CN109535107B - Preparation method of (R) -4-propyl-dihydrofuran-2-ketone - Google Patents
Preparation method of (R) -4-propyl-dihydrofuran-2-ketone Download PDFInfo
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- CN109535107B CN109535107B CN201811611146.4A CN201811611146A CN109535107B CN 109535107 B CN109535107 B CN 109535107B CN 201811611146 A CN201811611146 A CN 201811611146A CN 109535107 B CN109535107 B CN 109535107B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 59
- 238000003756 stirring Methods 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 38
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 239000012448 Lithium borohydride Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- -1 allyl p-toluenesulfinate Chemical compound 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N (4r)-4-propyloxolan-2-one Chemical compound CCC[C@H]1COC(=O)C1 NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 229960002161 brivaracetam Drugs 0.000 description 7
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing (R) -4-propyl-dihydrofuran-2-ketone, a key intermediate compound of the formula B compound, a key intermediate compound of the formula C compound and a preparation method thereof; the preparation method of (R) -4-propyl-dihydrofuran-2-ketone has strong process operability and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and relates to a preparation method of (R) -4-propyl-dihydrofuran-2-ketone
Background
(R) -4-propyl-dihydrofuran-2-one is a key intermediate in the synthesis of the novel antiepileptic drug, Brivaracetam. At present, a plurality of literatures report the synthesis method of the compound. Synthetic methods were first described in Journal of American Chemical Society, 1985, 107, 4088-. The allyl p-toluenesulfinate which is not supplied by the market is adopted as the starting material, so the cost is high and the industrial value is not high; after that, there are documents reporting synthesis methods (e.g., Journal of American Chemical Society, 2003, 125, 11253-11258) that are expensive and not industrially valuable.
Patent CN106008411A, reports a relatively low cost method. The synthetic route is as follows:
the patent describes that after an intermediate 6 is obtained, an intermediate 7 is obtained through hydrolysis, and then the target product (R) -4-propyl-dihydrofuran-2-one is obtained through reduction by borane dimethyl sulfide or sodium borohydride. The company, when reproducing the process of this patent, has found that the reduction step generates a large amount of gas, limiting further industrial scale-up. And the yield of the two steps of hydrolysis and reduction is low, and the cost is relatively high.
Therefore, the preparation method which has low cost and strong operability and is suitable for industrial production and preparation of (R) -4-propyl-dihydrofuran-2-ketone becomes a problem which needs to be solved urgently at present.
Disclosure of Invention
The invention overcomes the defects of the prior art, provides the preparation method of the intermediate compound of formula D of the brivaracetam, has low cost, strong operability and little waste gas generated in the production process, is suitable for industrial production, and has high optical purity of the compound of formula D.
The invention provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone, which comprises the following steps:
after the compound of the formula C is subjected to reduction reaction, acid water is added for quenching to obtain a compound of a formula D,
preferably, the reduction reaction is: dissolving the compound of the formula C in an organic solvent 1, adding a reducing agent while stirring, and dropwise adding an alcohol solvent to perform a reduction reaction.
More preferably, the amount of the organic solvent is,
the organic solvent 1 is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile and N, N-dimethylformamide;
and/or the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and lithium borohydride;
and/or the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol;
and/or the adding mode is dripping;
and/or the temperature when the alcohol solvent is added is-70 to-10 ℃, preferably-25 to-10 ℃;
and/or after the alcohol solvent is added, the reaction temperature is 10-40 ℃, and preferably 20-30 ℃;
and/or quenching the acid water, wherein the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and perchloric acid;
and/or the specific steps are as follows: dissolving the compound of the formula C in an organic solvent 1, stirring, adding a reducing agent, dropwise adding an alcohol solvent at-25 to-10 ℃, and reacting for 1 to 5 hours after dropwise adding; then heating to 10-40 ℃, reacting for 5-15 h, and adding acid water for quenching to obtain a compound shown in the formula D;
and/or, further comprising a refining step;
and/or, further comprising: and (3) pulping the obtained compound of the formula D with a solvent, filtering, concentrating the filtrate to be dry, wherein the solvent for pulping is preferably one or more of n-heptane, n-hexane, methyl tert-butyl ether and diethyl ether.
Preferably, the reduction reaction is: dissolving the compound of formula C in alcohol solvent, adding reducing agent in batches while stirring, and carrying out reduction reaction.
More preferably still, the first and second liquid crystal compositions are,
and/or the reducing agent is added in batches;
and/or the temperature of the reducing agent is-70 to-10 ℃ and is preferably-25 to-10 ℃;
and/or the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol;
and/or after the alcohol solvent is added, the reaction temperature is 10-40 ℃, and preferably 20-30 ℃;
and/or quenching the acid water, wherein the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and perchloric acid;
and/or the specific steps are as follows: dissolving the compound of the formula C in an alcohol solvent, adding a reducing agent in batches at the temperature of-25 to-10 ℃ while stirring, and reacting for 1 to 5 hours; then heating to 10-40 ℃, reacting for 5-15 h, and adding acid water for quenching to obtain a compound shown in the formula D;
and/or, further comprising a refining step;
and/or, further comprising: and (3) pulping the obtained compound of the formula D with a solvent, filtering, concentrating the filtrate to be dry, wherein the solvent for pulping is preferably one or more of n-heptane, n-hexane, methyl tert-butyl ether and diethyl ether.
The present invention provides compounds of formula C
The invention also provides a preparation method of the compound of the formula C, which comprises the following steps:
and under the protection of inert gas, adding a tetrahydrofuran solution containing the bis (trimethylsilyl) amino alkali metal salt into an organic solvent 2 solution containing the intermediate B, stirring, and adding tert-butyl bromoacetate to react to obtain the compound shown in the formula C.
Preferably, the organic solvent 2 is one or more selected from methyl tert-butyl ether, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether; more preferably one or both of tetrahydrofuran and 2-methyltetrahydrofuran.
Preferably, the bis (trimethylsilyl) amino alkali metal salt is one or more of sodium bis (trimethylsilyl) amino alkali and potassium bis (trimethylsilyl) amino alkali;
preferably, the reaction temperature is-70 to-30 ℃, preferably-40 to-30 ℃;
preferably, the stirring time is 0.5-5 h, preferably 1.5-3 h;
preferably, the adding mode is dropwise adding; more preferably, the reaction temperature is-70 ℃ to-30 ℃ when the solution of the sodium salt or the potassium salt of the bis (trimethylsilyl) amino base is dropwise added, and the solution is stirred for 0.5h to 5.0h within the temperature range after the dropwise addition.
Preferably, a post-treatment step is further included.
Preferably, the method further comprises a recrystallization step, wherein the solvent adopted for recrystallization is one or more solvents selected from methyl tert-butyl ether, diethyl ether, n-heptane, n-hexane and ethyl acetate; more preferably, the mixed solvent is methyl tert-butyl ether and n-heptane, and the preferred ratio of the mixed solvent is 1: 1-1: 10.
The invention also provides compounds of formula B
The present invention also provides a process for the preparation of a compound of formula B, comprising the steps of:
(1) dissolving n-pentanoic acid and organic base in an organic solvent 3, adding pivaloyl chloride, and stirring for reaction;
(2) dissolving the compound of the formula A in an organic solvent 3, adding the solution into the reaction solution obtained in the step (1), and reacting under the action of lithium salt to obtain the compound of the formula B.
Preferably, the organic solvent 3 is one or more selected from methyl tert-butyl ether, toluene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether;
preferably, the organic base is selected from one or more of triethylamine, pyridine and diisopropylethylamine;
preferably, the reaction temperature in the step (1) is-70-20 ℃, preferably-20-5 ℃;
preferably, the reaction temperature in the step (2) is-70-20 ℃, preferably-20-5 ℃;
preferably, the adding mode of the step (1) and/or the step (2) is dropwise adding; more preferably, the step (1) and the step (2) are both dropwise added, the temperature of the step (1) is-20 to-5 ℃, and the reaction time is 2 to 5 hours after the dropwise addition.
Preferably, in the step (2), the lithium salt may be one or more of lithium bromide and lithium chloride.
The invention also provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone, which adopts the following reaction equation:
preferably, the reaction conditions for preparing the compound of formula C from the compound of formula B are as described above.
Preferably, the reaction conditions for preparing the compound of formula D from the compound of formula C are as described above.
The invention also provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone, which adopts the following reaction equation:
preferably, the reaction conditions for preparing the compound of formula B from the compound of formula a are as described above.
Preferably, the reaction conditions for preparing the compound of formula C from the compound of formula B are as described above.
Preferably, the reaction conditions for preparing the compound of formula D from the compound of formula C are as described above.
The invention also provides application of the compound of the formula A, the compound of the formula B and the compound of the formula C in preparation of the brivaracetam.
The invention has the beneficial technical effects that:
1. the invention provides novel intermediate compounds of formula B and formula C of brivaracetam.
2. According to the preparation method of the intermediate compound of formula C of the brivaracetam, the compound of formula C is further recrystallized, and the optical purity is high (generally more than 99.0%).
3. The preparation method of the intermediate compound D of the brivaracetam, provided by the invention, is prepared by reducing the compound C in one step, so that a large amount of gas generated in the reduction reaction process under the reaction condition in the prior art is overcome, and the yield of the compound D of the formula is improved.
4. Compared with the currently disclosed preparation method, the preparation method of the intermediate compound of formula D of the brivaracetam has the advantages that the reaction steps are only 3, the compound of formula A is prepared into the compound of formula B, and then the compound of formula D is prepared, the process is low in cost, strong in operability, and the compound of formula D with high optical purity can be stably obtained.
Further, after the crude product of the compound D is pulped and filtered, the purity of a filter cake is 97-99 percent, and the reactant A can be recovered with high yield; the recovered compound of formula a can be directly used as a starting material in a re-engineering process to prepare a compound of formula D.
Detailed Description
The invention will be further elucidated with reference to specific embodiments. The operating parameters in the examples are for illustration only and are not intended to be a full limitation of the scope of the invention; the raw materials used in the following examples are all commercially available raw materials without specific description.
Examples 1-5 preparation of Compounds of formula B
Example 1
Adding 428.31g of n-pentanoic acid and 6.0L of tetrahydrofuran into a 30L reaction kettle, adding 951.23g of triethylamine while stirring, cooling to-15 ℃ under the protection of nitrogen, dropwise adding 510.77g of pivaloyl chloride, reacting for 1.0h at-20 ℃, adding 187.21g of lithium chloride, preserving heat for 10min, dropwise adding a tetrahydrofuran solution (2.4L of tetrahydrofuran) containing 600.0g of reactant A, and controlling the temperature to be-20 ℃; after the dropwise addition, reacting for 4.0h, heating to 20 ℃, stirring for 12.0h, after the reaction is finished, adding 6.0L of 10% potassium carbonate aqueous solution, stirring for 10.0min, concentrating under reduced pressure to remove tetrahydrofuran, and adding 6L of methyl tert-butyl ether for extraction; extracting the water phase with 4.8L methyl tert-butyl ether, mixing organic layers, washing the organic layer with 3.0L 1M hydrochloric acid and 3.0L sodium bicarbonate water solution, concentrating to remove solvent to obtain 849.46g, with yield of 96.0% and purity of 96.77%; the nuclear magnetic data are as follows: 1.23-1.26(t, 3H), 1.38-1.42(m, 6H), 2.74-2.80(m, 1H), 3.19-3.23(m, 1H), 4.12-4.21(m, 2H), 4.66-4.72(m, 1H), 7.20-7.34(m,5H)ESI+，[M+H]+：262.3，[M+Na]+： 284.1
example 2
Adding 428.31g of n-pentanoic acid and 6.0L of 2-methyltetrahydrofuran into a 30L reaction kettle, adding 743.54g of pyridine while stirring, cooling to-15 ℃ under the protection of nitrogen, dropwise adding 510.77g of pivaloyl chloride, reacting at-5 ℃ for 1.0h after the dropwise adding is finished, adding 187.21g of lithium chloride, keeping the temperature for 10min, dropwise adding a 2-methyltetrahydrofuran solution (2.4L 2-methyltetrahydrofuran) containing 600.0g of reactant A, and controlling the temperature to be-5 ℃; after the dropwise addition, reacting for 2.0h, heating to 20 ℃, stirring for 12.0h, after the reaction is finished, adding 6.0L of 10% potassium carbonate aqueous solution, stirring for 10.0min, concentrating under reduced pressure to remove 2-methyltetrahydrofuran, and adding 6L of methyl tert-butyl ether for extraction; extracting the water phase with 4.8L methyl tert-butyl ether, mixing organic layers, washing the organic layer with 3.0L 1M hydrochloric acid and 3.0L sodium bicarbonate water solution, concentrating to remove solvent to obtain 852.09g, with yield of 96.30% and purity of 97.20%; the nuclear magnetic data were as in example 1.
Example 3
Adding 428.31g of n-pentanoic acid and 6.0L of diethyl ether into a 30L reaction kettle, adding 1214.85g of diisopropylethylamine while stirring, cooling to-20 ℃ under the protection of nitrogen, dropwise adding 510.77g of pivaloyl chloride, reacting for 1.0h at 10 ℃, adding 187.21g of lithium bromide, preserving heat for 10min, dropwise adding a diethyl ether solution (2.4L of diethyl ether) containing 600.0g of reactant A, and controlling the temperature to-20 ℃; after the dropwise addition, after reacting for 3.0h, heating to 20 ℃, stirring for 12.0h, after the reaction is finished, adding 6.0L of 10% potassium carbonate aqueous solution, stirring for 10.0min, concentrating under reduced pressure to remove ether, and adding 6L of methyl tert-butyl ether for extraction; the aqueous phase was extracted once more with 4.8L of methyl tert-butyl ether, the organic layers were finally combined and washed once more with 3.0L of 1M hydrochloric acid and 3.0L of aqueous sodium bicarbonate solution, respectively, and finally concentrated to remove the solvent to give 862.08g, yield 97.43%, purity 97.85%. The nuclear magnetic data were as in example 1.
Example 4
Adding 428.31g of n-pentanoic acid and 6.0L of toluene into a 30L reaction kettle, adding 475.61g of triethylamine and 371.77g of pyridine while stirring, cooling to-10 ℃ under the protection of nitrogen, dropwise adding 510.77g of pivaloyl chloride, reacting for 1.0h at-30 ℃, adding 187.21g of lithium bromide, preserving heat for 10min, dropwise adding a toluene solution (2.4L of toluene) containing 600.0g of reactant A, and controlling the temperature to be-70 ℃; after the dropwise addition, after the reaction is carried out for 5.0h, the temperature is raised to 20 ℃, the stirring is carried out for 12.0h, after the reaction is finished, 6.0L of 10 percent potassium carbonate aqueous solution is added, the stirring is carried out for 10.0min, the toluene is removed by reduced pressure concentration, and then 6L of methyl tert-butyl ether is added for extraction; the aqueous phase was extracted once more with 4.8L of methyl tert-butyl ether, the organic layers were finally combined and washed once more with 3.0L of 1M hydrochloric acid and 3.0L of aqueous sodium bicarbonate solution, respectively, and finally concentrated to remove the solvent to give 865.81g, 97.85% yield, 98.13% purity. The nuclear magnetic data were as in example 1.
Example 5
Adding 428.31g of n-pentanoic acid and 6.0L of tetrahydrofuran into a 30L reaction kettle, adding 951.23g of triethylamine under stirring, cooling to-15 ℃ under the protection of nitrogen, dropwise adding 510.77g of pivaloyl chloride, reacting for 1.0h at-20 ℃ after the dropwise adding is finished, adding 187.21g of lithium chloride, preserving heat for 10min, dropwise adding a tetrahydrofuran solution (2.4L of tetrahydrofuran) containing 600.0g of reactant A, and controlling the temperature to be-20 ℃; after the dropwise addition, the reaction was carried out for 4.0 hours, the temperature was raised to 20 ℃ and the mixture was stirred for 12.0 hours, after the reaction was completed, 868.19g was obtained by post-treatment, the yield was 98.12%, and the purity was 98.74%. The nuclear magnetic data were as in example 1.
EXAMPLE 6 to 10 preparation of the Compound of formula C
Example 6
222.2.0g B obtained in example 1 is weighed and added into a 5L reaction bottle, 1.60L tetrahydrofuran is added, the temperature is reduced to-40 ℃ under the protection of nitrogen, 920ml tetrahydrofuran solution of 1M bis (trimethylsilyl) amino alkali sodium salt is dripped, the temperature is controlled to-40 ℃, the dripping is finished, and the temperature is kept for 1.0 h. Cooling to-50 ℃, and dropwise adding 196.51g of tert-butyl 2-bromoacetate, controlling the temperature to-40 ℃; after dripping, stirring for 1.5h, heating to 15 ℃, reacting for 2h, sampling and detecting, and finishing the reaction. 1.0L of 15 percent ammonium chloride aqueous solution is added dropwise to quench the reactionStirring for 30.0min, standing, and separating an organic layer; the organic layer was washed once more with 20% sodium chloride solution. The organic layer was concentrated to dryness to give 383.00g of a yellow solid. Recrystallizing with mixed solvent of 250ml methyl tert-butyl ether and 2500ml n-heptane, and oven drying to obtain 259.15g white solid compound of formula C with yield 81.25%, purity 99.46%, and chiral purity 100%; (ii) a The nuclear magnetic data are as follows: CDCl3，400MHz，0.89-0.93(t，3H)，1.33-1.48(m，12H)，1.61-1.67 (m，1H)，2.45-2.50(dd，1H)，2.71-2.84(m，2H)，3.33-3.37(dd，1H)，4.14-4.21(m， 4H)，4.64-4.68(m，1H)，7.25-7.36(m，5H)；ESI+，[M+Na]+：398.2。
Example 7
222.2.0g B obtained in example 4 is weighed and added into a 5L reaction bottle, 1.60L tetrahydrofuran is added, the temperature is reduced to minus 30 ℃ under the protection of nitrogen, 920ml of tetrahydrofuran solution of bis (trimethylsilyl) amino alkali sodium salt with the concentration of 1M is dripped, the temperature is controlled to minus 30 ℃, the dripping is finished, and the temperature is kept for 1.0 h. Cooling to-20 ℃, and dropwise adding 196.51g of tert-butyl 2-bromoacetate, controlling the temperature to-30 ℃; after dripping, stirring for 3h, heating to 10 ℃, reacting for 2h, sampling and detecting, and finishing the reaction. Dropwise adding 1.0L of 15% ammonium chloride aqueous solution to quench the reaction, stirring for 30.0min, standing, and separating an organic layer; the organic layer was washed once more with 20% sodium chloride solution. The organic layer was concentrated to dryness to give 391.03g of a yellow solid. Recrystallizing with a mixed solvent of 250ml of methyl tert-butyl ether and 2500ml of n-heptane, and drying to obtain 262.03g of a white solid compound of formula C, wherein the yield is 82.15%, the purity is 99.59%, and the chiral purity is 100%; the nuclear magnetic data were as in example 6.
Example 8
222.2.0g B obtained in example 2 is weighed and added into a 5L reaction bottle, 1.60L tetrahydrofuran is added, the temperature is reduced to minus 30 ℃ under the protection of nitrogen, 920ml of tetrahydrofuran solution of bis (trimethylsilyl) amino alkali sodium salt with the concentration of 1M is dripped, the temperature is controlled to minus 70 ℃, and after the dripping is finished, the temperature is kept for 1.0 h. Cooling to-40 ℃, and dropwise adding 196.51g of 2-bromoacetic acid tert-butyl ester, controlling the temperature to-20 ℃; after dripping, stirring for 5h, heating to 5 ℃, reacting for 2h, sampling and detecting, and finishing the reaction. Dropwise adding 1.0L of 15% ammonium chloride aqueous solution to quench the reaction, stirring for 30.0min, standing, and separating an organic layer; the organic layer was washed once more with 20% sodium chloride solution. The organic layer was concentrated to dryness to give 380.05g of a yellow solid. Recrystallizing with mixed solvent of 250ml ethyl acetate and 2500ml n-heptane, oven drying to obtain 255.58g white solid compound of formula C with yield 80.13%, purity 99.37%, chiral purity 99.98%; the nuclear magnetic data were as in example 6.
Example 9
222.2.0g B obtained in example 3 is weighed and added into a 5L reaction bottle, 1.60L tetrahydrofuran is added, the temperature is reduced to minus 45 ℃ under the protection of nitrogen, 920ml of tetrahydrofuran solution of bis (trimethylsilyl) amino alkali sodium salt with the concentration of 1M is dripped, the temperature is controlled to minus 35 ℃, the dripping is finished, and the temperature is kept for 1.0 h. Cooling to-30 ℃, and dropwise adding 196.51g of 2-bromoacetic acid tert-butyl ester, controlling the temperature to-50 ℃; after dripping, stirring for 0.5h, heating to 15 ℃, reacting for 2h, sampling and detecting, and finishing the reaction. Dropwise adding 1.0L of 15% ammonium chloride aqueous solution to quench the reaction, stirring for 30.0min, standing, and separating an organic layer; the organic layer was washed once more with 20% sodium chloride solution. The organic layer was concentrated to dryness to give 378.95.g of a yellow solid. Recrystallizing with mixed solvent of 250ml methyl tert-butyl ether and 2500ml n-heptane, and oven drying to obtain 254.69g white solid compound of formula C with yield 79.85%, purity 99.57%, and chiral purity 99.99%; the nuclear magnetic data were as in example 6.
Example 10
222.2.0g B obtained in example 5 is weighed and added into a 5L reaction bottle, 1.60L tetrahydrofuran is added, the temperature is reduced to-40 ℃ under the protection of nitrogen, 920ml of tetrahydrofuran solution of bis (trimethylsilyl) amino alkali sodium salt with the concentration of 1M is dripped, the temperature is controlled to-40 ℃, the dripping is finished, and the temperature is kept for 1.0 h. Cooling to-50 ℃, and dropwise adding 196.51g of tert-butyl 2-bromoacetate, controlling the temperature to-40 ℃; after dripping, stirring for 1.5h, heating to 15 ℃, reacting for 2h, sampling and detecting, after the reaction is finished, dripping 1.0L of 15% ammonium chloride aqueous solution to quench the reaction, and performing post-treatment and refining to obtain 252.29g of a white solid C compound with yield of 79.10%, purity of 99.89% and chiral purity of 100%; the nuclear magnetic data were as in example 6.
Example 11 preparation of 18(R) -4-propyl-dihydrofuran-2-one (Compound of formula D)
Example 11
111.00g of the compound C obtained in example 6 and 1100ml of tetrahydrofuran are added into a 2L three-necked flask, stirred, the temperature is controlled between-25 ℃ and-10 ℃, 34.02g of solid sodium borohydride is added in batches, after the addition is finished, the temperature is controlled between-25 ℃ and-10 ℃, and 220ml of methanol is added dropwise. After the dropwise addition, preserving heat for 2h, naturally heating to room temperature, reacting for 5h, after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 500ml of 6M hydrochloric acid, after the dropwise addition is finished, stirring for 6h at room temperature, adding 500ml of toluene, and after stirring, standing and separating; separating out a water layer, and extracting the water layer once by using 500ml of toluene; mixing the organic layers, washing with 500ml of water, 500ml of 5% sodium bicarbonate aqueous solution and 500ml of saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 1000ml of n-heptane, stirring at room temperature for 2h, cooling to 0 ℃, stirring for 2h, filtering, drying the filter cake to obtain 49.30g of white solid, recovering the obtained A at a recovery rate of 95.0% and a purity of 98.7%; concentrating the filtrate to dryness to obtain 33.22g of light yellow liquid, namely (R) -4-propyl-dihydrofuran-2-ketone, with the yield of 88.47% and the chemical purity of 99.96%; isomer content 0.18%; specific rotation degree: +6.70(1g/100ml, ethanol, 20 ℃); the nuclear magnetic data are as follows: CDCl3, 400MHz, 0.92-0.94(m, 3H), 1.28-1.30(m, 2H), 1.32-1.34(m, 2H), 2.01-2.14(m, 1H), 2.13-2.63(m, 2H), 3.80-3.84 (dd, 1H), 4.39-4.44(dd, 1H); ESI+，[M+H]+:129.2。
Example 12
111.00g of the compound C obtained in example 7 and 1100ml of 2-methyltetrahydrofuran are added into a 2L three-necked flask, stirred, the temperature is controlled between-25 ℃ and-10 ℃, 48.50g of potassium borohydride solid is added in batches, the temperature is controlled between-25 ℃ and-10 ℃ after the addition is finished, and 220ml of ethanol is added dropwise. After the dropwise addition, preserving heat for 5h, naturally heating to 10 ℃, reacting for 6h, after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 500ml of 2M sulfuric acid, after the dropwise addition is finished, stirring for 6h at room temperature, adding 500ml of toluene, and standing for liquid separation after stirring; the aqueous layer was separated and the organic layer was extracted once more with 500ml toluene; combining the organic layers, washing with 500ml of water, 500ml of 5% sodium bicarbonate aqueous solution and 500ml of saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 1000ml of n-hexane, stirring at room temperature for 1 hour, cooling to 0 ℃, stirring for 1.5 hours, filtering, drying the filter cake to obtain 49.22g of white solid, recovering the obtained A with a recovery rate of 94.82% and a purity of 99.47%; concentrating the filtrate to dryness to obtain 32.22g of light yellow liquid, namely (R) -4-propyl-dihydrofuran-2-ketone, with the yield of 85.83% and the chemical purity of 100.00%; isomer content 0.08%; specific rotation degree: +7.20(1g/100ml, ethanol, 20 ℃), NMR data similar to example 11.
Example 13
111.00g of the compound C obtained in example 8 and 1100ml of N, N-dimethylformamide are added into a 2L three-necked flask, stirred, the temperature is controlled between minus 30 ℃ and minus 10 ℃, 19.60g of lithium borohydride solid is added in batches, the temperature is controlled between minus 30 ℃ and minus 10 ℃ after the addition is finished, and 220ml of N-butanol is added dropwise. After the dropwise addition, preserving heat for 3h, naturally heating to 30 ℃, reacting for 8h, after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 100ml of trifluoroacetic acid, after the dropwise addition is finished, stirring for 6h at room temperature, adding 500ml of toluene, and standing for liquid separation after stirring; the aqueous layer was separated and the organic layer was extracted once more with 500ml of toluene; combining the organic layers, washing with 500ml of water, 500ml of 5% sodium bicarbonate aqueous solution and 500ml of saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 1000ml of n-hexane, stirring at room temperature for 1h, cooling to 0 ℃, stirring for 1.5h, filtering, drying the filter cake to obtain 49.23g of white solid, recovering the obtained A with recovery rate of 94.80% and purity of 99.48%; concentrating the filtrate to dryness to obtain 32.23 light yellow liquid, namely (R) -4-propyl-dihydrofuran-2-ketone, wherein the yield is 85.84%, and the chemical purity is 100.00%; isomer content 0.09%; specific rotation degree: +7.10(1g/100ml, ethanol, 20 ℃), the nuclear magnetic data are the same as in example 11.
Example 14
111.00g of the compound C obtained in example 9 and 1100ml of 1, 4-dioxane are added into a 2L three-necked flask, stirred, the temperature is controlled between-25 ℃ and-10 ℃, 17.01g of sodium borohydride 9.80g of lithium borohydride solid is added in batches, and after the addition is finished, the temperature is controlled between-25 ℃ and-10 ℃, and 220ml of isopropanol is added. After the dropwise addition, preserving heat for 4h, naturally heating to 40 ℃, reacting for 15h, after the reaction is finished, cooling to 0 ℃, slowly dropwise adding 100ml of perchloric acid, stirring for 6h at room temperature after the dropwise addition is finished, adding 500ml of toluene, and standing for liquid separation after stirring; the aqueous layer was separated and the organic layer was extracted once more with 500ml of toluene; combining organic layers, washing with 500ml of water, 500ml of 5% sodium bicarbonate aqueous solution and 500ml of saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 1000ml of n-heptane, stirring at room temperature for 3 hours, cooling to 0 ℃, stirring for 1 hour, filtering, drying the filter cake to obtain 49.05g of white solid, recovering the obtained A, wherein the recovery rate is 94.50%, and the purity is 98.93%; concentrating the filtrate to dryness to obtain 31.65g of light yellow liquid, namely the preparation of (R) -4-propyl-dihydrofuran-2-ketone, wherein the yield is 84.29%, and the chemical purity is 98.33%; isomer content 0.16%; specific rotation degree: +6.80(1g/100ml, ethanol, 20 ℃ C.), the nuclear magnetic data is the same as in example 11.
Example 15
111.00g of the compound C obtained in the example 6 and 1100ml of methanol are added into a 2L three-necked bottle, the temperature is controlled between-25 ℃ and-10 ℃, 34.10g of sodium borohydride solid is added in batches under stirring, the temperature is controlled between-25 ℃ and-10 ℃, the temperature is kept for 1h after the addition, the temperature is naturally raised to 20 ℃, the reaction is carried out for 15h, the reaction is finished, the temperature is reduced to 0 ℃, 100ml of trifluoroacetic acid is slowly dripped, the dripping is finished, the stirring is carried out for 6h at room temperature, and after post-treatment, 33.51g of (R) -4-propyl-dihydrofuran-2-one is obtained, the yield is 89.25%, and the chemical purity is 98.88%; isomer content 0.13%; specific rotation + 7.10: (1g/100ml, ethanol, 20 ℃ C.), the same nuclear magnetic data as in example 11.
Example 16
111.00g of the compound C obtained in the example 8 and 1100ml of ethanol are added into a 2L three-necked bottle, the temperature is controlled between minus 20 ℃ and minus 10 ℃, 48.50g of potassium borohydride solid is added in batches under stirring, the temperature is controlled between minus 20 ℃ and minus 10 ℃, the addition is finished, the temperature is kept for 2 hours, the temperature is naturally raised to 10 ℃, the reaction is carried out for 10 hours, the reaction is finished, the temperature is lowered to 0 ℃, 100ml of trifluoroacetic acid is slowly dripped, the dripping is finished, the stirring is carried out for 6 hours at room temperature, and after-treatment, 31.20g of (R) -4-propyl-dihydrofuran-2-one is obtained, the yield is 83.12 percent, and the chemical purity is 99.12 percent; isomer content 0.13%; specific rotation + 6.95: (1g/100ml, ethanol, 20 ℃ C.), the same nuclear magnetic data as in example 11.
Example 17
111.00g of the compound C obtained in the example 9 and 1100ml of isopropanol are added into a 2L three-necked bottle, the temperature is controlled between-70 ℃ and-40 ℃, 48.50g of potassium borohydride solid is added in batches under stirring, the temperature is controlled between-70 ℃ and-40 ℃, the addition is finished, the temperature is kept for 4h, the temperature is naturally raised to 30 ℃, the reaction is carried out for 10h, the reaction is finished, the temperature is reduced to 0 ℃, 100ml of trifluoroacetic acid is slowly dripped, the dripping is finished, the stirring is carried out for 6h at room temperature, and after post-treatment, 32.06g of (R) -4-propyl-dihydrofuran-2-one is obtained, the yield is 85.39 percent, and the chemical purity is 98.97 percent; isomer content 0.09%; specific rotation + 7.00: (1g/100ml, ethanol, 20 ℃ C.), the same nuclear magnetic data as in example 11.
Example 18
111.00g of the compound C obtained in the example 10 and 1100ml of tert-butyl alcohol are added into a 2L three-necked bottle, the temperature is controlled between minus 40 ℃ and minus 10 ℃, 19.60g of lithium borohydride solid is added in batches under stirring, the temperature is controlled between minus 40 ℃ and minus 10 ℃, the temperature is kept for 5h, the temperature is naturally raised to 40 ℃, the reaction is carried out for 5h, the reaction is finished, the temperature is reduced to 0 ℃, 100ml of trifluoroacetic acid is slowly dripped, the dripping is finished, the stirring is carried out for 6h at room temperature, and after post-treatment, 31.27g of (R) -4-propyl-dihydrofuran-2-one is obtained, the yield is 83.29%, and the chemical purity is 98.57%; isomer content 0.10%; specific rotation + 7.05: (1g/100ml, ethanol, 20 ℃ C.), the same nuclear magnetic data as in example 11.
Claims (5)
1. A composition ofR) A process for the preparation of (E) -4-propyl-dihydrofuran-2-one comprising the steps of:
dissolving the compound shown in the formula C in an organic solvent 1, adding a reducing agent while stirring, dropwise adding an alcohol solvent, carrying out reduction reaction, and adding acid water for quenching to obtain a compound shown in the formula D; wherein,
the organic solvent 1 is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile and N, N-dimethylformamide;
the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and lithium borohydride;
the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol;
the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and perchloric acid;
2. the method of claim 1, wherein:
the adding mode is dripping;
and/or the temperature is-70 to-10 ℃ when the alcohol solvent is added;
and/or after the alcohol solvent is added, the reaction temperature is 10-40 ℃;
and/or the specific steps are as follows: dissolving the compound of the formula C in an organic solvent 1, adding a reducing agent, stirring, dropwise adding an alcohol solvent at-25 to-10 ℃, and reacting for 1 to 5 hours after dropwise adding; then heating to 10-40 ℃, reacting for 5-15 h, and adding acid water for quenching to obtain a compound shown in the formula D;
and/or, further comprising a refining step;
and/or, further comprising: the resulting compound of formula D is slurried with a solvent, filtered, and the filtrate is concentrated to dryness.
3. The method of claim 2, wherein:
the temperature is-25 to-10 ℃ when the alcohol solvent is added;
and/or after the alcohol solvent is added, the reaction temperature is 20-30 ℃;
and/or the solvent for pulping is one or more of n-heptane, n-hexane, methyl tert-butyl ether and diethyl ether.
4. The method of claim 1, wherein:
the adding mode of the reducing agent is adding in batches;
and/or the temperature of the reducing agent is-70 to-10 ℃ when the reducing agent is added;
and/or after the alcohol solvent is added, the reaction temperature is 10-40 ℃;
and/or, further comprising a refining step;
and/or, further comprising: and (3) pulping the obtained compound of the formula D with a solvent, filtering, concentrating the filtrate to be dry, wherein the solvent for pulping is one or more of n-heptane, n-hexane, methyl tert-butyl ether and diethyl ether.
5. The method of manufacturing according to claim 4, characterized in that:
the temperature of the reducing agent is-25 to-10 ℃;
and/or after the alcohol solvent is added, the reaction temperature is 20-30 ℃.
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| CN109535107A (en) | 2019-03-29 |
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