CN109651290B - Preparation method of mirabegron - Google Patents
Preparation method of mirabegron Download PDFInfo
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- CN109651290B CN109651290B CN201811283756.6A CN201811283756A CN109651290B CN 109651290 B CN109651290 B CN 109651290B CN 201811283756 A CN201811283756 A CN 201811283756A CN 109651290 B CN109651290 B CN 109651290B
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- mirabegron
- amino
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- reduction
- condensation
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- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 title claims abstract description 48
- 229960001551 mirabegron Drugs 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006722 reduction reaction Methods 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000009833 condensation Methods 0.000 claims abstract description 24
- 230000005494 condensation Effects 0.000 claims abstract description 24
- TUAHDMSPHZSMQN-INIZCTEOSA-N (1r)-2-[2-(4-aminophenyl)ethylamino]-1-phenylethanol Chemical compound C1=CC(N)=CC=C1CCNC[C@H](O)C1=CC=CC=C1 TUAHDMSPHZSMQN-INIZCTEOSA-N 0.000 claims abstract description 19
- 230000009467 reduction Effects 0.000 claims abstract description 17
- GXTZAIGFWQRDSQ-INIZCTEOSA-N (1r)-2-[2-(4-nitrophenyl)ethylamino]-1-phenylethanol Chemical compound C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C([N+]([O-])=O)C=C1 GXTZAIGFWQRDSQ-INIZCTEOSA-N 0.000 claims abstract description 14
- JMWPXJYTORPHOB-UHFFFAOYSA-N 2-(4-amino-1,3-thiazol-2-yl)acetic acid Chemical compound NC1=CSC(CC(O)=O)=N1 JMWPXJYTORPHOB-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 (4-nitrophenylethyl) amino Chemical group 0.000 claims abstract description 10
- NDXLKCBBPVHYSO-UHFFFAOYSA-N 2-(4-nitrophenyl)acetaldehyde Chemical compound [O-][N+](=O)C1=CC=C(CC=O)C=C1 NDXLKCBBPVHYSO-UHFFFAOYSA-N 0.000 claims abstract description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000011946 reduction process Methods 0.000 claims description 3
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- PXNJGLAVKOXITN-UHFFFAOYSA-N 2-(4-nitrophenyl)acetonitrile Chemical compound [O-][N+](=O)C1=CC=C(CC#N)C=C1 PXNJGLAVKOXITN-UHFFFAOYSA-N 0.000 description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- AWMVMTVKBNGEAK-QMMMGPOBSA-N (R)-styrene oxide Chemical compound C1O[C@@H]1C1=CC=CC=C1 AWMVMTVKBNGEAK-QMMMGPOBSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- LNJUVOPKIUQOQK-UHFFFAOYSA-N (4-nitrophenyl)azanium;chloride Chemical compound Cl.NC1=CC=C([N+]([O-])=O)C=C1 LNJUVOPKIUQOQK-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- QXHDYMUPPXAMPQ-UHFFFAOYSA-N 2-(4-aminophenyl)ethanol Chemical compound NC1=CC=C(CCO)C=C1 QXHDYMUPPXAMPQ-UHFFFAOYSA-N 0.000 description 1
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 102000012367 Beta 3 adrenoceptor Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 108040005346 beta3-adrenergic receptor activity proteins Proteins 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Abstract
The invention discloses a preparation method of mirabegron, which comprises the following steps: s1, carrying out reduction reaction on p-nitroacetonitrile to obtain p-nitroacetophenol; s2, performing condensation reduction on p-nitrophenylacetaldehyde and (R) -2-amino-1-phenylethyl alcohol to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol; s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol; s4, condensing (R) -2- ((4-aminophenethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid to obtain the mirabegron. The preparation method of mirabegron provided by the invention has the advantages of cheap and easily-obtained starting materials, controllable reaction conditions, few steps of synthetic route, high yield, low cost and high purity of the prepared mirabegron.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of mirabegron.
Background
Mirabegron is developed by astela pharmaceutical company (astella) of japan, and the pharmaceutical company, japan, 1997, 10, 17, applied for the compound patent of mirabegron, protected the preparation method thereof, and currently applied for patent protection in several countries and regions, such as the united states, europe, and china, 2011, 9, 16, mirabegron is marketed in japan, 2012, 6, and approved by the U.S. FDA in the united states. The successful marketing of mirabegron, the first orally effective beta 3 adrenoceptor agonist drug for the treatment of overactive bladder, fills the gap in the treatment of overactive bladder with beta adrenoceptor agonists.
The currently disclosed synthetic routes mainly include the following:
the first synthetic route is as follows: patent WO9920607A1 reports a synthesis method using R-styrene oxide as a starting material, in the method, p-nitrophenylethylamine and R-styrene oxide are subjected to ring opening reaction firstly, secondary amine is protected by a protective agent, palladium-carbon catalytic reduction is performed, and finally mirabegron is obtained through condensation and deprotection.
This route is the earliest synthetic route for mirabegron. The route requires multiple steps for column chromatography separation, and has the advantages of long steps, low yield, high cost and difficulty in realizing industrial production.
The second synthetic route is as follows: patent WO2015044965A1 reports a synthesis method of mirabegron, which takes R-mandelic acid as a starting material, and obtains the mirabegron by condensation with p-nitroaniline hydrochloride, reduction of amide carbonyl by a borane-tetrahydrofuran system, catalytic reduction of nitro by palladium-carbon and condensation with aminothiazole acetic acid.
The mirabegron is obtained by four-step reaction in the route, which seems to be an industrialized route with a wide prospect, but the reaction uses a condensation reagent with high price, uses borane with high toxicity and high risk, uses the condensation reagent EDCl twice, has high cost, and is difficult to realize industrialized large-scale production.
The third synthetic route is as follows: chinese patent CN103232352A reports a synthetic route using p-aminophenylethanol as a starting material, which is subjected to amino protection, alcohol oxidation, condensation, reduction, deprotection, and finally condensation with aminothiazole acetic acid to obtain mirabegron.
The route is a brand new route, but the route uses potassium permanganate with high pollution by oxidation, and the starting raw materials are not easy to obtain, so that the industrial production is difficult to realize.
As can be seen from the above review, the current synthesis of mirabegron has a broad prospect because the synthesis route is too long and the yield is low, or because expensive reagents are used and the cost is high, or because the starting materials which are difficult to obtain are used, so that the industrial production is difficult to realize.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a preparation method of mirabegron.
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, carrying out reduction reaction on p-nitroacetonitrile to obtain p-nitroacetophenol;
s2, performing condensation reduction on p-nitrophenylacetaldehyde and (R) -2-amino-1-phenylethyl alcohol to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol;
s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol;
s4, condensing (R) -2- ((4-aminophenethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid to obtain the mirabegron.
Preferably, in S1, diisobutyl aluminum hydride is used as a reducing agent in the reduction reaction, and the molar ratio of diisobutyl aluminum hydride to p-nitrophenylacetonitrile is 1.1-1.5: 1.
Preferably, in S1, the molar ratio of diisobutylaluminum hydride to p-nitrophenylacetonitrile is 1.2: 1.
Preferably, in S2, the condensation reduction temperature is-78 ℃ to 50 ℃.
Preferably, in S2, the condensation reduction temperature is 0-10 ℃.
Preferably, in S2, the condensation reduction temperature is-20 to 20 ℃.
Preferably, in S2, the condensation reduction temperature is 0 ℃.
Preferably, in S2, at least one of diethylamine, triethylamine, pyridine, and 4-N, N-lutidine is used as a catalyst during the condensation reaction.
Preferably, triethylamine is selected as the catalyst in the condensation reaction in S2.
Preferably, in S2, at least one of sodium borohydride, potassium borohydride, and sodium triacetoxyborohydride is used as a reducing agent in the condensation reduction process; preferably, sodium borohydride is used as a reducing agent in the condensation reduction process.
Preferably, in S3, the reaction system in the reduction reaction is an ammonium formate-Pd/C system.
Preferably, in S3, the reduction reaction temperature is 10-65 ℃.
Preferably, in S3, the reduction reaction temperature is 55 ℃.
Preferably, in S3, the reduction reaction time is 2-8 hours; preferably, the reduction reaction time is 6 hours.
Preferably, in S4, 4-dimethylaminopyridine is used as a catalyst in the condensation reaction.
The invention has the beneficial effects that:
the invention is a brand new synthetic route, the synthetic route is short, cheap and easily available p-nitroacetonitrile is used as an initial raw material, over-temperature and cheap diisobutyl aluminum hydride is reduced, the reaction yield is high, the purity is high, an amine alkylate is obtained by adopting a Schiff base mode, boron trifluoride ether with certain corrosivity is avoided, nitro is reduced by catalysis of green ammonium formate on palladium-carbon, and finally the mirabegron is obtained by condensation. The mirabegron prepared by the method has the advantages of high purity, few steps, low cost, mild and controllable conditions, simple and convenient operation, suitability for industrial production, wide market prospect and industrial application value.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, carrying out reduction reaction on p-nitroacetonitrile to obtain p-nitroacetophenol;
s2, performing condensation reduction on p-nitrophenylacetaldehyde and (R) -2-amino-1-phenylethyl alcohol to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol;
s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol;
s4, condensing (R) -2- ((4-aminophenethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid to obtain the mirabegron.
Example 2
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, carrying out reduction reaction on the p-nitroacetonitrile by using diisobutylaluminum hydride as a reduction reagent to obtain p-nitroacetophenone; wherein the molar ratio of diisobutylaluminum hydride to p-nitrophenylacetonitrile is 1.1: 1;
s2, using diethylamine and 4-N, N-dimethylpyridine as catalysts, and carrying out condensation reduction on p-nitroacetophenol and (R) -2-amino-1-phenethyl alcohol through potassium borohydride, wherein the condensation reduction temperature is-78 ℃, so as to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol;
s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol; wherein the reaction system in the reduction reaction is an ammonium formate-Pd/C system; the reduction reaction temperature is 10 ℃, and the reduction reaction time is 8 hours;
s4, condensing (R) -2- ((4-aminophenyl ethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid by using 4-dimethylamino pyridine as a catalyst to obtain the mirabegron.
Example 3
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, carrying out reduction reaction on the p-nitroacetonitrile by using diisobutylaluminum hydride as a reduction reagent to obtain p-nitroacetophenone; wherein the molar ratio of diisobutylaluminum hydride to p-nitrophenylacetonitrile is 1.5: 1;
s2, using pyridine as a catalyst, and carrying out condensation reduction on p-nitroacetophenol and (R) -2-amino-1-phenylethyl alcohol by sodium triacetoxyborohydride, wherein the condensation reduction temperature is 50 ℃ to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol;
s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol; wherein the reaction system in the reduction reaction is an ammonium formate-Pd/C system; the reduction reaction temperature is 65 ℃, and the reduction reaction time is 2 hours;
s4, condensing (R) -2- ((4-aminophenyl ethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid by using 4-dimethylamino pyridine as a catalyst to obtain the mirabegron.
Example 4
The invention provides a preparation method of mirabegron, which comprises the following synthetic route:
the method comprises the following steps:
s1, synthesis of p-nitroacetophenone (MB-03):
under the protection of nitrogen, sequentially adding 2000mL of toluene and 300g (1.85mol, 1.0eq) of p-nitroacetonitrile into a 5000mL four-neck flask with a mechanical stirrer, reducing the temperature of a reaction system to 0 ℃, slowly dropwise adding 2220mL (2.22mol, 1.2eq) of diisobutylaluminum hydride (DIBAL-H) toluene solution of 1.0mol/L, controlling the temperature of the reaction system to be 10 ℃, continuously stirring for 2 hours after dropwise adding is finished, pouring the reaction solution into 5 wt% of dilute hydrochloric acid, extracting with toluene, drying and concentrating to obtain 284g of p-nitroacetaldehyde, wherein the yield is 92%, and the purity is 99.3%;
synthesis of S2, (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol (MB-04):
under the protection of nitrogen, 2000mL of methanol, 280g (1.7mol, 1.1eq) of p-nitroacetophenol, (1.7mol, 1.1eq) of (R) -2-amino-1-phenethyl alcohol and 205g (2.03mol, 1.2eq) of triethylamine are sequentially added into a 5000mL four-neck flask with a mechanical stirrer, the mixture is stirred for 2 hours at room temperature, the temperature of a reaction system is reduced to 0 ℃, 77g (2.03mol, 1.2eq) of sodium borohydride is slowly added in batches, the mixture is kept at 0 ℃ for reaction for 1 hour after the addition, sampling is carried out for HPLC detection, after the conversion of raw materials is completed, 500mL of water is added into the reaction system for quenching, extraction is carried out by dichloromethane, drying and concentration are carried out to obtain 427g of R-2- ((4-nitrobenzyl) amino) -1-phenylethanol, the purity of which is 98.4%, and the yield of 87%.
Synthesis of S3, (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol (MB-05):
in a 5000mL four-necked flask, 322g (1.0mol, 1.0eq) of (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol (MB-04), 3200mL of methanol, 315g (5.0mol,5.0eq) of ammonium formate, Pd/C16g (0.05meq) were added in one portion; heating to 50 ℃ for reaction for 6h, monitoring by HPLC that the reaction is completely converted, filtering, and concentrating the filtrate to dryness; adding 1500mL of water into the concentrated residue, adjusting pH to 10 with 10 wt% sodium hydroxide to precipitate a large amount of white solid, filtering the product, and drying to obtain 241g of off-white solid with yield of 94% and purity of 98.6%;
s4, synthesis of Mirabegron (MB):
in a 5000mL four-mouth reaction flask, 220g (0.86mol,1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 136g (0.86mol,1.0eq) of aminothiazole acetic acid were added to a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of 4-Dimethylaminopyridine (DMAP) were sequentially added under mechanical stirring, the mixture was stirred at room temperature for 6 hours, 10 wt% of sodium hydroxide was adjusted to pH 12, a large amount of solid was precipitated, a white-like solid was obtained by filtration, and 269g of white solid mirabegron was obtained by recrystallization from 800mL of isopropanol, the yield was 79%, and the purity was 99.6%.
Example 5
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, synthesis of p-nitroacetophenone:
under the protection of nitrogen, sequentially adding 2000mL of toluene and 300g (1.85mol, 1.0eq) of p-nitroacetonitrile into a 5000mL four-neck flask with a mechanical stirrer, reducing the temperature of a reaction system to 0 ℃, slowly dropwise adding 2780mL (2.78mol, 1.5eq) of diisobutylaluminum hydride (DIBAL-H) toluene solution of 1.0mol/L, controlling the temperature of the reaction system to be-10 ℃, continuously stirring for 3 hours after the dropwise addition is finished, pouring the reaction solution into 8 wt% of dilute hydrochloric acid, extracting by toluene, drying and concentrating to obtain p-nitroacetophenol;
s2 synthesis of (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol:
under the protection of nitrogen, 2000mL of methanol, 280g (1.7mol, 1.1eq) of p-nitroacetophenol, (1.7mol, 1.1eq) of (R) -2-amino-1-phenylethyl alcohol and 205g (2.03mol, 1.2eq) of triethylamine are sequentially added into a 5000mL four-neck flask with a mechanical stirrer, the mixture is stirred for 2 hours at room temperature, the temperature of a reaction system is reduced to 0 ℃, 77g (2.03mol, 1.2eq) of sodium borohydride is slowly added in batches, after the addition is finished, the mixture is kept at-10 ℃ for reaction for 1.5 hours, a sample is sampled for HPLC detection, after the conversion of raw materials is completed, 500mL of water is added into the reaction system for quenching, and the mixture is extracted by dichloromethane, dried and concentrated to obtain R-2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol.
S3 synthesis of (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol:
in a 5000mL four-necked flask, 322g (1.0mol, 1.0eq) of (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol (MB-04), 3200mL of methanol, 315g (5.0mol,5.0eq) of ammonium formate, Pd/C16g (0.05meq) were added in one portion; heating to 60 ℃ for reaction for 4h, monitoring by HPLC that the reaction conversion is complete, filtering, and concentrating the filtrate to dryness; adding 1500mL of water into the concentrated residue, adjusting the pH to 10 with 10 wt% of sodium hydroxide to precipitate a large amount of white solid, and filtering and drying the product to obtain a white-like solid;
s4, synthesis of Mirabegron (MB):
in a 5000mL four-mouth reaction bottle, 220g (0.86mol,1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 136g (0.86mol,1.0eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of 4-Dimethylaminopyridine (DMAP) are sequentially added under mechanical stirring, the mixture is stirred at room temperature for 6 hours, the pH value is adjusted to 12 by 10 wt% of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtering, and white solid mirabegron is obtained by recrystallization of 900mL isopropanol.
Example 6
The invention provides a preparation method of mirabegron, which comprises the following steps:
s1, synthesis of p-nitroacetophenone:
under the protection of nitrogen, sequentially adding 2000mL of toluene and 300g (1.85mol, 1.0eq) of p-nitroacetonitrile into a 5000mL four-neck flask with mechanical stirring, reducing the temperature of a reaction system to 0 ℃, slowly dropwise adding 2040mL (2.04mol, 1.1eq) of diisobutylaluminum hydride (DIBAL-H) toluene solution of 1.0mol/L, controlling the temperature of the reaction system to be 40 ℃, continuously stirring for 0.5H after the dropwise addition is finished, pouring the reaction solution into 5 wt% of dilute hydrochloric acid, extracting by toluene, drying and concentrating to obtain p-nitroacetophenol;
s2 synthesis of (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol:
under the protection of nitrogen, 2000mL of methanol, 280g (1.7mol, 1.1eq) of p-nitroacetophenol, (1.7mol, 1.1eq) of (R) -2-amino-1-phenylethyl alcohol and 205g (2.03mol, 1.2eq) of triethylamine are sequentially added into a 5000mL four-neck flask with a mechanical stirrer, the mixture is stirred for 2 hours at room temperature, the temperature of a reaction system is reduced to 0 ℃, 77g (2.03mol, 1.2eq) of sodium borohydride is slowly added in batches, after the addition is finished, the mixture is kept at 5 ℃ for reaction for 0.5 hour, a sample is sampled for HPLC detection, after the conversion of raw materials is completed, 500mL of water is added into the reaction system for quenching, and the mixture is extracted by dichloromethane, dried and concentrated to obtain R-2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol.
S3 synthesis of (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol:
in a 5000mL four-necked flask, 322g (1.0mol, 1.0eq) of (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol (MB-04), 3200mL of methanol, 315g (5.0mol,5.0eq) of ammonium formate, Pd/C16g (0.05meq) were added in one portion; heating to 15 ℃ for reaction for 7.5h, monitoring by HPLC that the reaction is completely converted, filtering, and concentrating the filtrate to dryness; adding 1500mL of water into the concentrated residue, adjusting the pH to 10 with 10 wt% of sodium hydroxide to precipitate a large amount of white solid, and filtering and drying the product to obtain a white-like solid;
s4, synthesis of Mirabegron (MB):
in a 5000mL four-mouth reaction bottle, 220g (0.86mol,1.0eq) of intermediate (R) -2- ((4-aminophenethyl) amino) -1-phenylethanol and 136g (0.86mol,1.0eq) of aminothiazole acetic acid are added into a reaction kettle, 100mL of concentrated hydrochloric acid and 52g (0.43mol,0.5eq) of 4-Dimethylaminopyridine (DMAP) are sequentially added under mechanical stirring, the mixture is stirred at room temperature for 6 hours, the pH value is adjusted to 12 by 10 wt% of sodium hydroxide, a large amount of solid is separated out, a white-like solid is obtained by filtering, and white solid mirabegron is obtained by recrystallization through 1000mL of isopropanol.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. The preparation method of mirabegron is characterized by comprising the following steps:
s1, carrying out reduction reaction on p-nitroacetonitrile to obtain p-nitroacetophenol;
s2, performing condensation reduction on p-nitrophenylacetaldehyde and (R) -2-amino-1-phenylethyl alcohol to obtain (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethyl alcohol;
s3, carrying out reduction reaction on (R) -2- ((4-nitrophenylethyl) amino) -1-phenylethanol to obtain an intermediate (R) -2- ((4-aminophenylethyl) amino) -1-phenylethanol;
s4, condensing (R) -2- ((4-aminophenethyl) amino) -1-phenyl ethanol and aminothiazole acetic acid to obtain the mirabegron.
2. The method for preparing mirabegron as claimed in claim 1, wherein diisobutylaluminum hydride is used as a reducing agent in the reduction reaction in S1, and the molar ratio of diisobutylaluminum hydride to p-nitroacetonitrile is 1.2: 1.
3. The method for producing mirabegron as claimed in claim 1 or 2, wherein the condensation reduction temperature in S2 is 0 to 10 ℃.
4. The method according to claim 1, wherein the condensation-reduction temperature in S2 is 0 ℃.
5. The method for preparing mirabegron as claimed in claim 1, wherein at least one of diethylamine, triethylamine, pyridine and 4-N, N-dimethylpyridine is used as a catalyst in the condensation reaction in S2.
6. The method for preparing mirabegron as claimed in claim 1, wherein sodium borohydride is used as a reducing agent in the condensation reduction process in S2.
7. The method according to claim 1, wherein the reaction system in the reduction reaction is ammonium formate-Pd/C system in S3.
8. The method according to claim 1, wherein the reduction reaction temperature in S3 is 55 ℃.
9. The method according to claim 1, wherein the reduction reaction time in S3 is 6 hours.
10. The method for preparing mirabegron as claimed in claim 1, wherein 4-dimethylaminopyridine is used as a catalyst in the condensation reaction in S4.
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| CN111440126B (en) * | 2020-04-03 | 2023-11-28 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of mirabegron |
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