CN1683355A - Process for preparing DL-nebivolol and its hydrochloride - Google Patents
Process for preparing DL-nebivolol and its hydrochloride Download PDFInfo
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- CN1683355A CN1683355A CNA200510051266XA CN200510051266A CN1683355A CN 1683355 A CN1683355 A CN 1683355A CN A200510051266X A CNA200510051266X A CN A200510051266XA CN 200510051266 A CN200510051266 A CN 200510051266A CN 1683355 A CN1683355 A CN 1683355A
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- nebivolol
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- chromene
- dihydro
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- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 title claims abstract description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 238000001953 recrystallisation Methods 0.000 claims abstract description 10
- 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 abstract description 5
- 238000010956 selective crystallization Methods 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 229940068174 nebivolol hydrochloride Drugs 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 229960000619 nebivolol Drugs 0.000 claims description 45
- 239000012043 crude product Substances 0.000 claims description 41
- 238000002425 crystallisation Methods 0.000 claims description 40
- 230000008025 crystallization Effects 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 32
- 239000012267 brine Substances 0.000 claims description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 29
- 239000000047 product Substances 0.000 claims description 28
- 239000008367 deionised water Substances 0.000 claims description 23
- 229910021641 deionized water Inorganic materials 0.000 claims description 23
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 17
- 230000005494 condensation Effects 0.000 claims description 12
- 229910052745 lead Inorganic materials 0.000 claims description 12
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 claims description 11
- 238000009833 condensation Methods 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- SIAHEHVKQBIXGV-UHFFFAOYSA-N butyl(diethyl)silicon Chemical group CCCC[Si](CC)CC SIAHEHVKQBIXGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052759 nickel Inorganic materials 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 238000004904 shortening Methods 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 14
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 109
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000011521 glass Substances 0.000 description 28
- 229960004756 ethanol Drugs 0.000 description 27
- -1 benzo tetrahydropyrans Chemical class 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 238000005984 hydrogenation reaction Methods 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 239000012266 salt solution Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- XUPPZVPERJUUGU-UHFFFAOYSA-N CCCC[SiH](CC)CC.[O] Chemical group CCCC[SiH](CC)CC.[O] XUPPZVPERJUUGU-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000007530 Essential hypertension Diseases 0.000 description 3
- 239000002876 beta blocker Substances 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- BCEPTKBQFGPAIQ-UHFFFAOYSA-N butyl-chloro-diethylsilane Chemical group CCCC[Si](Cl)(CC)CC BCEPTKBQFGPAIQ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical class C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical class CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention discloses the preparation process of DL-nebivolol and its hydrochloride. The preparation process includes the following steps: 1) preparing intermediate compound I and compound II as shown; and 2) catalytic hydrocondensation of compounds I and II and successive deprotection, forming hydrochloride, selective crystallization and re-crystallization to obtain DL-nebivolol hydrochloride. The preparation process of the present invention has less steps, low cost, high product yield and other advantages and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of beta-blocker, relate in particular to the preparation method of DL-nebivolol and hydrochloride thereof.
Background technology
Nebivolol (DL-Nibivolol) is a kind of heart selectivity beta-blocker that has vasorelaxation action concurrently, be mainly used in treatment essential hypertension, it have evident in efficacy, take medicine conveniently, advantage such as untoward reaction is few, be a new promising antihypertensive drugs.Nebivolol is at first by U.S. Johnson﹠amp; Johnson company develops.Get permission listing in German and Holland first in 1997 and be used for the treatment of essential hypertension.In May, 2004, beta receptor blocker Nebilet (nebivolol) obtains the listing approval in the U.S., has begun the market experience at north America region.
Nebivolol has four chiral carbon atoms, has eight isomer, is wherein a pair of enantiomer, i.e. the mixture D L-nebivolol (DL-Nibivolol) of D-Nibivolol and L-Nibivolol and be used for the treatment of the medicinal target product of essential hypertension.
U.S. Johnson ﹠amp; Patent EP0145067 that Johnson company has and US4654362 are the method for the synthetic DL-nebivolol (DL-Nibivolol) of initial development.This patent is a key intermediate with benzo tetrahydropyrans epoxy construction thing, synthesizes the DL-nebivolol according to synthetic route 1:
Benzo tetrahydropyrans epoxy construction thing
Synthetic route 1
U.S. Johnson ﹠amp; Another patent EP0334429 that Johnson company has is on the basis of EP0145067 and US4654362, the patent of synthetic L-nebivolol (L-Nibivolol).Synthetic method is wherein seen synthetic route 2:
Synthetic route 2
Document Tetrahedron 2000,56,6339-6344 have reported a similar patent EP0334429 route, are used for synthetic D-nebivolol (D-Nibivolol), see synthetic route 3:
Synthetic route 3
The document is actually the patented method of having utilized EP0145067 and synthesizes the D-nebivolol, but has adopted the method that is different from patent to synthesize two key intermediates in the above route.
Document: J.Am.Chem.Soc.1998,120,8340-8347 has reported another synthetic D-nebivolol (D-Nibivolol) method, sees synthetic route 4:
Synthetic route 4
Adopted NaBH (OAc) in this synthetic method
3As the catalyzer in the condensation reaction, NaBH (OAc)
3Be not easy preparation, be difficult to obtain, and with NaBH (OAc)
3Make catalyzer,, and be not suitable for for above condensation and reduction reaction, because, NaBH (OAc)
3The reducing activity height, be easy to the aldehyde radical of raw material is directly reduced, thereby do not carry out condensation reaction; Therefore, the condensation reaction in the synthetic route 4 does not meet industrialized requirement.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of new method for preparing DL-nebivolol and hydrochloride thereof that meets industrialized requirement is provided.
Synthetic route is as follows:
Technical problem to be solved by this invention realizes by following technological approaches:
Prepare the method for DL-nebivolol and hydrochloride thereof, may further comprise the steps:
1) prepare intermediate general formula compound I and II by art methods:
Midbody compound I
Wherein, R is selected from hydrogen atom or benzyl; P
1Be selected from hydrogen atom, trimethyl silicane, tertiary butyl dimethyl-silicon, tertiary butyl diethyl silicon, THP trtrahydropyranyl or p-methyl benzenesulfonic acid root;
Midbody compound II
Wherein, P
2Be selected from trimethyl silicane, tertiary butyl dimethyl-silicon or tertiary butyl diethyl silicon;
2) general formula compound I and II are carried out the shortening condensation, carry out the deprotection base then successively, become hydrochloride, selective crystallization, recrystallization promptly to get DL-nebivolol hydrochloride finished product.
Among the above-mentioned preparation method, step 2) the used catalyzer of hydrocondensation described in is 5%Pd-CaCO
3-1～5%Pb catalyzer or active nickel catalyst; Described 5%Pd-CaCO
3-1～5%Pb Preparation of Catalyst mode is: do skeleton with lime carbonate, 5% palladium catalyst that the lead of adding 1～5% is partly poisoned palladium abbreviates as: 5%Pd-CaCO
3-1～5%Pb catalyzer.Catalyzer 5%Pd-CaCO
3-1～5%Pb can buy from market and obtain (as purchasing the company in Acros).
5%Pd-CaCO
3-1～5%Pb catalyzer can make the condensation of key intermediate I and II under the relative gentle condition of reaction conditions, is converted into next step product with high yield, and the purity height, produces by product and other impurity hardly.TLC point plate, product point is main point, can't see impure point;
The preparation method of active nickel catalyst is as follows: add 20～40 purpose alumino nickels, one weight part (nickeliferous 50%) in warding off the glass reactor, deionized water 5～20 weight parts.With the chuck chilled brine temperature in the kettle is chilled to below 5 ℃.Slowly add analytically pure sodium hydroxide 1.5～2.5 weight parts, feed rate is no more than 5 ℃ with temperature and is advisable.Behind reinforced the end ,-5～5 ℃ of reactions 30 minutes.With deionized water displacement-alkali water, till pH is 7.With dehydrated alcohol displacement 6 times, promptly obtain required active nickel catalyst.This catalyzer can make the condensation of key intermediate I and II carry out under relative gentle reaction conditions condition, is converted into next step product with high yield, and the purity height, produces by product and other impurity hardly.TLC point plate, product point is main point, can't see impure point.
Step 2) crystallization method described in is as follows: with weight is that the absolute dehydrated alcohol of 5～10 times of nebivolol crude product weight or absolute anhydrous isopropyl alcohol are with the nebivolol dissolving crude product, the needle-use activated carbon that is incorporated as nebivolol crude product weight 1% again decoloured 10～30 minutes, logical then chilled brine carries out crystallization under-20～-30 ℃ of environment.Crystallization time is 2～3 days.
But the preparation reference literature Tetrahedron 2000,56 of intermediate general formula compound I, the described method of 6339-6344 directly or is further synthesized; But intermediate general formula compound II reference literature J.Am.Chem.Soc.1998,120, the described method of 8340-8347 directly obtains.
The inventive method has practical, and cost is low, but advantages such as industrialization.
Further describe beneficial effect of the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit protection scope of the present invention.
Embodiment
[the preparation embodiment of midbody compound I class]
1, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A)
According to document Tetrahedron 2000,56, the method for 6339-6344 is raw material with the p-fluorophenol, can directly obtain compound 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A).
2, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-trimethyl silicane ether (midbody compound I-B)
With 45 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 25 kilograms of trimethylchlorosilanes below 10 ℃, drip off 20 ℃ of reactions 8 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 55 kilograms of scarlet viscous liquids, be midbody compound I-B, yield: 96.6%, TLC point plate is a point.
3, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl dimethyl-silicon ether (midbody compound I-C)
With 45 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 30 kilograms of TERT-BUTYL DIMETHYL CHLORO SILANE below 10 ℃, drip off 15 ℃ of reactions 4 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 60 kilograms of scarlet viscous liquids, be midbody compound I-C, yield: 90.8%, TLC point plate is a point.
4, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl diethyl silicon ether (midbody compound I-D)
With 45 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 35 kilograms of tertiary butyl diethyl chlorosilanes below 10 ℃, drip off 15 ℃ of reactions 4 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 65 kilograms of scarlet viscous liquids, both midbody compound I-D, yield: 90.5%, TLC point plate is a point.
5, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-(2-tetrahydropyrans)-ether (midbody compound I-E)
With 45 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 2 kilograms of tosic acid pyridinium salts, controlled temperature is adding 3 below 10 ℃, and 18 kilograms of 4-dihydropyrane were 35 ℃ of reactions 8 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 56 kilograms of scarlet viscous liquids, both midbody compound I-E, yield: 89.9%, TLC point plate is a point.
6, Synthetic 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethyl p-toluenesulfonate (midbody compound I-F)
With 45 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) joins warding off in the glass reactor of 500L, dissolve with the 400L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of pyridines, controlled temperature is adding 40 kilograms of Tosyl chlorides below 10 ℃, 45 ℃ of reactions 6 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 73 kilograms of scarlet viscous liquids, both midbody compound I-F, yield: 95.1%, TLC point plate is a point.
7, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G)
So that 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A) is raw material, through amidation, reduction obtains midbody compound I-G, and reaction formula is as follows:
With 50 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-A), joining 500L wards off in the glass reactor, add the 200L methylene dichloride, stirring and dissolving,, drip off at 20 ℃ of solution that drip 45 kilograms of Benzoyl chlorides and 100L methylene dichloride down with the chilled brine controlled temperature 0～20 ℃ of reaction 4 hours.Then, add 100L water, stirred 30 minutes, left standstill branch vibration layer 20 minutes.With 100L washing twice, the evaporated under reduced pressure methylene dichloride obtains the thick thing of scarlet to dichloromethane layer again, promptly obtain 2-benzamide base-1-(6-fluoro-3,4-dihydro-2-H-chromene)-and 80 kilograms of 1-ethyl benzoates, yield: 81.8%, TLC point plate is a point.
Warding off in the glass reactor of 1000L, add the 400L tetrahydrofuran (THF), 40 kilograms of POTASSIUM BOROHYDRIDE, 50 kilograms of zinc chloride are used water quench, and 40 ℃ were stirred 2 hours down.Drip the solution that 50 kilograms of 2-benzamide base-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethyl benzoate and 200L toluene are formed then, drip off 80～90 ℃ of following back flow reaction 10 hours.Be cooled to normal temperature, get rid of filter,, merge all filtrates to the 1500L separator,, wash three times with 200L water * 3 extractions with 200L toluene filter wash slag.Evaporated under reduced pressure toluene obtains faint yellow thick material, is 30 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G).Yield: 74.1%, TLC point plate is a point.
8, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-trimethyl silicane ether (midbody compound I-H)
With 31 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 13 kilograms of trimethylchlorosilanes below 10 ℃, drip off 20 ℃ of reactions 8 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 35 kilograms of scarlet viscous liquids, be midbody compound I-H, yield: 95.5%, TLC point plate is a point.
9, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl dimethyl-silicon ether (midbody compound I-I)
With 31 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 15 kilograms of TERT-BUTYL DIMETHYL CHLORO SILANE below 10 ℃, drip off 15 ℃ of reactions 4 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 39 kilograms of scarlet viscous liquids, be midbody compound I-I, yield: 95.3%, TLC point plate is a point.
10, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl diethyl silicon ether (midbody compound I-J)
With 31 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of sodium bicarbonates, controlled temperature is dripping 17 kilograms of tertiary butyl diethyl chlorosilanes below 10 ℃, drip off 15 ℃ of reactions 4 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 40 kilograms of scarlet viscous liquids, both midbody compound I-J, yield: 91.4%, TLC point plate is a point.
11, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-(2-tetrahydropyrans)-ether (midbody compound I-K)
With 31 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 2 kilograms of tosic acid pyridinium salts, controlled temperature is adding 3 below 10 ℃, and 10 kilograms of 4-dihydropyrane were 35 ℃ of reactions 8 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 38 kilograms of scarlet viscous liquids, both midbody compound I-K, yield: 95.8%, TLC point plate is a point.
12, Synthetic 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1--ethyl p-toluenesulfonate (midbody compound I-L)
With 31 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) joins warding off in the glass reactor of 500L, dissolve with the 300L methylene dichloride, be cooled to below 10 ℃ with chilled brine, add 20 kilograms of pyridines, controlled temperature is adding 21 kilograms of Tosyl chlorides below 10 ℃, 45 ℃ of reactions 6 hours.So be dispersed in 1000L 10% salt solution, separate, water layer with the 100L dichloromethane extraction once, the combined dichloromethane layer, it is inferior to give a baby a bath on the third day after its birth with the deionized water of 50L * 3, the evaporated under reduced pressure methylene dichloride, obtain 35 kilograms of scarlet viscous liquids, both midbody compound I-L, yield: 95.7%, TLC point plate is a point.
[the preparation embodiment of midbody compound II class]
Adopt document J.Am.Chem.Soc.1998,120, the method for 8340-8347 can directly obtain following compound:
1), 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A).
2), 2-tertiary butyl dimethyl-silicon alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-B).
3), 2-tertiary butyl diethylsilane oxygen base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-C).
[the preparation embodiment of active nickel catalyst]
Ward off at 300L and to add 20～40 purpose alumino nickel 12kg (nickeliferous 50%), deionized water 100L in the glass reactor.With the chuck chilled brine temperature in the kettle is chilled to below 5 ℃.Slowly add analytically pure sodium hydroxide 19.2kg, feed rate is no more than 5 ℃ with temperature and is advisable.Behind reinforced the end, 0 ℃ of reaction 30 minutes.With deionized water displacement-alkali water, till pH is 7.With dehydrated alcohol displacement 6 times, promptly obtain required active nickel 6kg.
[embodiment 1]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) and 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) is raw material, uses 5%Pd-CaCO
3-1～5%Pb catalyzer is done condensation and reduction, handles obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 30 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) and 25 kilograms of 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) joins in the autoclave of 500L, add the 300L dehydrated alcohol, add 5%Pd-CaCO again
33 kilograms of-1～5%Pb catalyzer.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 60 ℃; Reaction times is 24hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in deionized water, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is underpressure distillation under the 80C, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-A) 50 kilograms in vacuum tightness.Yield: 89.7%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 50 kilograms of above compound III-A (red dope), add the absolute anhydrous alcohol solution of 200L, and add the absolute anhydrous hydrochloric acid ethanol that 10 kilograms of dried HCl gases and the absolute dehydrated alcohol of 200L are made into, heated and stirred is reacted.Temperature control: 60 ℃; Reaction times: 10hr.
After reaction finished, logical chilled brine carried out crystallization under-30 ℃ of environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 35 kilograms of nebivolol crude products.Yield 89.6%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 30 kilograms of above nebivolol crude products, add the absolute dehydrated alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 30 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-30 ℃ of environment.Crystallization time is 3 days.After white crystals falls filter through whizzer, operate through above six recrystallizations with absolute dehydrated alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 33%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 2]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-G) and 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) is raw material, route according to embodiment 1, do condensation and reduction with active nickel catalyst, handle obtaining the nebivolol hydrochloric acid crude product then with HCl.
With 30 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-ethanol (midbody compound I-H) and 25 kilograms of 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) joins in the autoclave of 500L, add the 300L dehydrated alcohol, add 3 kilograms of active nickel catalysts again.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 80 ℃; Reaction times is 24hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is deposited in deionized water for useless active nickel catalyst, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is 80 ℃ of following underpressure distillation, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-A) 48 kilograms in vacuum tightness.Yield: 86.2%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 48 kilograms of above compound III-A (red dope), add the absolute anhydrous alcohol solution of 200L, and add the absolute anhydrous hydrochloric acid ethanol that 10 kilograms of dried HCl gases and the absolute dehydrated alcohol of 200L are made into, heated and stirred is reacted.Temperature control: 50 ℃; Reaction times: 20hr.
After reaction finished, logical chilled brine carried out crystallization under-30 ℃ of environment.Crystallization time is 2 days.White crystals falls filter through whizzer and promptly obtains 30 kilograms of nebivolol crude products.Yield 79.0%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 30 kilograms of above nebivolol crude products, add the absolute anhydrous isopropyl alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 20 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-20 environment.Crystallization time is 3 days.After white crystals falls filter through whizzer, operate through above eight recrystallizations with absolute anhydrous isopropyl alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 33%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 3]
With 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-trimethyl silicane ether (midbody compound I-B) and 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) is raw material, do condensation and reduction with active nickel catalyst, handle obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 23 kilograms of 2-amino-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-trimethyl silicane ether (midbody compound I-B) and 21 kilograms of 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) joins in the autoclave of 500L, add the 300L anhydrous methanol, add 2.3 kilograms of active nickel catalysts again.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 80 ℃; Reaction times is 24hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is deposited in deionized water for useless active nickel catalyst, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is 80 ℃ of following underpressure distillation, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-B) 40 kilograms in vacuum tightness.Yield: 94.3%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 40 kilograms of above compound III-B (red dope), add the absolute anhydrous alcohol solution of 200L, and add the absolute anhydrous hydrochloric acid ethanol that 8 kilograms of dried HCl gases and the absolute dehydrated alcohol of 200L are made into, heated and stirred is reacted.Temperature control: 40 ℃; Reaction times: 20hr.
After reaction finished, logical chilled brine carried out crystallization under-20 environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 30 kilograms of nebivolol crude products.Yield 89.5%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 30 kilograms of above nebivolol crude products, add the absolute anhydrous isopropyl alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 30 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-30 ℃ of environment.Crystallization time is 3 days.After white crystals falls filter through whizzer, operate through above six recrystallizations with absolute anhydrous isopropyl alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 33%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 4]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl dimethyl-silicon ether (midbody compound I-I) and 2-tertiary butyl dimethyl-silicon alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-B) is raw material, uses 5%Pd-CaCO
3-1～5%Pb catalyzer is done condensation and reduction, handles obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 35 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl dimethyl-silicon ether (midbody compound I-I) and 25 kilograms of 2-tertiary butyl dimethyl-silicon alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-B) joins in the autoclave of 500L, add the 300L anhydrous isopropyl alcohol, add 5%Pd-CaCO again
33.5 kilograms of-1～5%Pb catalyzer.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 70 ℃; Reaction times is 14hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in deionized water, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is 80 ℃ of following underpressure distillation, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-C) 55 kilograms in vacuum tightness.Yield: 97.0%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 55 kilograms of above compound III-C (red dope), add the absolute anhydrous alcohol solution of 200L, and add the absolute anhydrous hydrochloric acid ethanol that 10 kilograms of dried HCl gases and the absolute dehydrated alcohol of 200L are made into, heated and stirred is reacted.Temperature control: 50 ℃; Reaction times: 20hr.
After reaction finished, logical chilled brine carried out crystallization under-20 ℃ of environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 30 kilograms of nebivolol crude products.Yield 85.2%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 30 kilograms of above nebivolol crude products, add the absolute dehydrated alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 20 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-30 ℃ of environment.Crystallization time is 2 days.After white crystals falls filter through whizzer, operate through above eight recrystallizations with absolute dehydrated alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 33%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 5]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl diethyl silicon ether (midbody compound I-J) and 2-tertiary butyl diethylsilane oxygen base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-C) is raw material, do condensation and reduction with active nickel catalyst, handle obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 36 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-tertiary butyl diethyl silicon ether (midbody compound I-J) and 26 kilograms of 2-tertiary butyl diethylsilane oxygen base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-C) joins in the autoclave of 500L, add the 300L anhydrous methanol, add 2.3 kilograms of active nickel catalysts again.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 60 ℃; Reaction times is 24hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is deposited in deionized water for useless active nickel catalyst, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is 80 ℃ of following underpressure distillation, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-D) 55 kilograms in vacuum tightness.Yield: 94.2%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 55 kilograms of above compound III-D (red dope), add the absolute anhydrous alcohol solution of 300L, and add the absolute anhydrous hydrochloric acid ethanol that 8 kilograms of dried HCl gases and the absolute dehydrated alcohol of 150L are made into, heated and stirred is reacted.Temperature control: 60 ℃; Reaction times: 5hr.
After reaction finished, logical chilled brine carried out crystallization under-30 ℃ of environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 29 kilograms of nebivolol crude products.Yield 88.3%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 29 kilograms of above nebivolol crude products, add the absolute anhydrous isopropyl alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 30 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-30 ℃ of environment.Crystallization time is 2 days.After white crystals falls filter through whizzer, operate through above six recrystallizations with absolute anhydrous isopropyl alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 34.5%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 6]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-(2-tetrahydropyrans)-ether (midbody compound I-K) and 2-tertiary butyl diethylsilane oxygen base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-C) is raw material, do condensation and reduction with active nickel catalyst, handle obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 32 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1-(2-tetrahydropyrans)-ether (midbody compound I-K) and 26 kilograms of 2-tertiary butyl diethylsilane oxygen base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-C) joins in the autoclave of 500L, add the 300L anhydrous methanol, add 3.2 kilograms of active nickel catalysts again.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 70 ℃; Reaction times is 10hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is deposited in deionized water for useless active nickel catalyst, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is 80 ℃ of following underpressure distillation, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-E) 53 kilograms in vacuum tightness.Yield: 95.9%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 53 kilograms of above compound III-E (red dope), add the absolute anhydrous alcohol solution of 300L, and add the absolute anhydrous hydrochloric acid ethanol that 8 kilograms of dried HCl gases and the absolute dehydrated alcohol of 150L are made into, heated and stirred is reacted.Temperature control: 60 ℃; Reaction times: 5hr.
After reaction finished, logical chilled brine carried out crystallization under-30 ℃ of environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 30 kilograms of nebivolol crude products.Yield 90.7%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 30 kilograms of above nebivolol crude products, add the absolute dehydrated alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 20 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-20 ℃ of environment.Crystallization time is 3 days.After white crystals falls filter through whizzer, operate through above eight recrystallizations with absolute dehydrated alcohol again, promptly obtain 10 kilograms of DL-nebivolol finished products.Yield: 33%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
[embodiment 7]
With 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1--ethyl p-toluenesulfonate (midbody compound I-L) and 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) is raw material, do condensation and reduction with active nickel catalyst, handle obtaining the nebivolol hydrochloric acid crude product then with HCl.Synthetic route is as follows:
With 38 kilograms of 2-benzamido group-1-(6-fluoro-3,4-dihydro-2-H-chromene)-1--ethyl p-toluenesulfonate (midbody compound I-L) and 21 kilograms of 2-trimethyl silicane alcoxyl base-2-(6-fluoro-3,4-dihydro-2-H-chromene) acetaldehyde (midbody compound II-A) joins in the autoclave of 500L, add the 300L anhydrous methanol, add 3.8 kilograms of active nickel catalysts again.
Then, carry out hydrogenation reaction: hydrogen pressure is 0.5～5.0Mpa; Temperature of reaction is 70 ℃; Reaction times is 18hr.
Hydrogenation reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is deposited in deionized water for useless active nickel catalyst, focuses on the back recovery set and uses.Faint yellow filtrate is-0.09MPa that temperature is underpressure distillation under 80 ℃ of conditions, obtains the incarnadine dope, is present embodiment purpose compound crude product (compound III-F) 50 kilograms in vacuum tightness.Yield: 88.8%.TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reflection still at 500L, add 50 kilograms of above compound III-F (red dope), add the absolute anhydrous alcohol solution of 200L, and add the absolute anhydrous hydrochloric acid ethanol that 8 kilograms of dried HCl gases and the absolute dehydrated alcohol of 200L are made into, heated and stirred is reacted.Temperature control: 40 ℃; Reaction times: 10hr.
After reaction finished, logical chilled brine carried out crystallization under-30 ℃ of environment.Crystallization time is 3 days.White crystals falls filter through whizzer and promptly obtains 28 kilograms of nebivolol crude products.Yield 88.2%, TLC point plate, product point is main point, can't see impure point.
Ward off in the glass reactor at 500L and to add 28 kilograms of above nebivolol crude products, add the absolute anhydrous isopropyl alcohol of 200L, the heated and stirred dissolving adds nebivolol crude product weight 300 gram needle-use activated carbons decolourings 30 minutes again, and filtered while hot is fallen gac.
Filtrate is transferred to crystallization kettle, and logical chilled brine carries out crystallization under-20 ℃ of environment.Crystallization time is 2 days.After white crystals falls filter through whizzer, operate through above eight recrystallizations with absolute anhydrous isopropyl alcohol again, promptly obtain 9 kilograms of DL-nebivolol finished products.Yield: 32%, TLC point plate is a point.HPLC analyzes, and purity is greater than 99%.
Claims (4)
1, prepare the method for DL-nebivolol and hydrochloride thereof, may further comprise the steps:
1) prepare intermediate general formula compound I and II by art methods:
Intermediate general formula compound I
Wherein, R is selected from hydrogen atom or benzyl; P
1Be selected from hydrogen atom, trimethyl silicane, tertiary butyl dimethyl-silicon, tertiary butyl diethyl silicon, THP trtrahydropyranyl or p-methyl benzenesulfonic acid root;
Intermediate general formula compound II
Wherein, P
2Be selected from trimethyl silicane, tertiary butyl dimethyl-silicon or tertiary butyl diethyl silicon;
2) general formula compound I and II are carried out the shortening condensation, carry out the deprotection base then successively, become hydrochloride, selective crystallization, recrystallization promptly to get DL-nebivolol hydrochloride finished product.
D-Nebivolol (S, R, R, R configuration)
L-Nebivolol (R, S, S, S configuration)
2, according to the method for claim 1, it is characterized in that: step 2) described in the used catalyzer of shortening condensation reaction be 5%Pd-CaCO
3-1～5%Pb catalyzer or active nickel catalyst.
3, according to the method for claim 2, it is characterized in that described active nickel catalyst prepares by the following method: in reactor, be incorporated as nickeliferous 50% alumino nickel of 20～40 purposes 1 weight part, deionized water 5～20 weight parts, temperature in the kettle is chilled to below 5 ℃, add sodium hydroxide 1.5～2.5 weight parts, the control feed rate makes temperature of reaction be no more than 5 ℃, behind reinforced the end, reaction is 30 minutes under-5～5 ℃ of temperature condition, with deionized water displacement-alkali water, till pH is 7, again with dehydrated alcohol displacement 6 times, promptly.
4, according to the method for claim 1, it is characterized in that: step 2) described in the selective crystallization mode for the absolute dehydrated alcohol of 5～10 times of nebivolol crude product weight or absolute anhydrous isopropyl alcohol with the nebivolol dissolving crude product, the needle-use activated carbon that is incorporated as nebivolol crude product weight 1% again decoloured 10～30 minutes, logical then chilled brine, carry out crystallization under-20～-30 ℃ of environment, crystallization time is 2～3 days.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510051266XA CN100546987C (en) | 2005-03-03 | 2005-03-03 | Preparation method of DL-nebivolol and its hydrochloride |
| PCT/CN2005/000570 WO2006092086A1 (en) | 2005-03-03 | 2005-04-25 | A method for the preparation of dl-nebivovol and its hydrochloride salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510051266XA CN100546987C (en) | 2005-03-03 | 2005-03-03 | Preparation method of DL-nebivolol and its hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1683355A true CN1683355A (en) | 2005-10-19 |
| CN100546987C CN100546987C (en) | 2009-10-07 |
Family
ID=35262879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510051266XA Expired - Fee Related CN100546987C (en) | 2005-03-03 | 2005-03-03 | Preparation method of DL-nebivolol and its hydrochloride |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100546987C (en) |
| WO (1) | WO2006092086A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007009143A3 (en) * | 2005-07-19 | 2007-04-05 | Pharmacon Forschung & Beratung Gmbh | Method for producing nebivolol |
| CN101952270B (en) * | 2008-03-31 | 2013-04-24 | Zach系统股份公司 | Process for preparing nebivolol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1337432C (en) * | 1988-03-23 | 1995-10-24 | Raymond M. Xhonneux | Method of lowering the blood pressure |
-
2005
- 2005-03-03 CN CNB200510051266XA patent/CN100546987C/en not_active Expired - Fee Related
- 2005-04-25 WO PCT/CN2005/000570 patent/WO2006092086A1/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007009143A3 (en) * | 2005-07-19 | 2007-04-05 | Pharmacon Forschung & Beratung Gmbh | Method for producing nebivolol |
| CN101952270B (en) * | 2008-03-31 | 2013-04-24 | Zach系统股份公司 | Process for preparing nebivolol |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006092086A1 (en) | 2006-09-08 |
| CN100546987C (en) | 2009-10-07 |
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