CN119431209A - A preparation method and application of a key intermediate of Vibelon - Google Patents
A preparation method and application of a key intermediate of Vibelon Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 239000002585 base Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229930003231 vitamin Natural products 0.000 claims abstract description 5
- 229940088594 vitamin Drugs 0.000 claims abstract description 5
- 235000013343 vitamin Nutrition 0.000 claims abstract description 5
- 239000011782 vitamin Substances 0.000 claims abstract description 5
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000005917 acylation reaction Methods 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 230000000911 decarboxylating effect Effects 0.000 claims abstract description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 19
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229930003427 Vitamin E Natural products 0.000 claims description 9
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 9
- 229940046009 vitamin E Drugs 0.000 claims description 9
- 235000019165 vitamin E Nutrition 0.000 claims description 9
- 239000011709 vitamin E Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical group CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 7
- 239000007864 aqueous solution Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- 206010020853 Hypertonic bladder Diseases 0.000 description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 208000020629 overactive bladder Diseases 0.000 description 3
- DJXRIQMCROIRCZ-XOEOCAAJSA-N vibegron Chemical compound C1([C@H]([C@@H]2N[C@H](CC=3C=CC(NC(=O)[C@H]4N5C(=O)C=CN=C5CC4)=CC=3)CC2)O)=CC=CC=C1 DJXRIQMCROIRCZ-XOEOCAAJSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004061 bleaching Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229950007643 vibegron Drugs 0.000 description 2
- WWYDYZMNFQIYPT-UHFFFAOYSA-L 2-phenylpropanedioate Chemical compound [O-]C(=O)C(C([O-])=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-L 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 239000005626 Tribenuron Substances 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- BQZXUHDXIARLEO-UHFFFAOYSA-N tribenuron Chemical compound COC1=NC(C)=NC(N(C)C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C(O)=O)=N1 BQZXUHDXIARLEO-UHFFFAOYSA-N 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a key intermediate of a vitamin E-Betula with a structural formula II and application of the key intermediate in preparation of the vitamin E-Betula. The preparation method comprises the steps of A, taking a compound of a structural formula III as a starting material, carrying out acylation reaction with sulfonyl chloride compounds in the presence of alkali to obtain a compound of a structural formula IV, B, reacting the compound of the structural formula IV with the compound of the structural formula V in the presence of alkali to obtain a compound of the structural formula VI, C, decarboxylating the compound of the structural formula VI in the presence of alkali, then removing protecting groups in the presence of acid, and cyclizing to obtain a compound of the structural formula VII, and D, reducing the compound of the structural formula VII into a vitamin-base key intermediate of the structural formula II under the action of a metal catalyst and hydrogen.Wherein R 1 is selected from methylsulfonyl or phenylsulfonyl, and R 2 is selected from C 1-C2 alkyl or benzyl.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of a key intermediate of velbegron and application of the key intermediate in preparation of the velbegron.
Background
Vebenone (Vibegron, CAS: 1190389-15-1), also known as View Bei Gelong, trade nameChemical name (S) -N- (4- (((2S, 5R) -5- ((R) -hydroxy (phenyl) methyl) pyrrolidine) methyl) phenyl) -4-carbonyl-4, 6,7, 8-tetrahydropyrrole [1,2-a ] pyrimidine-6-carboxamide, structural formula is shown as I.
Vebeston (Vibegron) is a β3 adrenergic receptor (β3-AR) agonist developed by the company moesadong and is used to treat overactive bladder (OAB) with symptoms of adult urge incontinence, urgency and frequency. A large number of researches show that the product has less adverse reaction, high curative effect and good tolerance, and can provide a new treatment option for patients with OAB.
PCT patent application publication No. WO2013062881A1 (publication No. 2013, 5, 2) discloses a method for coupling compound I-11 and compound I-12 to prepare Vebenone (I).
The key intermediates of the above formula i-11 are prepared by the following route:
The protecting group on the compound i-5 is used for obtaining a compound i-6, and then TEMPO oxidation and NaClO bleaching are carried out for obtaining a compound i-7. And carrying out HWE coupling reaction on the compound i-7 and the compound a-4 to obtain unsaturated ketone i-8. The compound i-8 is reduced to the compound i-9 by palladium carbon and hydrogen. Under acidic conditions, compound i-9 forms compound i-10 by cyclization to form an imine and deprotection. The compound i-10 is converted into a key intermediate i-11 of the Vebenone under the reduction of platinum alumina and hydrogen.
The above-mentioned route has problems in that, first, the compound i-6 is oxidized by TEMPO to form the compound i-7, bleaching with a sodium hypochlorite (NaClO) solution which is not easy to handle is required, and at the same time, the sodium hypochlorite solution must be slowly dropped below 0 ℃ and the excessive oxidation is liable to occur under slightly controlled conditions. Secondly, the HWE coupling reaction of the route adopts the compound with the structural formula a-4, which can generate phosphine-containing waste, is very unfavorable for production and environmental protection, and has complex synthesis process. Thirdly, the route has more steps, involves more protecting groups, has complex protecting and deprotecting reactions, and has poor atom economy and low atom utilization rate along with the removal of the protecting groups, thereby being unfavorable for reducing the cost and not conforming to the aim of green chemistry.
In view of the foregoing, there is a need to develop a new method for preparing a key intermediate of velbegron, which is short in route, low in cost, and environmentally friendly, and does not involve a phosphine intermediate.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel preparation method of a key intermediate of the velbegron and provides application of the preparation method in preparation of the velbegron. The novel method for preparing the vitamin E intermediate has few steps, avoids using phosphine-containing raw materials which are high in cost and difficult to treat, can reduce the production cost, and enables the preparation of the vitamin E to be more environment-friendly and efficient.
For this purpose, the invention adopts the following technical scheme:
a preparation method of a key intermediate of a Vebenone with a structural formula II,
The method comprises the following steps:
A. The compound with the structural formula III is taken as a starting material, and is subjected to acylation reaction with sulfonyl chloride compounds in the presence of alkali to obtain the compound with the structural formula IV,
Wherein R 1 is selected from methylsulfonyl or phenylsulfonyl;
B. Reacting a compound of the structural formula IV with a compound of the structural formula V in the presence of a base to obtain a compound of the structural formula VI,
Wherein R 2 is selected from C 1-C2 alkyl or benzyl;
C. Decarboxylating the compound with the structural formula VI in the presence of alkali, removing the protecting group in the presence of acid, and simultaneously cyclizing to obtain the compound with the structural formula VII,
D. The compound with the structural formula VII is reduced into a vitamin Begron key intermediate with the structural formula II under the action of a metal catalyst and hydrogen,
Preferably, R 1 is methylsulfonyl.
Preferably, R 2 is methyl or ethyl.
Preferably, in the step a, the molar ratio of the compound of structural formula III to the sulfonyl chloride compound is 1:1 to 1:6, more preferably 1:1 to 1:2.
Preferably, in step a, the base is selected from triethylamine, diisopropylethylamine, diisopropylamine or sodium carbonate, more preferably triethylamine.
Preferably, in step a, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, DMSO or toluene, more preferably dichloromethane.
Preferably, in the step a, the reaction temperature is 25 to 80 ℃, more preferably 25 to 40 ℃.
Preferably, in the step B, the molar ratio of the compound of the structural formula IV to the compound of the structural formula V is 1:1 to 1:5, more preferably 1:1 to 1:2.
Preferably, in step B, the base is selected from magnesium ethoxide, sodium methoxide, potassium tert-butoxide, cesium carbonate or sodium carbonate, more preferably magnesium ethoxide.
Preferably, in step B, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, DMSO or toluene, more preferably toluene.
Preferably, in the step B, the reaction temperature is-20 to 25 ℃, more preferably 0 ℃.
Preferably, in step C, the base is selected from the group consisting of saturated sodium carbonate solution, saturated sodium bicarbonate solution, 30% w/w sodium hydroxide solution, more preferably 30% w/w sodium hydroxide solution.
Preferably, in step C, the acid is selected from a 15% w/w solution of isopropanol hydrochloride, a 15% w/w solution of ethanol hydrochloride or a 15% w/w solution of aqueous hydrochloric acid, most preferably a 15% w/w solution of isopropanol hydrochloride.
Preferably, in the step C, the molar ratio of the compound VI to the acid is 1:1 to 1:20, more preferably 1:10 to 1:12.
Preferably, the reaction temperature in the step C is 25-80 ℃, and more preferably 25-40 ℃.
Preferably, in step D, the metal catalyst is selected from 5% pd/C, 5% Pt/Al 2O3 or 5% raney nickel, more preferably 5% Pt/Al 2O3.
Preferably, in the step D, the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, dichloromethane or toluene, more preferably tetrahydrofuran.
Preferably, the reaction temperature in the step D is 25 to 80 ℃, and more preferably 25 to 40 ℃.
In step B above, the compound of formula V may be prepared from p-nitroacetyl chloride and a malonic acid monoester (e.g., methyl malonate, ethyl malonate, or benzyl malonate) according to methods conventional in the art.
The synthesis route of the key intermediate of the vitamin Begron with the structural formula II is shown as follows by taking the compound with the structural formula III as a starting material:
The invention also aims to provide the application of the preparation method of the key intermediate of the vitamin E in the structural formula II in the preparation of the vitamin E, namely, the key intermediate of the vitamin E in the structural formula II is prepared by the method and then reacts with the compound in the structural formula VIII to obtain the vitamin E in the structural formula I;
The reaction of the above compound of formula II and the compound of formula VIII may be carried out according to the process conditions already disclosed in the prior art, such as the reaction conditions disclosed in PCT patent application publication No. WO2013062881A1 (publication date 2013, 5, 2).
The preparation method of the key intermediate of the vitamin E provided by the invention has the advantages of short route, low price and easy obtainment of all raw materials, no use of phosphine-containing raw materials and environmental friendliness. In addition, the preparation method disclosed by the invention is mild in process condition and suitable for industrial production.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified.
EXAMPLE 1 preparation of Compounds of formula IV-1
1.1A reaction flask was charged with 10.75g (35 mmol) of the compound of formula III, 5ml of triethylamine, 4.79g (42 mmol) of methanesulfonyl chloride was slowly added dropwise, and then 30ml of dichloromethane was added as a solvent. After completion of TLC detection, excess triethylamine was removed by rotary evaporator, and 20 ml.times.3 of water was added to the reaction mixture to extract it sufficiently, and after the organic phases were combined, the solvent was distilled off to obtain a compound of formula IV-1 (12.13 g, yield 90%).
1.2 Reaction flask 9.21g (30 mmol) of the compound of formula III and 4.5ml of diisopropylethylamine are added in succession, 4.10g (36 mmol) of methylsulfonyl chloride are slowly added dropwise, and then 30ml of tetrahydrofuran are added as solvent. After completion of TLC detection, excess diisopropylethylamine was removed by rotary evaporator, and 20ml×3 of ethyl acetate and 20ml×3 of water were added to conduct extraction, and the organic phases were combined and the solvent was distilled off to give a compound of formula IV-1 (9.81 g, yield 85%).
1H-NMR(400M,DMSO-d6)：7.43-7.11(5H,m),5.04(1H,d),4.44-4.42(1H,m),4.15-3.96(2H,d),3.03(3H,s),1.47(9H,s),1.45(6H,s).
EXAMPLE 2 preparation of Compounds of formula IV-2
2.1 Reaction flask 9.21g (30 mmol) of the compound of formula III and 5ml of triethylamine are added in succession, 5.29g (30 mmol) of benzenesulfonyl chloride are slowly added dropwise, and then 30ml of dichloromethane are added as solvent. After completion of TLC detection, excess triethylamine was removed by rotary evaporator, and 20ml of 3 water was added to the reaction mixture to extract the mixture sufficiently, followed by combining the organic phases and distilling off the solvent to give a compound of formula IV-2 (11.93 g, yield 89%).
1H-NMR(400M,DMSO-d6)：7.92(2H,d),7.73-7.65(3H,m),7.45-7.30(3H,m)7.11(2H,d),5.11(1H,m),4.47(1H,m),3.90(1H,m),3.70(1H,m),1.47(9H,s),1.42(6H,s).
EXAMPLE 3 preparation of Compounds of formula VI-1
3.1 Reaction flask 13.48g (35 mmol) of the compound of formula IV-1 prepared as described in example 1, 12.44g (52.5 mmol) of the compound of formula V-1 and 20ml of toluene as solvent were added in sequence, and a toluene solution of magnesium ethoxide (35 ml, 1M) prepared beforehand was slowly added dropwise. After completion of the reaction by TLC, 30ml of 3 water was added to the reaction mixture to extract the mixture sufficiently, and the organic phase was combined and the solvent was distilled off to obtain a compound of formula VI-1 (16.94 g, yield 92%).
3.2A reaction flask was charged with 14.63g (38.0 mmol) of the compound of formula IV-1 prepared as described in example 1 and 14.41g (60.8 mmol) of the compound of formula V-1 in this order, 15ml of tetrahydrofuran was added dropwise as solvent, and then a solution of sodium methoxide (38 ml, 1M) in tetrahydrofuran prepared beforehand was added dropwise. After completion of the reaction by TLC, 30ml of 3 water was added to the reaction mixture to extract the mixture sufficiently, and the organic phase was combined and the solvent was distilled off to obtain a compound of formula VI-1 (17.59 g, yield 88%).
1H-NMR(400M,DMSO-d6)：7.72-7.33(5H,m),7.15-6.90(4H,m),4.97(1H,d),4.42(1H,q),4.31-4.25(2H,m),3.80-3.78(1H,m),3.76(1H,t),3.44-3.42(1H,m),2.67-2.64(1H,m),2.31-2.29(1H,m),1.50(6H,s),1.47(9H,s),1.23(3H,s)
EXAMPLE 4 preparation of Compounds of formula VI-2
4.1A reaction flask was charged with 14.30g (32 mmol) of the compound of formula IV-2 prepared as described in example 2, 11.38g (48 mmol) of the compound of formula V-2, and then 20ml of toluene as solvent, followed by slowly dropping a pre-prepared toluene solution of magnesium ethoxide (35 ml, 1M). After completion of the reaction by TLC, 30ml of 3 water was added to the reaction mixture to extract the mixture sufficiently, and the organic phase was combined and the solvent was distilled off to obtain a compound of formula VI-1 (15.15 g, yield 90%).
4.2A reaction flask was charged with 15.65g (35.0 mmol) of the compound of formula IV-2 prepared as described in example 2 and 12.44g (52.5 mmol) of the compound of formula V-2 in this order, 15ml of tetrahydrofuran was added dropwise as solvent, and then a solution of sodium methoxide (38 ml, 1M) in tetrahydrofuran prepared beforehand was added dropwise. After completion of the reaction by TLC, 30ml of 3 water was added to the reaction mixture to extract the mixture sufficiently, and the organic phase was combined and the solvent was distilled off to obtain a compound of formula VI-1 (15.65 g, yield 85%).
1H-NMR(400M,DMSO-d6)：7.72(2H,d),7.45-6.90(7H,m),4.99(1H,d),4.43-4.41(1H,m),3.80-3.76(2H,m),3.61(3H,s),3.44-3.42(1H,m),2.67-2.64(1H,m),2.31-2.29(1H,m),1.48(6H,s),1.46(9H,s).
EXAMPLE 5 preparation of Compound F
5.1A reaction flask was charged with 15.78g (30.0 mmol) of the compound of formula VI-1 prepared as described in example 3, 15ml of tetrahydrofuran and 30ml of 30% w/w sodium hydroxide solution. The reaction was stirred overnight at 60 ℃, monitored by TLC, and after complete consumption of the starting material 150ml of 15% w/w isopropanol hydrochloride solution was added and reacted for 24 hours at 60 ℃. The reaction system was adjusted to pH 8 with saturated sodium bicarbonate solution, and 30ml of ethyl acetate (X3) was added to conduct sufficient extraction, and after the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the cake was washed with 10ml of ethyl acetate, and the organic phases were combined, and the solvent was distilled off to obtain a compound of formula VII (8.37 g, yield 91%).
5.2A reaction flask was charged with 15.78g (30.0 mmol) of the compound of formula VI-2 prepared as described in example 4, 20ml of tetrahydrofuran and 35ml of a 30% w/w sodium hydroxide solution. After the complete consumption of the starting materials, 170ml of 15% w/w ethanol hydrochloride solution was added, followed by reaction at 65℃for 24 hours by TLC monitoring, after the completion of the TCL monitoring, a saturated sodium carbonate solution was slowly added dropwise, after no bubbles had appeared, dropwise addition was stopped (at which time pH was. Apprxeq.8), 30ml of X3 ethyl acetate was added for sufficient extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with 10ml of ethyl acetate, the organic phases were combined, and the solvent was distilled off to give the compound of formula VII (7.70 g, yield 91%).
1H-NMR(400M,DMSO-d6)：7.47-7.28(9H,m),5.07-5.05(1H,m),4.74(1H,d),4.23(1H,m),3.67-3.31(2H,m),2.89(1H,m),2.78(1H,m),1.96(1H,m),1.86(1H,m).
EXAMPLE 6 preparation of Compounds of formula II
6.1A hydrogenation reactor was charged with 19.74g (70.0 mmol) of the compound of formula VII prepared as described in example 3 and 0.98g of 5% Pt/Al 2O3, then 50ml of tetrahydrofuran was added as a solvent, the reaction was carried out at room temperature under a hydrogen pressure of 0.6MPa overnight, after the completion of the TLC detection, pt/Al 2O3 was removed by filtration, and the reaction solvent was removed by a rotary evaporator to give the compound of formula II (18.75 g, yield 95%)
6.2 In a hydrogenation reactor, 22.94g (74.0 mmol) of the compound of formula VII prepared as described in example 3 and 1.15g of 5% Pt/C were added, and then, 20ml of methanol was added as a solvent, and the reaction was carried out overnight at 40℃under a hydrogen pressure of 0.4MPa, after the completion of the TLC detection, pt/C was removed by filtration, and the reaction solvent was removed by rotary evaporator to give the compound of formula II (18.78 g, yield 90%).
1H NMR(400MHz,d6-DMSO):7.27(4H,m),7.17(1H,m),6.81(2H,d),6.45(2H,d),5.07(1H,s),4.75(2H,s),4.18(1H,d),3.05(2H,m),2.47(1H,dd),2.40(1H,dd),1.53(1H,m),1.34(1H,m),1.22(2H,m).
The preparation of the tribenuron from the compound of formula II can be carried out according to the reaction conditions already described in the prior art, as for EXAMPLE in EXAMPLE 3 (EXAMPLE 3) of the PCT patent application publication WO2013/062881A 1.
Claims (10)
1. A preparation method of a key intermediate of a Vebenone with a structural formula II,
The method comprises the following steps:
A. The compound with the structural formula III is taken as a starting material, and is subjected to acylation reaction with sulfonyl chloride compounds in the presence of alkali to obtain the compound with the structural formula IV,
Wherein R 1 is selected from methylsulfonyl or phenylsulfonyl;
B. Reacting a compound of the structural formula IV with a compound of the structural formula V in the presence of a base to obtain a compound of the structural formula VI,
Wherein R 2 is selected from C 1-C2 alkyl or benzyl;
C. Decarboxylating the compound with the structural formula VI in the presence of alkali, removing the protecting group in the presence of acid, and simultaneously cyclizing to obtain the compound with the structural formula VII,
D. The compound with the structural formula VII is reduced into a vitamin Begron key intermediate with the structural formula II under the action of a metal catalyst and hydrogen,
2. The method of claim 1, wherein R 1 is methylsulfonyl;
Preferably, R 2 is methyl or ethyl.
3. The preparation method according to claim 1 or 2, wherein in the step a, the molar ratio of the compound of structural formula III to the sulfonyl chloride compound is 1:1 to 1:6, more preferably 1:1 to 1:2;
Preferably, in step a, the base is selected from triethylamine, diisopropylethylamine, diisopropylamine or sodium carbonate, more preferably triethylamine;
Preferably, in step a, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, DMSO or toluene, more preferably dichloromethane;
Preferably, in the step a, the reaction temperature is 25 to 80 ℃, more preferably 25 to 40 ℃.
4. A method according to any one of claims 1 to 3, wherein in step B the molar ratio of the compound of formula IV to the compound of formula V is 1:1 to 1:5, more preferably 1:1 to 1:2.
5. The process according to any one of claims 1 to 4, wherein in step B, the base is selected from magnesium ethoxide, sodium methoxide, potassium tert-butoxide, cesium carbonate or sodium carbonate, more preferably magnesium ethoxide;
Preferably, in said step B, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, DMSO or toluene, more preferably toluene;
preferably, in the step B, the reaction temperature is-20 to 25 ℃, more preferably 0 ℃.
6. The method of any one of claims 1 to 5, wherein in step C, the base is selected from saturated sodium carbonate solution, saturated sodium bicarbonate solution, 30% w/w sodium hydroxide solution, more preferably 30% w/w sodium hydroxide solution;
Preferably, in step C, the acid is selected from a 15% w/w hydrochloric acid isopropyl alcohol solution, a 15% w/w hydrochloric acid ethanol solution, or a 15% w/w hydrochloric acid aqueous solution, most preferably a 15% w/w hydrochloric acid isopropyl alcohol solution;
Preferably, in the step C, the molar ratio of the compound VI to the acid is 1:1 to 1:20, more preferably 1:10 to 1:12.
7. The method according to any one of claims 1 to 6, wherein the reaction temperature in step C is 25 to 80 ℃, more preferably 25 to 40 ℃.
8. The method of any one of claims 1 to 7, wherein in step D the metal catalyst is selected from 5% pd/C, 5% pt/Al 2O3 or 5% raney nickel, more preferably 5% pt/Al 2O3.
9. The process according to any one of claims 1 to 8, wherein in step D the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, dichloromethane or toluene, more preferably tetrahydrofuran;
Preferably, the reaction temperature in the step D is 25 to 80 ℃, and more preferably 25 to 40 ℃.
10. The use of the process for the preparation of the key intermediate of formula II according to any one of claims 1 to 9 for the preparation of vitamin E comprises preparing the key intermediate of formula II by the process according to any one of claims 1 to 9 and then reacting with the compound of formula VIII to obtain the key intermediate of formula I;
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