin (21.45 g,0.05 mol) is added into ethanol (200 ml), temperature is controlled for reflux, the temperature is reduced to 40 ℃ after dissolution, 30% hydrochloric acid-ethanol solution (12.87 g) is added dropwise for heat preservation reaction, TCL detection reaction is completed, cooling crystallization is completed, suction filtration is carried out, and drying is carried out, thus 20.25g of alfuzosin hydrochloride is obtained, the yield is 95.09%, and the purity is 99.95%.
Example 27
Alfuzosin (21.45 g,0.05 mol) is added into ethanol (250 ml), temperature is controlled for reflux, the temperature is reduced to 45 ℃ after dissolution, 30% hydrochloric acid-ethanol solution (6.44 g) is added dropwise, the temperature is kept for reaction, TCL detection reaction is finished, cooling crystallization is finished, suction filtration is carried out, and drying is carried out, thus obtaining 20.07g of alfuzosin hydrochloride with the yield of 94.25% and the purity of 99.97%.
Claims (9)
1. An alfuzosin hydrochloride intermediate compound shown in a formula I:
。
2. a process for the preparation of alfuzosin hydrochloride intermediate compound i according to claim 1, comprising the steps of: sequentially adding 2-chloro-4-amino-6, 7-dimethoxy quinazoline and 1, 3-propane diamine into an organic solvent, controlling the temperature to react, and obtaining an intermediate compound I after the reaction is completed and the hydrochloride of the intermediate compound I is subjected to alkali treatment, wherein the reaction route is as follows:
。
3. the method for preparing the alfuzosin hydrochloride intermediate compound I according to claim 2, wherein the temperature-controlled reaction temperature is 80-120 ℃.
4. A process for the preparation of alfuzosin hydrochloride intermediate compound i according to claim 3 wherein the organic solvent is selected from one or more of isopropanol, diglyme, N-dimethylformamide, N-dimethylacetamide, t-butanol, hexamethylphosphoramide.
5. Use of an alfuzosin hydrochloride intermediate compound i according to claim 1 for the preparation of alfuzosin hydrochloride, comprising the steps of: 1) Under alkaline condition, adding the intermediate compound I into an organic solvent, then dropwise adding 2-tetrahydrofuran formyl chloride, and performing temperature control reaction to obtain an intermediate compound II; 2) Under alkaline condition, sequentially adding the intermediate II and methyl iodide into an organic solvent, and performing temperature control reaction to obtain alfuzosin after the reaction is finished; 3) The alfuzosin is dissolved in an organic solvent, hydrochloric acid-alcohol solution is added dropwise, and the alfuzosin hydrochloride is obtained after the reaction is finished, wherein the reaction route is as follows:
。
6. the method according to claim 5, wherein the temperature-controlled reaction temperature in step 1) is 20-30 ℃.
7. The use according to claim 5, wherein the temperature-controlled reaction temperature in step 2) is 40-45 ℃.
8. The method according to claim 5, wherein the alkaline conditions in steps 1) and 2) are the addition of an organic or inorganic base.
9. The use according to claim 5, wherein the hydrochloric acid-alcohol solution in step 3) is selected from one of hydrochloric acid-methanol solution, hydrochloric acid-ethanol solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010542304.6A CN113801069B (en) | 2020-06-15 | 2020-06-15 | Alfuzosin hydrochloride intermediate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010542304.6A CN113801069B (en) | 2020-06-15 | 2020-06-15 | Alfuzosin hydrochloride intermediate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113801069A CN113801069A (en) | 2021-12-17 |
| CN113801069B true CN113801069B (en) | 2024-03-15 |
Family
ID=78944005
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010542304.6A Active CN113801069B (en) | 2020-06-15 | 2020-06-15 | Alfuzosin hydrochloride intermediate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113801069B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573506B (en) * | 2022-03-21 | 2022-09-30 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Drug intermediate and synthetic method thereof, isoquinoline derivative and synthetic method thereof |
| 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 |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2466462A2 (en) * | 1978-02-06 | 1981-04-10 | Synthelabo | Antihypertensive quinazoline derivs. - substd. by 2-acylamino: alkylamino group |
| US4315007A (en) * | 1978-02-06 | 1982-02-09 | Synthelabo | 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines |
| EP0875506A1 (en) * | 1997-05-01 | 1998-11-04 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy |
| CN1616438A (en) * | 2004-09-24 | 2005-05-18 | 鲁南制药股份有限公司 | Process for preparing alfuzosin hydrochloride |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| WO2009001369A1 (en) * | 2007-06-22 | 2008-12-31 | Alembic Limited | An improved process for the preparation of alfuzosin hydrochloride |
| CN101397296A (en) * | 2007-09-29 | 2009-04-01 | 仁合益康医药科技（天津）有限公司 | Levalfuzosin, preparation method and use thereof |
| CN106632280A (en) * | 2016-11-24 | 2017-05-10 | 辽宁可济药业有限公司 | Method for preparing alfuzosin hydrochloride |
| CN108003141A (en) * | 2017-08-08 | 2018-05-08 | 辽宁可济药业有限公司 | A kind of modified technique for preparing quinazoline ditosylate salt medicine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8716476B2 (en) * | 2007-08-02 | 2014-05-06 | Cipla Limited | Process for the preparation of alfuzosin hydrochloride |
-
2020
- 2020-06-15 CN CN202010542304.6A patent/CN113801069B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2466462A2 (en) * | 1978-02-06 | 1981-04-10 | Synthelabo | Antihypertensive quinazoline derivs. - substd. by 2-acylamino: alkylamino group |
| US4315007A (en) * | 1978-02-06 | 1982-02-09 | Synthelabo | 4-Amino-6,7-dimethoxyquinazol-2-yl alkylenediamines |
| EP0875506A1 (en) * | 1997-05-01 | 1998-11-04 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy |
| CN1616438A (en) * | 2004-09-24 | 2005-05-18 | 鲁南制药股份有限公司 | Process for preparing alfuzosin hydrochloride |
| WO2006090268A2 (en) * | 2005-02-28 | 2006-08-31 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alfuzosin and salts thereof and novel crystalline forms of alfuzosin |
| WO2009001369A1 (en) * | 2007-06-22 | 2008-12-31 | Alembic Limited | An improved process for the preparation of alfuzosin hydrochloride |
| CN101397296A (en) * | 2007-09-29 | 2009-04-01 | 仁合益康医药科技（天津）有限公司 | Levalfuzosin, preparation method and use thereof |
| CN106632280A (en) * | 2016-11-24 | 2017-05-10 | 辽宁可济药业有限公司 | Method for preparing alfuzosin hydrochloride |
| CN108003141A (en) * | 2017-08-08 | 2018-05-08 | 辽宁可济药业有限公司 | A kind of modified technique for preparing quinazoline ditosylate salt medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113801069A (en) | 2021-12-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10807953B2 (en) | Processes and intermediates for the preparation of Pimavanserin | |
| JP6061158B2 (en) | Synthesis intermediate of 6- (7-((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide, or a pharmaceutically acceptable salt thereof, and its use | |
| CN113801069B (en) | Alfuzosin hydrochloride intermediate compound | |
| CN109020881B (en) | Preparation method of apatinib | |
| AU2005289099A1 (en) | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide | |
| US8680277B2 (en) | Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same | |
| AU2008237749A1 (en) | Process for the preparation of gefitinib | |
| KR101114134B1 (en) | Process for the preparation of 4-3'-chloro-4'-fluoroanilino-7-methoxy-6-3-morpholinopropoxyquinazoline | |
| CN108623567A (en) | Ao Si replaces the preparation method of Buddhist nun | |
| CN109748902B (en) | Preparation method of erlotinib hydrochloride | |
| CN107337664A (en) | One koji Ge Lieting preparation method | |
| CN113698317A (en) | Synthetic method of apatamide, intermediate and synthetic method thereof | |
| TWI541235B (en) | Process of preparing a quinazoline derivative | |
| CN109721552B (en) | Preparation method of gefitinib | |
| WO2005028421A2 (en) | Process for the synthesis of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-ethoxy-quinoline-3-carbonitrile | |
| CN110483388B (en) | Preparation method of nicotinic acid derivative | |
| CN108409648B (en) | Preparation method of sorafenib tosylate related intermediate | |
| WO2004092129A1 (en) | New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate | |
| CN109503499A (en) | A kind of Fan get Ta Ni intermediate and preparation method thereof | |
| CN110452215A (en) | A kind of Ai Le replaces the preparation method of Buddhist nun for Buddhist nun's intermediate and Ai Le | |
| CN117567466B (en) | Preparation method of quinazoline derivative | |
| US10836751B2 (en) | Methods for preparing Nintedanib and intermediates thereof | |
| CN116478090A (en) | Preparation method of tivozanib key intermediate | |
| CN116589372A (en) | Synthesis method of Orientinib intermediate | |
| CN111662273A (en) | Preparation method of tyrosine kinase inhibitor AZD3759 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |