CN114380661B - Synthetic method of (+/-) -lavender alcohol - Google Patents
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- CN114380661B CN114380661B CN202210064824.XA CN202210064824A CN114380661B CN 114380661 B CN114380661 B CN 114380661B CN 202210064824 A CN202210064824 A CN 202210064824A CN 114380661 B CN114380661 B CN 114380661B
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- 239000001102 lavandula vera Substances 0.000 title claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000010189 synthetic method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 244000178870 Lavandula angustifolia Species 0.000 claims abstract description 23
- 235000010663 Lavandula angustifolia Nutrition 0.000 claims abstract description 23
- 235000018219 lavender Nutrition 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- JRMAQQQTXDJDNC-UHFFFAOYSA-M 2-ethoxy-2-oxoacetate Chemical compound CCOC(=O)C([O-])=O JRMAQQQTXDJDNC-UHFFFAOYSA-M 0.000 claims abstract description 10
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 10
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- JYPWHOZZLIGGIV-UHFFFAOYSA-N ethyl 2-acetyl-5-methylhex-4-enoate Chemical compound CCOC(=O)C(C(C)=O)CC=C(C)C JYPWHOZZLIGGIV-UHFFFAOYSA-N 0.000 claims abstract description 8
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- 125000004185 ester group Chemical group 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000012535 impurity Substances 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- GKRMUUAVMCXOGV-UHFFFAOYSA-N 2-acetyl-5-methylhex-4-enoic acid Chemical compound CC(C)=CCC(C(C)=O)C(O)=O GKRMUUAVMCXOGV-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 238000007239 Wittig reaction Methods 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
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 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
- 238000010791 quenching Methods 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000171 lavandula angustifolia l. flower oil Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 238000005821 Claisen rearrangement reaction Methods 0.000 description 1
- 241001227551 Lavandula x intermedia Species 0.000 description 1
- 241001647769 Mirza Species 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 238000010478 Prins reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000001053 badasse Nutrition 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229940087124 spike lavender oil Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing (+/-) -lavender alcohol, which comprises the following steps: (1) The ethyl acetoacetate and 1-bromo-3-methyl-2-butene undergo substitution reaction under alkaline conditions to prepare 2-acetyl-5-methylhex-4-enoic acid ethyl ester; (2) 2-acetyl-5-methyl hex-4-ethyl enoate reacts with methyl Wittig reagent in organic solvent to prepare lavender ethyl oxalate; (3) And (3) reducing the ester group of the lavender ethyl oxalate into alcohol under the action of lithium aluminum hydride to obtain a final product (+/-) -lavender alcohol. The invention has the advantages of low raw material price, short process route, few post-treatment steps and high reaction yield, and is a production process with a relatively good production prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing (+/-) -lavender alcohol.
Background
(±) -lavender alcohol, also known as laval Du Chun, is an important terpene natural perfume raw material, widely exists in lavender oil, hybrid lavender oil, spike lavender oil and some natural essential oils, and is an important index component for evaluating lavender oil. Lavender alcohol has Lavender-like flower fragrance and green spicy fragrance, and can be applied to the field of daily chemical essence. Because the content of the (+/-) -lavender alcohol in the common lavender oil is low, the yield of extracting the (+/-) -lavender alcohol from the natural essential oil is low, the price is high, and the economy is not realistic, so the (+/-) -lavender alcohol is generally synthesized by chemical synthesis.
The current method for synthesizing (+/-) -lavender alcohol is less and mainly synthesized through Claisen rearrangement reaction (Matsui, M.; stara-Bourdilron, B.agric.biol.chem.1968,32, 1246-1249) and Prins reaction (Cookson, R.C.; mirza, N.S. Synthi.Commun.1981, 11, 299-301.), but the application of lavender alcohol is greatly limited due to complicated synthesis steps and harsh conditions.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a novel method for synthesizing (+/-) -lavender alcohol. The method has the advantages of low raw material price, short process route, few post-treatment steps and high reaction yield, and is a production process with a relatively good production prospect.
The structural formula of (+ -) -lavender alcohol is as follows:
the invention (+/-) -lavender alcohol is synthesized by using ethyl acetoacetate and 1-bromo-3-methyl-2-butene as raw materials, and preparing 2-acetyl-5-methylhex-4-enoate by substitution reaction; then, carrying out Wittig reaction on the 2-acetyl-5-methyl hex-4-enoic acid ethyl ester and a methyl Wittig reagent to prepare the lavender ethyl oxalate; and reducing the ester group of the obtained ethyl lavender oxalate into alcohol under the action of lithium aluminum hydride to obtain a final product (+ -) -lavender alcohol. The reaction scheme is as follows:
the synthesis method of (+/-) -lavender alcohol comprises the following steps:
step 1: dissolving ethyl acetoacetate 1 and 1-bromo-3-methyl-2-butene 2 in an organic solvent at 0-100 ℃, adding alkali and potassium iodide into a reaction mixture, and keeping stirring at 0-100 ℃ for reaction for 0.5-100 hours; after the reaction is finished, water and saturated saline water are sequentially added for washing, the organic phases are combined and dried, insoluble matters are removed by filtration, the residual organic solvent is removed by decompression and concentration, and the 2-acetyl-5-methylhex-4-enoate 3 is prepared and can be directly used for the next reaction without purification;
step 2: sequentially adding the 2-acetyl-5-methylhex-4-enoate 3 obtained in the step 1 and a methyl Wittig reagent generated in situ into an organic solvent, and stirring and reacting for 0.5-100 hours at the temperature of 0-100 ℃; filtering to remove insoluble impurities after the reaction is finished, concentrating under reduced pressure to remove redundant organic solvents, and purifying the crude product by column chromatography (eluent is formed by mixing petroleum ether and ethyl acetate) to obtain the lavender ethyl oxalate 5;
step 3: adding the lavender ethyl oxalate 5 obtained in the step 2 into an organic solvent, adding lithium aluminum hydride into the reaction mixture batch by batch under intense stirring at the temperature of 0-100 ℃, and reacting for 0.5-100 hours at the temperature of 0-100 ℃ after the addition is completed; after the completion of the reaction, sodium sulfate decahydrate (Na 2 SO 4 ·10H 2 O) quenching reaction, filtering to remove insoluble impurities, drying the organic phase by anhydrous magnesium sulfate, filtering to remove insoluble impurities, concentrating under reduced pressure to remove redundant organic solvent, purifying the crude product by column chromatography (eluent is formed by mixing petroleum ether and ethyl acetate), and obtaining the lavender alcohol I.
The alkali is one or more than two of potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium methoxide, sodium hydroxide, lithium bistrimethylsilylamino, potassium bistrimethylsilylamino and sodium hydride.
The organic solvent is one or more of methanol, ethanol, tetrahydrofuran, dioxane, diethyl ether, toluene, acetonitrile, N-dimethylformamide and dimethyl sulfoxide.
The volume ratio of petroleum ether to ethyl acetate in the eluent is 1-100:1.
In the step 1, the feeding mole ratio of the ethyl acetoacetate 1 to the 1-bromo-3-methyl-2-butene 2 to the alkali to the potassium iodide is 1:1-10:1-10:0.1-1.
In the step 2, the feeding mole ratio of the 2-acetyl-5-methyl hex-4-enoic acid ethyl ester 3 to the methyl Wittig reagent 4 is 1:1-10.
In the step 3, the feeding mole ratio of the lavender ethyl oxalate 5 to the lithium aluminum hydride to the sodium sulfate is 1:1-10:1-100.
The lavender alcohol synthesis method has the advantages of simplicity, high efficiency, low cost and low pollution. The reaction process has the advantages of simple operation, small environmental pollution, high reaction yield, low production cost and convenience for industrial production, and is a production process with great industrial application prospect.
Detailed Description
The present invention will be further described with reference to specific examples, but the scope of the present invention is not limited to the examples, and if those skilled in the art make some insubstantial improvements and modifications in the present invention based on the above description, it is still within the scope of the present invention.
Example 1: synthesis of ethyl 2-acetyl-5-methylhex-4-enoate
Ethyl acetoacetate (50 mmol), 1-bromo-3-methyl-2-butene (60 mmol), potassium carbonate (75 mmol) and potassium iodide (40 mmol) were added sequentially to a 250mL reaction flask, N-dimethylformamide (100 mL) was added and stirring was turned on to allow it to stir uniformly, the reaction was stirred at room temperature for 24 hours, and after the starting material had completely disappeared, stirring was stopped. The reaction mixture was washed with water (100 mL. Times.3) and saturated brine (100 mL) in this order, and the organic phases were combined and dried over anhydrous magnesium sulfate (5 g). Insoluble matters are removed by filtration, redundant organic solvents are removed by decompression concentration, and the 2-acetyl-5-methyl hex-4-enoate is prepared and can be directly used for the next reaction without purification.
Example 2: synthesis of ethyl lavender oxalate
In a 250mL round bottom flask, ethyl 2-acetyl-5-methylhex-4-enoate 3 and methyl Wittig reagent (50 mmol) were added sequentially and toluene (100 mL) was added to dissolve and the reaction stirred at room temperature for 72 hours. After the reaction was completed, diethyl ether (100 mL) was added, insoluble impurities were removed by filtration, and the excess organic solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (volume ratio of eluent: petroleum ether: ethyl acetate=50:1) to give ethyl lavender oxalate (6.08 g, yield 62%).
Example 3: synthesis of Lavender alcohol
In a 250mL round bottom flask, the ethyl lavender oxalate (31 mmol) obtained in the above step was added, diethyl ether (100)mL) was dissolved, the reaction mixture was cooled to 0 ℃, lithium aluminum hydride (93 mmol) was added to the reaction in portions, and after the addition was completed, the reaction was slowly warmed to room temperature and stirred at room temperature for 6 hours. After the reaction was completed, sodium sulfate decahydrate (NaSO) was added 4 ·10H 2 O,300 mmol), filtering to remove insoluble impurities, washing the filter cake with diethyl ether (100 mL), combining the organic phases and drying over anhydrous magnesium sulfate (10 g), concentrating under reduced pressure to remove excess organic solvent, and purifying the crude product by column chromatography (eluent volume ratio is petroleum ether: ethyl acetate=3:1) to give lavender alcohol (4.39 g, yield 92%).
1 H NMR(600MHz,CDCl 3 )δ5.03(tt,J＝7.9,1.3Hz,1H),4.91-4.89(m,1H),4.75(s,1H),3.28(dd,J＝9.8,5.8Hz,1H),3.19(dd,J＝9.8,7.7Hz,1H),2.29(dt,J＝14.3,7.1,1H),2.24(dt,J＝14.3,7.1Hz,1H),2.11(dt,J＝14.3,7.0Hz,1H),1.69(s,3H),1.68(s,3H),1.63(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ145.5,133.4,121.5,112.8,49.4,39.9,25.8,19.3,18.0,11.3.
Claims (8)
1. A method for synthesizing (+/-) -lavender alcohol is characterized in that:
firstly, preparing 2-acetyl-5-methylhex-4-ethyl acrylate by substitution reaction by taking ethyl acetoacetate and 1-bromo-3-methyl-2-butene as raw materials; then, carrying out Wittig reaction on the 2-acetyl-5-methyl hex-4-enoic acid ethyl ester and a methyl Wittig reagent to prepare the lavender ethyl oxalate; reducing the ester group of the obtained ethyl lavender oxalate into alcohol under the action of lithium aluminum hydride to obtain a final product (+/-) -lavender alcohol;
the reaction scheme is as follows:
(1)
(2)
(3)
2. the synthesis method according to claim 1, characterized by comprising the steps of:
step 1: dissolving ethyl acetoacetate 1 and 1-bromo-3-methyl-2-butene 2 in an organic solvent at 0-100 ℃, adding alkali and potassium iodide into a reaction mixture, and keeping stirring at 0-100 ℃ for reaction for 0.5-100 hours; after the reaction is finished, water and saturated saline water are sequentially added for washing, the organic phases are combined and dried, insoluble matters are removed by filtration, the residual organic solvent is removed by decompression and concentration, and the 2-acetyl-5-methylhex-4-enoate 3 is prepared and can be directly used for the next reaction without purification;
step 2: adding the ethyl 2-acetyl-5-methylhex-4-enoate 3 obtained in the step 1 and a methyl Wittig reagent into an organic solvent in sequence, and stirring and reacting for 0.5-100 hours at the temperature of 0-100 ℃; filtering to remove insoluble impurities after the reaction is finished, concentrating under reduced pressure to remove redundant organic solvents, and purifying the crude product by column chromatography to obtain the lavender ethyl oxalate 5;
step 3: adding the lavender ethyl oxalate 5 obtained in the step 2 into an organic solvent, stirring at 0-100 ℃, adding lithium aluminum hydride into the reaction mixture batch by batch, and reacting at 0-100 ℃ for 0.5-100 hours after the addition is completed; after the reaction is finished, adding sodium sulfate decahydrate into the reaction mixture to quench the reaction, filtering to remove insoluble impurities, adding an organic phase into anhydrous magnesium sulfate to dry, filtering to remove insoluble impurities, concentrating under reduced pressure to remove redundant organic solvent, and purifying the crude product through column chromatography to obtain the lavender alcohol I.
3. The synthesis method according to claim 2, characterized in that:
the alkali is one or more than two of potassium carbonate, potassium phosphate, cesium carbonate, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium methoxide, sodium hydroxide, lithium bistrimethylsilylamino, potassium bistrimethylsilylamino and sodium hydride.
4. The synthesis method according to claim 2, characterized in that:
the organic solvent is one or more of methanol, ethanol, tetrahydrofuran, dioxane, diethyl ether, toluene, acetonitrile, N-dimethylformamide and dimethyl sulfoxide.
5. The synthesis method according to claim 2, characterized in that:
the eluent used in the column chromatography purification is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 1-100:1.
6. A synthetic method according to claim 2 or 3, characterized in that:
in the step 1, the feeding mole ratio of the ethyl acetoacetate 1 to the 1-bromo-3-methyl-2-butene 2 to the alkali to the potassium iodide is 1:1-10:1-10:0.1-1.
7. The synthesis method according to claim 2, characterized in that:
in the step 2, the feeding mole ratio of the 2-acetyl-5-methyl hex-4-enoic acid ethyl ester 3 to the methyl Wittig reagent 4 is 1:1-10.
8. The synthesis method according to claim 2, characterized in that:
in the step 3, the feeding mole ratio of the lavender ethyl oxalate 5, the lithium aluminum hydride and the sodium sulfate decahydrate is 1:1-10:1-100.
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| CN104302290A (en) * | 2012-01-13 | 2015-01-21 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
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| CN104302290A (en) * | 2012-01-13 | 2015-01-21 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
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