CN102250050A - Method for synthesizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and alkyl ester thereof - Google Patents
Method for synthesizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and alkyl ester thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 125000005907 alkyl ester group Chemical group 0.000 title abstract description 6
- ZNJANLXCXMVFFI-UHFFFAOYSA-N 6-fluoro-3,4-dihydro-2h-chromene-2-carboxylic acid Chemical compound FC1=CC=C2OC(C(=O)O)CCC2=C1 ZNJANLXCXMVFFI-UHFFFAOYSA-N 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 38
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 208000006558 Dental Calculus Diseases 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 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 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 229910010272 inorganic material Inorganic materials 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- -1 tetracol phenixin Chemical compound 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 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 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- WMHHOVQSQZDVPW-UHFFFAOYSA-N 4-fluorophenol;sodium Chemical compound [Na].OC1=CC=C(F)C=C1 WMHHOVQSQZDVPW-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 0 C=**C([C@](*=CCBr)OC(C=C1)=CCC1F)=O Chemical compound C=**C([C@](*=CCBr)OC(C=C1)=CCC1F)=O 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- VNXZZPZKCMJBME-UHFFFAOYSA-N ethyl 2,4-dibromobutanoate Chemical compound CCOC(=O)C(Br)CCBr VNXZZPZKCMJBME-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229960000619 nebivolol Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JIXDOBAQOWOUPA-UHFFFAOYSA-N 1-fluoro-2-methoxybenzene Chemical compound COC1=CC=CC=C1F JIXDOBAQOWOUPA-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for synthesizing 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and alkyl ester thereof. 2,4-dibromoalkylbutyrate is used as a raw material, and the products are obtained by three-step reaction. According to the synthesizing method, the 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and the alkyl ester thereof serving as target products are obtained without hydrogenation reduction of expensive Pd/C catalyst; and the reaction process is simple, the conditions are mild, the raw materials are easily obtained, and the yield is high.
Description
Technical field
The present invention relates to a class cardiovascular agent key intermediate 6-fluoro-3, the new synthetic process method of 4-dihydro-2H-1-chromene-2-carboxylic acid and alkyl ester thereof.
Background technology
6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid are the key intermediates of synthetic cardiovascular agent nebivolol.Nebivolol is by Johnson ﹠amp; Selectivity β with hemangiectasis activity 1 adrenoceptor antagonists of Johnson company development.It in May, 1997 in German Initial Public Offering.
3 of present most of report, the synthetic method of 4-dihydro-2H-1-chromene-2-carboxylic acid are at first synthetic 4-oxos-3, and 4-dihydro-2H-1-chromene-2-carboxylic acid is then by the Pd/C catalytic hydrogenating reduction.
Describing among the EP264586 and can adopting 4-oxo-1-chromene is raw material, through bromo, dehydrobromination, upward itrile group, hydrolysis, obtains 4-oxo-2H-1-chromene-2-carboxylic acid at last.This route shortcoming is that reagent trimethylammonium itrile group silane is comparatively expensive.
Having described employing 4-oxo-4-phenoxy group-2-alkene butyric acid among the EP331078 is raw material, resets by Fries, closes ring again and obtains 4-oxo-2H-1-chromene-2-carboxylic acid.This route shortcoming is that Fries rearrangement productive rate is lower.
Also described among the EP331078 to be raw material,, closed ring again and obtain 4-oxo-3,4-dihydro-2H-1-chromene-2-carboxylic acid through the Friedel-Crafts reaction to fluoroanisole.
J.Med.Chem. (1971,14 (8): having described 758-766) with the p-fluorophenol is raw material, and through acetylize, Fries resets, and ring is closed in the Claisen ester condensation, and hydrolysis obtains 4-oxo-4H-1-chromene-2-carboxylic acid.This route steps is longer.
The product that above synthetic route obtains all needs to obtain target product 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid by expensive Pd/C catalyst hydrogenation reduction.
Summary of the invention
The objective of the invention is to overcome above the deficiencies in the prior art, provide that a kind of reaction process is simple, the 6-fluoro-3 of mild condition, the synthetic method of 4-dihydro-2H-1-chromene-2-carboxylic acid and alkyl ester thereof.
For achieving the above object, the present invention by the following technical solutions:
The method of the compound of a kind of synthesis type (IV), synthetic route is as follows:
1) the have formula compound of (I) and p-fluorophenol are reacted under the condition that alkali exists, obtain compound (II);
2) make and have formula the compound of (II) carries out ring-closure reaction under the katalysis of inorganic salt and Lewis acid, obtain compound (III);
Wherein, R ' is C
1-6Saturated alkyl; Be preferably methyl, ethyl, n-propyl or sec.-propyl.
Preferable, in the step 1), described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium hydride, hydrolith, yellow soda ash, salt of wormwood, diethylamine or the triethylamine.
Preferable, in the step 1), the mol ratio of described alkali and p-fluorophenol is 1-10: 1.
Preferable, in the step 1), temperature of reaction is 10-100 ℃, the reaction times is 1-24 hour.
Preferable, in the step 1), described reacting in the organic solvent carried out, described organic solvent includes but not limited to methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide, acetone, butanone, methyl iso-butyl ketone (MIBK), benzene, toluene or the dimethylbenzene.The weight ratio of described organic solvent and p-fluorophenol is 5-50.
Preferable, step 2) in, described inorganic salt are selected from one or more in sodium-chlor, Repone K, sodium sulfate, vitriolate of tartar, yellow soda ash or the salt of wormwood; Described Lewis acid is selected from one or more in iron(ic) chloride, zinc chloride or the aluminum chloride.
Preferable, step 2) in, the mol ratio of described inorganic salt and compound (II) is 0.5-5: 1, and described Lewis acid is 1-10 with the mol ratio of compound (II): 1.
Preferable, step 2) in, temperature of reaction is 20-200 ℃, the reaction times is 1-10 hour.
Step 2) in, the concrete operation method of described ring-closure reaction is: inorganic salt are become molten state with Lewis acid Hybrid Heating, add compound (II) again, make compound (III).
The present invention also further discloses the method for the compound of a kind of synthesis type (IV), and synthetic route is as follows:
1) adopts the compound of method synthesis type (III) of the compound of above-mentioned synthesis type (III);
2) make and have formula the compound of (III) carries out esterification with ROH under the effect of catalyzer, obtain compound (IV);
Wherein: R ' and R are respectively C
1-6Saturated alkyl; Be preferably methyl, ethyl, n-propyl or sec.-propyl.
Preferable, step 2) in, described catalyzer comprises and is selected from hydrogenchloride, the vitriol oil, Phenylsulfonic acid or the tosic acid one or more.
Preferable, step 2) in, esterification gained compound (IV) makes pure product through recrystallization purifying, and described solvent includes but not limited to sherwood oil, normal hexane, normal heptane, methyl tertiary butyl ether etc.
Further, employed compound (I) is made by following method among the present invention: gamma-butyrolactone, liquid bromine and R ' OH are reacted under the katalysis of red phosphorus, obtain compound (I), wherein R ' is C
1-6Saturated alkyl; Be preferably methyl, ethyl, propyl group or sec.-propyl.Reaction formula is as follows:
Preferable, the mol ratio of described liquid bromine and gamma-butyrolactone is 0.5-5: 1, and the mol ratio of described R ' OH and gamma-butyrolactone is 5-50: 1.
Above-mentioned synthetic method provided by the present invention does not need to obtain target product 6-fluoro-3 by expensive Pd/C catalyst hydrogenation reduction, 4-dihydro-2H-1-chromene-2-carboxylic acid, and reaction process is simple, mild condition, raw material are easy to get, yield is higher.
Embodiment
Further set forth the present invention below in conjunction with embodiment.Should be understood that these embodiment only are used to illustrate the present invention, but not limit the scope of the invention.
Among the present invention: 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid adopt following method preparation:
(1) red phosphorus with catalytic amount is dissolved in the gamma-butyrolactone, adds the normal liquid bromine of 0.5-5; Add 5-50 Fatty Alcohol(C12-C14 and C12-C18) doubly afterwards again, make 2,4-dibromo-butyric acid alkyl ester;
(2) p-fluorophenol is dissolved in the 5-50 times of organic solvent, adds 1-10 alkali doubly.Solution is splashed into 2, in the 4-dibromo-butyric acid alkyl ester.Make 4-bromo-2-(4-fluorophenoxy) butyric acid alkyl ester.Temperature of reaction is at the 10-100 degree.Reaction times is 1-24 hour.Described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium hydride, hydrolith, yellow soda ash, salt of wormwood, diethylamine or the triethylamine.Described organic solvent includes but not limited to methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide, acetone, butanone, methyl iso-butyl ketone (MIBK), benzene, toluene or the dimethylbenzene.
(3) the normal inorganic salt of 0.5-5.0 are become molten state with the normal Lewis acid of 1-10 Hybrid Heating, 4-bromo-2-(4-fluorophenoxy) butyric acid alkyl ester is added wherein reaction, make 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid.Temperature of reaction is at the 20-200 degree; Reaction times is 1-10 hour.Described inorganic salt can be selected from one or more in sodium-chlor, Repone K, sodium sulfate, vitriolate of tartar, yellow soda ash or the salt of wormwood; Described Lewis acid can be selected from one or more in iron(ic) chloride, zinc chloride or the aluminum chloride.
6-fluoro-3,4-dihydro-2H-1-chromene-2-alkyl carboxylates, adopt following method preparation: with above-mentioned gained 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid is under catalyst action, with C
1-C
6Alcohol reaction.Make 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylicesters crude product.Obtain 6-fluoro-3 by recrystallization, the 4-dihydro-2H-1-chromene-pure product of 2-carboxylicesters.Described catalyzer comprises and is selected from hydrogenchloride, the vitriol oil, Phenylsulfonic acid or the tosic acid one or more
Embodiment 1
With red phosphorus (4.8g, 0.16mol) be dissolved in gamma-butyrolactone (600.0g, 6.96mol) in.Heated and stirred is warming up to 100 ℃, and beginning dropping liquid bromine (1124.0g, 7.00mol).GC reduces to 10 ℃ with system with ice bath after following the tracks of and reacting completely, and adds 1200mL methyl alcohol, the 4mL vitriol oil.Stirred overnight at room temperature.With saturated sodium bicarbonate solution system pH is transferred to neutrality, add dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Filter the back distillation, get product 2, the 4-DIBROMOBUTYRATE is weak yellow liquid 1400.0g, purity 99.4%, yield 76.9%.
Embodiment 2
With red phosphorus (4.8g, 0.16mol) be dissolved in gamma-butyrolactone (600.0g, 6.96mol) in.Heated and stirred is warming up to 100 ℃, and beginning dropping liquid bromine (1124.0g, 7.00mol).GC reduces to 10 ℃ with system with ice bath after following the tracks of and reacting completely, and adds 1200mL ethanol, the 4mL vitriol oil.Stirred overnight at room temperature.With saturated sodium bicarbonate solution system pH is transferred to neutrality, add dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Filter the back distillation, get product 2,4-dibromo-butyric acid ethyl ester is weak yellow liquid 1470.0g, purity 99.1%, yield 76.4%.
Embodiment 3
With sodium hydride (90.0g 2.25mol), is dissolved in the 1500mL benzene, slowly add p-fluorophenol (224.0g, 2.00mol).40 ℃ of stirrings are spent the night.With embodiment 1 gained 2, the 4-DIBROMOBUTYRATE is dissolved in the 1500mL benzene, is warmed up to 60 ℃.Slowly splash into the ready-made p-fluorophenol sodium solution in front, stir 5h.Suction filtration, the filtrate water washing adds anhydrous sodium sulfate drying.Distill after the filtration product 4-bromo-2-(4-fluorophenoxy) methyl-butyrate, be colourless liquid 476.0g, purity 93.6%, yield 81.0%.
1H-NMR(DCCl
3，500Hz)：7.01-6.96(m，4H)，4.85(t，J＝10，1H)，4.51-4.46(m，1H)，4.35-4.296(m，1H)，3.75(s，3H)，2.71-2.64(m，1H)，2.48-2.40(m，1H).
Embodiment 4
With sodium hydride (90.0g 2.25mol), is dissolved in the 1500mL benzene, slowly add p-fluorophenol (224.0g, 2.00mol).40 ℃ of stirrings are spent the night.With embodiment 2 gained 2,4-dibromo-butyric acid ethyl ester is dissolved in the 1500mL benzene, is warmed up to 60 ℃.Slowly splash into the ready-made p-fluorophenol sodium solution in front, stir 5h.Suction filtration, the filtrate water washing adds anhydrous sodium sulfate drying.Distill after the filtration product 4-bromo-2-(4-fluorophenoxy) ethyl butyrate, be colourless liquid 498.7g, purity 93.5%, yield 80.7%.
1H-NMR(DCCl
3，500Hz)：7.01-6.96(m，4H)，4.85(t，J＝10，1H)，4.51-4.46(m，1H)，4.35-4.296(m，1H)，3.80(m，2H)，2.71-2.64(m，1H)，2.48-2.40(m，1H)，1.30(t，3H).
Embodiment 5
With sodium-chlor (29.0g, 0.50mol) and aluminum chloride (267.0g, 2.00mol) mix post-heating be warming up to 80 the degree, slowly drip embodiment 3 gained 4-bromo-2-(4-fluorophenoxy) methyl-butyrates (145.0g, 0.50mol).After dropwising, be warming up to 110 degree, reaction 5h.Pour in the cryosel acid, add dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Be spin-dried for solvent after the filtration and get product 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid is deep green solid 99.4g, purity 88.1%, yield 90.3%.
1H-NMR(DCCl
3，500Hz)：9.58(s，1H)，6.87-6.81(m，2H)，6.75-6.73(m，1H)，4.74-4.72(m，1H)，2.87-2.74(m，2H)，2.33-2.16(m，2H).
Embodiment 6
With sodium-chlor (29.0g, 0.50mol) and aluminum chloride (267.0g, 2.00mol) mix post-heating be warming up to 80 the degree, slowly drip embodiment 4 gained 4-bromo-2-(4-fluorophenoxy) ethyl butyrates (152.2g, 0.50mol).After dropwising, be warming up to 110 degree, reaction 5h.Pour in the cryosel acid, add dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Be spin-dried for solvent after the filtration and get product 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid is deep green solid 98.6g, purity 89.8%, yield 91.2%.
1H-NMR(DCCl
3，500Hz)：9.58(s，1H)，6.87-6.81(m，2H)，6.75-6.73(m，1H)，4.74-4.72(m，1H)，2.87-2.74(m，2H)，2.33-2.16(m，2H)。
Embodiment 7
With embodiment 5 gained 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid (94.2g 0.48mol) is dissolved in the 1000mL methyl alcohol, and the adding vitriol oil (4.7g, 0.05mol).Stir 5h.Methyl alcohol is removed in underpressure distillation, adds the entry dilution.Use dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Distill after the filtration 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylate methyl ester crude product.Crude product is dissolved in recrystallization gets white solid 63.5g in the 700mL normal hexane, purity 97.8%, yield 62.2%.
1H-NMR(DCCl
3，500Hz)：6.89-6.80(m，2H)，6.79-6.73(m，1H)，4.73-4.70(m，1H)，3.80(s，3H)，2.87-2.70(m，2H)，2.29-2.13(m，2H)。
Embodiment 8
With embodiment 6 gained 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid (94.2g 0.48mol) is dissolved in the 1000mL ethanol, and the adding vitriol oil (4.7g, 0.05mol).Stir 5h.Ethanol is removed in underpressure distillation, adds the entry dilution.Use dichloromethane extraction.Organic phase adds anhydrous sodium sulfate drying.Distill after the filtration 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid, ethyl ester crude product.Crude product is dissolved in recrystallization gets white solid 67.3g in the 700mL normal hexane, purity 98.0%, yield 61.9%.
1H-NMR(DCCl
3，500Hz)：6.89-6.80(m，2H)，6.79-6.73(m，1H)，4.73-4.70(m，1H)，3.80(m，2H)，2.87-2.70(m，2H)，2.29-2.13(m，2H)，1.30(t，3H)。
Claims (9)
1. the method for the compound of a synthesis type (III), synthetic route is as follows:
1) the have formula compound of (I) and p-fluorophenol are reacted under the condition that alkali exists, obtain compound (II);
2) make and have formula the compound of (II) carries out ring-closure reaction under the katalysis of inorganic salt and Lewis acid, obtain compound (III);
Wherein, R ' is C
1-6Saturated alkyl.
2. the method for the compound of synthesis type as claimed in claim 1 (III) is characterized in that, in the step 1), described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, sodium hydride, hydrolith, yellow soda ash, salt of wormwood, diethylamine or the triethylamine.
3. the method for the compound of synthesis type as claimed in claim 1 (III) is characterized in that, in the step 1), the mol ratio of described alkali and p-fluorophenol is 1-10: 1; Temperature of reaction is 10-100 ℃, and the reaction times is 1-24 hour.
4. the method for the compound of synthesis type as claimed in claim 1 (III) is characterized in that step 2) in, described inorganic salt are selected from one or more in sodium-chlor, Repone K, sodium sulfate, vitriolate of tartar, yellow soda ash or the salt of wormwood; Described Lewis acid is selected from one or more in iron(ic) chloride, zinc chloride or the aluminum chloride.
5. the method for the compound of synthesis type as claimed in claim 1 (III) is characterized in that step 2) in, the mol ratio of described inorganic salt and compound (II) is 0.5-5: 1, and described Lewis acid is 1-10 with the mol ratio of compound (II): 1; Temperature of reaction is 20-200 ℃, and the reaction times is 1-10 hour.
6. as the method for the compound of arbitrary described synthesis type (III) among the claim 1-5, it is characterized in that, described compound (I) is made by following method: gamma-butyrolactone, liquid bromine and R ' OH are reacted under the katalysis of red phosphorus, obtain compound (I), wherein R ' is C
1-6Saturated alkyl.
7. the method for the compound of synthesis type as claimed in claim 6 (III) is characterized in that, the mol ratio of described liquid bromine and gamma-butyrolactone is 0.5-5: 1, and the mol ratio of described R ' OH and gamma-butyrolactone is 5-50: 1.
8. the method for the compound of a synthesis type (IV), synthetic route is as follows:
1) employing is as the compound of the method synthesis type (III) of the compound of arbitrary described synthesis type (III) among the claim 1-6;
2) make and have formula the compound of (III) carries out esterification with ROH under the effect of catalyzer, obtain compound (IV); Wherein: R ' and R are respectively C
1-6Saturated alkyl.
9. the method for the compound of synthesis type as claimed in claim 8 (IV) is characterized in that step 2) in, described catalyzer is selected from one or more in hydrogenchloride, the vitriol oil, Phenylsulfonic acid or the tosic acid.
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|---|---|---|---|---|
| US20070149612A1 (en) * | 2005-12-28 | 2007-06-28 | Thomas Bader | Process for preparation of racemic Nebivolol |
| CN101020682A (en) * | 2007-03-14 | 2007-08-22 | 浙江大学 | Synthesis process of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-formaldehyde |
| CN101870670A (en) * | 2010-06-28 | 2010-10-27 | 浙江树人大学 | Synthesis method of cyclobutylamine-2-carboxylic acid |
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|---|---|---|---|---|
| US20070149612A1 (en) * | 2005-12-28 | 2007-06-28 | Thomas Bader | Process for preparation of racemic Nebivolol |
| CN101020682A (en) * | 2007-03-14 | 2007-08-22 | 浙江大学 | Synthesis process of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-formaldehyde |
| CN101870670A (en) * | 2010-06-28 | 2010-10-27 | 浙江树人大学 | Synthesis method of cyclobutylamine-2-carboxylic acid |
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