CN103030553A - Synthesis method of menthylformic acid - Google Patents
Synthesis method of menthylformic acid Download PDFInfo
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- CN103030553A CN103030553A CN2012104867717A CN201210486771A CN103030553A CN 103030553 A CN103030553 A CN 103030553A CN 2012104867717 A CN2012104867717 A CN 2012104867717A CN 201210486771 A CN201210486771 A CN 201210486771A CN 103030553 A CN103030553 A CN 103030553A
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- menthyl
- formic acid
- solvent
- synthetic method
- sodium sulfate
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- 239000002253 acid Substances 0.000 title abstract 3
- 238000001308 synthesis method Methods 0.000 title abstract 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims abstract description 19
- 238000010992 reflux Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012535 impurity Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- -1 TsIm Substances 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 62
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 31
- 235000019253 formic acid Nutrition 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 19
- 229940041616 menthol Drugs 0.000 claims description 19
- 238000010189 synthetic method Methods 0.000 claims description 14
- 150000002825 nitriles Chemical class 0.000 claims description 13
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 21
- 239000000047 product Substances 0.000 abstract description 20
- 238000010438 heat treatment Methods 0.000 abstract description 7
- 230000003287 optical effect Effects 0.000 abstract description 3
- FJMMZJZTJGGXHX-UHFFFAOYSA-N potassium sodium dicyanide Chemical compound [K+].[C-]#N.[Na+].[C-]#N FJMMZJZTJGGXHX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract 2
- 238000004821 distillation Methods 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 239000012043 crude product Substances 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 239000012264 purified product Substances 0.000 abstract 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 239000002585 base Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 5
- 240000002853 Nelumbo nucifera Species 0.000 description 5
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 5
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 5
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- VUNOFAIHSALQQH-UHFFFAOYSA-N Ethyl menthane carboxamide Chemical compound CCNC(=O)C1CC(C)CCC1C(C)C VUNOFAIHSALQQH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- MNVSUVYRIVXDBK-KXUCPTDWSA-N (1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexane-1-carboxylic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)=O MNVSUVYRIVXDBK-KXUCPTDWSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OMLOJNNKKPNVKN-KXUCPTDWSA-N CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1Cl Chemical compound CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1Cl OMLOJNNKKPNVKN-KXUCPTDWSA-N 0.000 description 1
- JDGJLPHFRJNJMN-OUAUKWLOSA-N CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC Chemical compound CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC JDGJLPHFRJNJMN-OUAUKWLOSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- XVVLAOSRANDVDB-UHFFFAOYSA-N formic acid Chemical compound OC=O.OC=O XVVLAOSRANDVDB-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses a synthesis method of menthylformic acid, which comprises the following steps: adding organic solvent, L-menthol, cuprous cyanide, TsIm, alkali and catalyst into a three-neck flask provided with a reflux condensation tube, and heating under reflux at 90-110 DEG C for 5-10 hours; after the reaction finishes, evaporating under reduced pressure to remove the solvent, adding a certain amount of water into the residue, extracting with n-hexane, drying with anhydrous sodium sulfate, and drying by distillation to remove the solvent, thereby obtaining menthylnitrile; adding the unrefined menthylnitrile into THF (tetrahydrofuran) solvent, adding a 40-45% NaOH water solution, heating under reflux at 90-110 DEG C for 5-8 hours, extracting with ethyl acetate to remove organic impurities, acidifying the water phase with dilute hydrochloric acid until the pH value is 6-7, extracting with CH2Cl2, drying with anhydrous sodium sulfate, drying by distillation to obtain a menthylformic acid crude product, and recrystallizing with anhydrous ethanol to obtain the purified product. The preparation method disclosed by the invention avoids uses virulent sodium (potassium) cyanide, and has the advantages of short synthetic technical route, mild reaction conditions and high optical purity of the product.
Description
Technical field
The present invention relates generally to a kind of synthetic method, relates in particular to a kind of synthetic method of menthyl formic acid.
Background technology
Menthol is traditional freshener, it acts on skin and the oral mucosa, can give product refrigerant, fresh sensation, and menthol has the extremely low and cheap advantage of threshold value, therefore be widely used in industries such as food, medicine, daily use chemicals, tobaccos.But it also has the shortcomings such as pungency is strong, action time short, water insoluble.Its range of application is limited by very large.
In order to overcome the shortcoming of traditional freshener n-ethyl-p-menthane-3 alcohol, since 20 century 70s, scientists is arisen at the historic moment by the molecular structure of MENTHOL being modified the novel coolant agent that obtains.Normally introduce a large group at hydroxyl, ester class and ethers such as MENTHOL, perhaps hydroxyl replace is generated ester class and the amides of menthyl-3-carboxylic acid, this compounds is proposed by Wilkinson sword and confirms, therefore is called as the WS series compound.This compounds has comparatively detailed description in US4150052, GB1351761-2.With N-ethyl-2-sec.-propyl-5-methylcyclohexane acid amides (referred to as: WS-3), N-(glycine ethyl ester base)-2-sec.-propyl-5-methylcyclohexane acid amides (referred to as: WS-5), N-(4-cyanogen aminomethyl phenyl)-2-sec.-propyl-5-methylcyclohexane acid amides (US 20070276667), N-(2-(2-pyridyl) ethyl)-2-sec.-propyl-5-methylcyclohexane acid amides (WO 2007019719) is the most commonly used, wherein WS-3's is most widely used.
In synthetic WS series compound reaction, intermediate (1R, 2S, 5R)-5-methyl-2-isopropyl hexahydrobenzoic acid (referred to as: menthyl formic acid, structural formula is compound 1 among Fig. 1) synthetic be crucial step, its synthetic method mainly contains format method and cyanide process.
With patent US4226988, US4193936 be representative synthetic menthyl formic acid format method synthetic route as shown in Figure 1:
Fig. 1
MENTHOL changes menthyl chlorine (bromine) into, then generates Grignard reagent with MAGNESIUM METAL---and menthyl chlorine (bromine) is changed magnesium, and menthyl chlorine (bromine) is changed magnesium and generated menthyl formic acid with the dry ice reaction again.In this synthetic method, because menthyl chlorine (bromine) torpescence generates relatively difficulty of menthyl chlorine (bromine) change magnesium, severe reaction conditions, productive rate is low, also exists simultaneously by product many, and the defectives such as difficult separation have limited its application.
The method of the synthetic menthyl formic acid of cyanide process has two kinds, and a kind of is first MENTHOL to be converted into new menthyl chlorine (bromine), then with NaCN(KCN) cyanogenation occurs, at last hydrolysis obtains menthyl formic acid.Study on the synthesis (fragrance flavor and cosmetic, 2005,1,7) such as New Cooling Agent N-ethyl-L-menthylformylamine.The synthetic route of taking is as shown in Figure 2:
Another is MENTHOL and methylsulfonyl chloride or Tosyl chloride reaction generation methylsulfonic acid menthyl ester or tosic acid menthyl ester, and then generate new menthyl nitrile (3 among Fig. 3) with sodium cyanide (potassium) reaction, generate menthyl formic acid finally by crossing configuration reversal.Such as Tetrahedron:Asymmetry, 1996,7 (7), 1967.Its synthetic route chart as shown in Figure 3.
Cyanide process is compared with the format method, and the former reaction conditions is relatively gentle, operate also simpler, but the used cyanating reagent of this route is hypertoxic sodium cyanide (potassium), brings very large hidden danger to production safety, its application is restricted.Owing to introduce methylsulfonyl or p-toluenesulfonyl, the Atom economy of reaction is very poor simultaneously, and production cost increases.
In order to overcome the deficiency of existing synthetic method, the present invention uses the cupric cyanide of low toxicity as cyanating reagent, and a step generates the menthyl nitrile, obtains menthyl formic acid through hydrolysis again.The synthesis technique circuit that adopts is short, reaction conditions is gentle, optical purity is high
Summary of the invention
The object of the invention just provides a kind of synthetic method of menthyl formic acid.
The present invention is achieved by the following technical solutions:
A kind of synthetic method of menthyl formic acid may further comprise the steps:
(1) synthetic (cyanogenation) of menthyl nitrile: in the there-necked flask with reflux condensing tube, add organic solvent, MENTHOL, cyanating reagent, TsIm, alkali and phase-transfer catalyst, at 90-110 ℃ of lower reflux 5-10 hour, after reaction finishes, remove solvent under reduced pressure, residuum adds a certain amount of water, uses n-hexane extraction, anhydrous sodium sulfate drying again, the evaporate to dryness desolventizing gets the thick product of menthyl nitrile;
(2) synthetic (hydrolysis reaction) of menthyl formic acid: the head product that obtains in the step (1) is joined in the THF solvent, the NaOH aqueous solution that adds 40-45%, at 90-110 ℃ of lower reflux 5-8 hour, remove organic impurity with ethyl acetate extraction, water is acidified to pH=6-7 with dilute hydrochloric acid, CH
2Cl
2Extraction, anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, and the dehydrated alcohol recrystallization gets sterling.
Chemical equation is as follows:
Described cyanating reagent is sodium cyanide, potassium cyanide, cuprous cyanide, preferred cuprous cyanide;
Described organic solvent is the HMPA(hexamethylphosphoramide), DMI(N, the N-dimethyl-imidazolinone), DMF(N, dinethylformamide), the DMSO(methyl-sulphoxide) or NMP(N-methyl--pyrrolidone), preferred DMI and HMPA;
Described alkali is the TEA(triethylamine), the TMA(Trimethylamine 99), Na
2CO
3, K
2CO
3, NaH or DMAP(4-Dimethylamino pyridine), preferred TEA;
Described catalyzer is the TBAF(tetrabutyl ammonium fluoride), the TBAC(tetrabutylammonium chloride), the TBAB(Tetrabutyl amonium bromide) or the TBAI(tetrabutylammonium iodide), preferred TBAI;
The ratio range of the amount of substance of described reactant MENTHOL, cyanating reagent, TsIm, TEA, phase-transfer catalyst is 1: 1.0-4.0: 1.0-2.0: 1.5-4.5:0.005-0.02;
Described substrate MENTHOL and organic solvent, THF, the NaOH aqueous solution, ethyl acetate, CH
2Cl
2Ratio be 1mol: 600-800mL, 550-750 mL, 275-375mL, 600-800mL, 1800-2000mL.
Advantage of the present invention is:
The present invention is in organic solvent, take MENTHOL as raw material, use the cupric cyanide of low toxicity and originate as cyanating reagent, under the effect of tolylsulfonyl imidazoles (TsIm), alkali, phase-transfer catalyst, one step generated the menthyl nitrile, obtained menthyl formic acid through hydrolysis again.Preparation method of the present invention avoids using hypertoxic sodium cyanide (potassium), and the synthesis technique circuit that adopts is short, reaction conditions is gentle, optical purity is high.
Embodiment
Below in conjunction with specific embodiment, further illustrate the present invention.
(1) cyanogenation (synthesizing of menthyl nitrile)
With MENTHOL (0.01mol), cuprous cyanide (0.03mol), TsIm(0.015mol), TEA(0.02mol), TBAI(0.1mmol) add in the agitator that the magnetic agitation heating is housed, add 25mLDMF, reflux stirs, and TLC point plate detects in the process, reaction times is about 6h, reaction terminating removes solvent under reduced pressure, and residuum adds a certain amount of water, use again n-hexane extraction, anhydrous sodium sulfate drying steams desolventizing, gets thick product.
(2) hydrolysis reaction (lotus base formic acid synthetic): the thick product (1.52g) that obtains in the step (1) is joined in the 30mL mixing solutions (THF: NaOH (40% the aqueous solution=2:1), TLC detects, the about 6h hydrolysis of reflux is finished, organic impurity is removed in ethyl acetate (10 mL * 3) extraction, water is acidified to acidity (pH=6～7), CH with dilute hydrochloric acid
2Cl
2Extraction (30 mL * 3), anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, and the dehydrated alcohol recrystallization gets sterling 1.58g(in MENTHOL, productive rate is 86.0%, and is lower same).
Embodiment 2
(1) cyanogenation (synthesizing of menthyl nitrile)
With MENTHOL (0.01mol), cuprous cyanide (0.01mol), TsIm(0.01mol), TEA(0.015mol), TBAI(0.05mmol) add in the agitator that the magnetic agitation heating is housed, add 20mLDMF, reflux stirs, and TLC point plate detects in the process, reaction times is about 5h, reaction terminating removes solvent under reduced pressure, and residuum adds a certain amount of water, use again n-hexane extraction, anhydrous sodium sulfate drying steams desolventizing, gets thick product.
(2) hydrolysis reaction (lotus base formic acid synthetic): the thick product (1.12g) that obtains in the step (1) is joined in the 20mL mixing solutions (THF: NaOH (40% the aqueous solution=2:1), TLC detects, the about 4h hydrolysis of reflux is finished, organic impurity is removed in ethyl acetate (10 mL * 3) extraction, water is acidified to acidity (pH=6～7), CH with dilute hydrochloric acid
2Cl
2Extraction (30 mL * 3), anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, it is 56.1% that the dehydrated alcohol recrystallization gets sterling 1.03g(productive rate).
Embodiment 3
(1) cyanogenation (synthesizing of menthyl nitrile)
With MENTHOL (0.01mol), cuprous cyanide (0.04mol), TsIm(0.02mol), TEA(0.03mol), TBAI(0.2mmol) add in the agitator that the magnetic agitation heating is housed, add 30 mLDMF, reflux stirs, and TLC point plate detects in the process, reaction times is about 6h, reaction terminating removes solvent under reduced pressure, and residuum adds a certain amount of water, use again n-hexane extraction, anhydrous sodium sulfate drying steams desolventizing, gets thick product.
(2) hydrolysis reaction (lotus base formic acid synthetic): the thick product (1.71g) that obtains in the step (1) is joined in the 35mL mixing solutions (THF: NaOH (40% the aqueous solution=2:1), TLC detects, the about 5h hydrolysis of reflux is finished, organic impurity is removed in ethyl acetate (10 mL * 3) extraction, water is acidified to acidity (pH=6～7), CH with dilute hydrochloric acid
2Cl
2Extraction (30 mL * 3), anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, it is 88.6% that the dehydrated alcohol recrystallization gets sterling 1.63g(productive rate).
Embodiment 4
(1) cyanogenation (synthesizing of menthyl nitrile)
With MENTHOL (0.01mol), cuprous cyanide (0.04mol), TsIm(0.02mol), TEA(0.045mol), TBAI(0.2mmol) add in the agitator that the magnetic agitation heating is housed, add 35mLDMF, reflux stirs, and TLC point plate detects in the process, reaction times is about 6.5h, reaction terminating removes solvent under reduced pressure, and residuum adds a certain amount of water, use again n-hexane extraction, anhydrous sodium sulfate drying steams desolventizing, gets thick product.
(2) hydrolysis reaction (lotus base formic acid synthetic): the thick product (1.72g) that obtains in the step (1) is joined in the 40mL mixing solutions (THF: NaOH (40% the aqueous solution=2:1), TLC detects, the about 6h hydrolysis of reflux is finished, organic impurity is removed in ethyl acetate (10 mL * 3) extraction, water is acidified to acidity (pH=6～7), CH with dilute hydrochloric acid
2Cl
2Extraction (30 mL * 3), anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, it is 87.6% that the dehydrated alcohol recrystallization gets sterling 1.61g(productive rate).
Embodiment 5
(1) cyanogenation (synthesizing of menthyl nitrile)
With MENTHOL (0.01mol), cuprous cyanide (0.02mol), TsIm(0.01mol), TEA(0.02mol), TBAI(0.1mmol) add in the agitator that the magnetic agitation heating is housed, add 25mLDMF, reflux stirs, and TLC point plate detects in the process, reaction times is about 6h, reaction terminating removes solvent under reduced pressure, and residuum adds a certain amount of water, use again n-hexane extraction, anhydrous sodium sulfate drying steams desolventizing, gets thick product.
(2) hydrolysis reaction (lotus base formic acid synthetic): the thick product (1.31g) that obtains in the step (1) is joined in the 30mL mixing solutions (THF: NaOH (40% the aqueous solution=2:1), TLC detects, the about 4h hydrolysis of reflux is finished, organic impurity is removed in ethyl acetate (10 mL * 3) extraction, water is acidified to acidity (pH=6～7), CH with dilute hydrochloric acid
2Cl
2Extraction (30 mL * 3), anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, it is 68.6% that the dehydrated alcohol recrystallization gets sterling 1.26g(productive rate).
Claims (6)
1. the synthetic method of a menthyl formic acid is characterized in that may further comprise the steps:
(1) the menthyl nitrile is synthetic: add organic solvent, MENTHOL, cyanating reagent, tolylsulfonyl imidazoles (TsIm), alkali and phase-transfer catalyst in the there-necked flask with reflux condensing tube, at 90-110 ℃ of lower reflux 5-10 hour, after reaction finishes, remove solvent under reduced pressure, residuum adds a certain amount of water, uses n-hexane extraction, anhydrous sodium sulfate drying again, the evaporate to dryness desolventizing gets the thick product of menthyl nitrile;
(2) menthyl formic acid is synthetic: the menthyl nitrile that obtains in the step (1) is joined in tetrahydrofuran (THF) (THF) solvent, the NaOH aqueous solution that adds 40-45%, at 90-110 ℃ of lower reflux 5-8 hour, remove organic impurity with ethyl acetate extraction, water is acidified to pH=6-7 with dilute hydrochloric acid, CH
2Cl
2Extraction, anhydrous sodium sulfate drying, evaporate to dryness get the thick product of menthyl formic acid, and the dehydrated alcohol recrystallization gets sterling.
Chemical equation is as follows:
2. the new synthetic method of menthyl formic acid according to claim 1 is characterized in that described cyanating reagent is cuprous cyanide.
3. the new synthetic method of menthyl formic acid according to claim 1, it is characterized in that described organic solvent is the HMPA(hexamethylphosphoramide), DMI(N, the N-dimethyl-imidazolinone), DMF(N, dinethylformamide), the DMSO(methyl-sulphoxide) or NMP(N-methyl-pyrrolidone).
4. the new synthetic method of menthyl formic acid according to claim 1 is characterized in that described alkali is the TEA(triethylamine), the TMA(Trimethylamine 99), Na
2CO
3, K
2CO
3, NaH or DMAP(4-Dimethylamino pyridine).
5. the new synthetic method of menthyl formic acid according to claim 1 is characterized in that described phase-transfer catalyst is the TBAF(tetrabutyl ammonium fluoride), the TBAC(tetrabutylammonium chloride), the TBAB(Tetrabutyl amonium bromide) or the TBAI(tetrabutylammonium iodide);
6. the new synthetic method of menthyl formic acid according to claim 1, the ratio range that it is characterized in that the amount of substance of described reactant MENTHOL, cuprous cyanide, TsIm, alkali, catalyzer is 1: 1.0-4.0: 1.0-2.0: 1.5-4.5:0.005-0.02.
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