CN102746143A - High-stereoselectivity synthetic method of L-peppermint carboxylic acid - Google Patents
High-stereoselectivity synthetic method of L-peppermint carboxylic acid Download PDFInfo
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- CN102746143A CN102746143A CN2012102576416A CN201210257641A CN102746143A CN 102746143 A CN102746143 A CN 102746143A CN 2012102576416 A CN2012102576416 A CN 2012102576416A CN 201210257641 A CN201210257641 A CN 201210257641A CN 102746143 A CN102746143 A CN 102746143A
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 title claims abstract description 43
- 238000010189 synthetic method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000000047 product Substances 0.000 claims abstract description 19
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 235000011089 carbon dioxide Nutrition 0.000 claims description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 235000016257 Mentha pulegium Nutrition 0.000 claims description 4
- 244000246386 Mentha pulegium Species 0.000 claims description 4
- 235000004357 Mentha x piperita Nutrition 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 235000001050 hortel pimenta Nutrition 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 abstract description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 abstract description 4
- -1 magnesium halide Chemical class 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229910052749 magnesium Inorganic materials 0.000 abstract 1
- 239000011777 magnesium Substances 0.000 abstract 1
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VUNOFAIHSALQQH-UHFFFAOYSA-N Ethyl menthane carboxamide Chemical compound CCNC(=O)C1CC(C)CCC1C(C)C VUNOFAIHSALQQH-UHFFFAOYSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000013019 agitation Methods 0.000 description 7
- 229910017053 inorganic salt Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005352 clarification Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- GCICAPWZNUIIDV-UHFFFAOYSA-N lithium magnesium Chemical compound [Li].[Mg] GCICAPWZNUIIDV-UHFFFAOYSA-N 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000011541 reaction mixture 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
- 241000894007 species Species 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a high-stereoselectivity synthetic method of L-peppermint carboxylic acid. The method comprises the following steps of: reacting menthane-based magnesium halide (3) with carbon dioxide in a solvent in the presence of a catalyst; and collecting L-peppermint carboxylic acid from a reaction product. The method disclosed by the invention has the characteristics of small using amount and ready availability of the catalyst, mild reaction conditions, easiness for operating, high yield and the like. Compared with other methods, the method reported by the invention has the advantages: the problems of difficulty in purifying a product, low yield and the like existing in the conventional compound synthesis process for the type of compound are solved, and production cost is greatly lowered. All reagents used in an entire reaction are readily-available, and a process flow has an important innovation, and is convenient to for industrial implementation.
Description
Technical field the invention belongs to the synthetic perfume technical field, relates to the novel highly-solid selectively compound method of the important intermediate L-peppermint carboxylic acid of a kind of WS-3 of preparation.
Background technology WS-3 has another name called amide of mint, and its chemical name is N-ethyl-2-sec.-propyl-5-methyl-cyclohexyl alkane methane amide, and English N-Ethyl-p-menthane-3-carboxamide by name is called for short WS-3, and its structural formula is following:
WS-3 as a kind of novel coolant agent in recent years the worldwide production scale increase year by year, the global demand amount had reached 200 tons/year in 2010.This coolant agent has fresh persistent cool flavor, and odorlessness can both cooperate with any cool taste substance well.On skin, have and be close to ice-cold sensation, have intensive antiperspirant effect.In cool taste substance consumption seldom, usually consumption just is enough to promote whole cold sense in 0.01% of product total mass.WS-3 can be used in the goods such as chewing gum, toothpaste, candy, cake and medicine.
L-peppermint carboxylic acid is the important intermediate of synthetic WS-3, and it has constituted the main skeleton of WS-3 compound structure.Its structural formula is following:
The acquisition of L-peppermint carboxylic acid now mainly obtains through chemical synthesis.What in known synthetic route, have using value most is to be that raw material and carbon dioxide reaction obtain L-peppermint carboxylic acid (2) after hydrolysis with L-peppermint alkylmagnesium chloride (3), and L-peppermint carboxylic acid obtains WS-3 through chloro, acidylate subsequently.Its chemical equation is following:
The balsamic shape article of refining; 2004,4; It is that raw material acquisition MAGNESIUM METAL 99 reagent obtains L-peppermint carboxylic acid with the carbon dioxide reaction method subsequently that 5-6 has reported with the L-Therapeutic Mineral Ice.This method synthetic route has produced a large amount of its structures of L-peppermint carboxyl acid optical isomer in the acquisition of committed step L-peppermint carboxylic acid following:
Utilize traditional route, the content of the optical isomer in the product is 20-30%, and the generation of this optical isomer has caused product yield low, and the finished product WS-3 separation difficulty can't obtain purified product.This optical isomer is deposited in the product simultaneously stimulates bitter sense because it has, and can influence the mouthfeel and the cooling effect of final product greatly.Because this step reaction yield is low, reasons such as impurity purification difficult cause production cost too high, are unfavorable for industrializing implementation.
Summary of the invention the purpose of this invention is to provide a kind of L-peppermint carboxylic acid compound method, to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
In solvent, catalyzer exists down with L-peppermint alkyl magnesium halide (3), reacts with carbonic acid gas, from reaction product, collects L-peppermint carboxylic acid (2) then;
Reaction times is 1～6 hour, and temperature of reaction is-10～30 ℃, and productive rate is 98～100%, and the optical siomerism body burden does not detect in the product.Reaction formula is following:
Wherein: X represents chlorine, bromine, iodine;
Preferred X is a chlorine;
The chemical name of said catalyzer is anhydrous lithium bromide, Lithium chloride (anhydrous), anhydrous lithium iodide;
Said solvent is selected from ether, THF, 1, one or more in 4-dioxane, toluene, benzene, YLENE, sherwood oil, the methyltetrahydrofuran;
The mol ratio of catalyzer and compound (3) is 0.01～0.1: 1;
Said L-peppermint alkyl magnesium halide (3) can adopt the document balsamic shape article of refining; 2004,4; The 5-6 reported method prepares.
Catalyzer is a commercial chemicals;
Method of the present invention; In the procurement process of compound (2); Utilize under the condition of catalyzer existence; The compound (2) of the acquisition L-configuration of the high yield of highly-solid selectively has made up the skeleton structure of WS-3, with after simple chloro, acidylate and purifying can obtain highly-solid selectively, highly purified WS-3 product.Traditional method makes up the WS-3 structural framework often needs comparatively violent reaction conditions; The low L configuration that obtains simultaneously of reaction yield and the mixtinite of D type configuration; It is extremely difficult to cause final product to receive purifies and separates, often can't obtain clean product, and we need to obtain title product be L formula structure.This patent utilizes little amount of catalyst to exist down; Form the lithium magnesium complex with peppermint alkyl magnesium halide; These species have characteristics such as reactive behavior height, stereoselectivity are good and can stable existence; With the compound (2) of the acquisition L formula configuration of the high yield of carbon dioxide reaction highly-solid selectively, the reaction back D type product content that finishes does not detect.Method of the present invention has characteristics such as catalyzer is easy to get that usage quantity is few, reaction conditions is gentle, simple to operate, yield height.Problems such as product purification difficulty, the yield that we's bright institute reported method has been avoided being run in this compounds traditional synthesis is low, greatly reduce production cost.This is that additive method is beyond one's reach.Employed reagent all comparatively is easy to get in entire reaction, and this operational path has great novelty and is convenient to industrializing implementation.
The practical implementation method
Embodiment 1
The preparation of L-peppermint carboxylic acid (2)
(2M 50mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is cooled to 0 ℃ with L-peppermint alkylmagnesium chloride tetrahydrofuran solution.(10mmol) in the disposable adding reaction system, keeping system temperature is 0 ℃ for 0.42g, Fw:42.39 with Lithium chloride (anhydrous).System continues to stir 20 minutes at 0 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 0 ℃, and the gas feeding time is about 1.5 hours.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets achromaticity and clarification liquid, concentrating under reduced pressure remove desolvate product (yield:99%).GC analyzes L-peppermint carboxylic acid content＞98%, and D-peppermint carboxylic acid content does not detect.
Embodiment 2
The preparation of L-peppermint carboxylic acid (2)
(2M 50mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is cooled to-10 ℃ with L-peppermint alkylmagnesium chloride tetrahydrofuran solution.(1mmol) in the disposable adding reaction system, keeping system temperature is-10 ℃ for 0.042g, Fw:42.39 with Lithium chloride (anhydrous).System continues to stir 20 minutes at-10 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 0 ℃, and the gas feeding time is about 6 hours.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets achromaticity and clarification liquid, concentrating under reduced pressure remove desolvate product (yield:98%).GC analyzes L-peppermint carboxylic acid content＞98%, and D-peppermint carboxylic acid content does not detect.
Embodiment 3
The preparation of L-peppermint carboxylic acid (2)
(2M 50mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is maintained 30 ℃ with L-peppermint alkylmagnesium chloride tetrahydrofuran solution.(1mmol) in the disposable adding reaction system, keeping system temperature is 30 ℃ for 0.042g, Fw:42.39 with Lithium chloride (anhydrous).System continues to stir 10 minutes at 30 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 30 ℃, and the gas feeding time is about 2 hours.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets achromaticity and clarification liquid, concentrating under reduced pressure remove desolvate product (yield:98%).GC analyzes L-peppermint carboxylic acid content＞99%, and D-peppermint carboxylic acid content does not detect.
Embodiment 4
The preparation of L-peppermint carboxylic acid (2)
(1M 100mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is maintained 30 ℃ with L-peppermint alkylmagnesium chloride diethyl ether solution.(10mmol) in the disposable adding reaction system, keeping system temperature is 30 ℃ for 0.42g, Fw:42.39 with Lithium chloride (anhydrous).System continues to stir 10 minutes at 30 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 30 ℃, and the gas feeding time is about 1 hour.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets achromaticity and clarification liquid, concentrating under reduced pressure remove desolvate product (yield:100%).GC analyzes L-peppermint carboxylic acid content＞99%, and D-peppermint carboxylic acid content does not detect.
Embodiment 5
The preparation of L-peppermint carboxylic acid (2)
(1M 100mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is maintained 30 ℃ with L-peppermint alkylmagnesium chloride diethyl ether solution.(10mmol) in the disposable adding reaction system, keeping system temperature is 30 ℃ for 0.87g, Fw:86.84 with anhydrous lithium bromide.System continues to stir 10 minutes at 30 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 30 ℃, and the gas feeding time is about 1 hour.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets achromaticity and clarification liquid, concentrating under reduced pressure remove desolvate product (yield:100%).GC analyzes L-peppermint carboxylic acid content＞99%, and D-peppermint carboxylic acid content does not detect.
Embodiment 6
(1M 100mL) injects reaction flask to the three mouthfuls of round-bottomed flasks of the 250mL that is equipped with magnetic agitation, TM that are full of nitrogen in drying, subsequently system is maintained 0 ℃ with L-peppermint alkylmagnesium chloride diethyl ether solution.(10mmol) in the disposable adding reaction system, keeping system temperature is 0 ℃ for 0.87g, Fw:86.84 with anhydrous lithium bromide.System continues to stir 20 minutes at 0 ℃, in system, feeds dry carbonic acid gas after reaction finishes, and system temperature maintains 0 ℃, and the gas feeding time is about 3 hours.In system, be added dropwise to 75 milliliters of 2M hydrochloric acid after feeding finishes, mixed solution is transferred in the separating funnel subsequently, and standing demix is told organic phase, and water extracts once with toluene again.Merge organic phase, organic phase is washed with water to neutrality, and organic phase removes by filter inorganic salt with anhydrous magnesium sulfate drying and gets the colourless clear liquid that disappears, concentrating under reduced pressure remove desolvate product (yield:100%).GC analyzes L-peppermint carboxylic acid content＞99%, and D-peppermint carboxylic acid content does not detect.
Embodiment 7
WS-3(1)
An exsiccant be equipped with magnetic agitation, constant pressure funnel, TM, reflux condensing tube the 100mL there-necked flask in add L-peppermint carboxylic acid 13.1g successively, 60mL toluene is stirred to dissolving.Add the 11.7g sulfur oxychloride to constant pressure funnel.System temperature is risen to 70～75 ℃, subsequently sulfur oxychloride is dropped in the system, about 1h dropwises.About 75 ℃, continue reaction 2h subsequently, get faint yellow clarified liq after reaction finishes.System temperature is cooled to room temperature, changes reflux condensing tube into vacuum distillation apparatus subsequently, the unreacted sulfur oxychloride of pressure reducing and steaming.It is for use that remaining liq is cooled to room temperature under dry atmosphere subsequently.
Be equipped with one to add the 100mL35% ethylamine solution in the 250mL there-necked flask of magnetic stirring apparatus, TM, constant pressure funnel, subsequently the peppermint acyl chlorides toluene solution that back makes be transferred in the constant pressure funnel.System temperature is cooled to 0～5 ℃, subsequently peppermint acyl chlorides toluene solution is slowly dropped in the system, keep system temperature at 5～10 ℃, about 1h dropwises.After dropwising, system temperature is risen to room temperature, continue stirring reaction 2h, reaction finishes.
After reaction finished, with the reaction mixture sat layering, (2 * 20mL) extracted water twice to water with toluene; Merge organic phase, (2 * 20mL) washing organic phases twice are used 5% aqueous sodium hydroxide solution (twice of 2 * 10mL) washing organic phase to water subsequently; (3 * 10mL) wash organic phases three times to water, and organic phase is used anhydrous magnesium sulfate drying, filters out inorganic salt subsequently; Boil off solvent, the 30mL of residuum adding subsequently acetone is heated to backflow, and it is little muddy in system, to add entry to system.In-10 ℃ of freezing and crystallizings, will separate out crystal and filter out, with 70% acetone and water mixed solvent wash solids of small amount of cold, dry white crystal 13.52g.Yield is 90%.GC content＞99.
Claims (4)
1.L-a kind of compound method of peppermint carboxylic acid is characterized in that following steps:
In solvent, catalyzer exists down with L-peppermint alkyl magnesium halide (3), reacts with carbonic acid gas, from reaction product, collects L-peppermint carboxylic acid (2) then;
Reaction times is 1～6 hour, and temperature of reaction is-10～30 ℃, and productive rate is 98～100%, and optical isomer does not detect in the product.Reaction formula is following:
Wherein: X represents chlorine, bromine, iodine;
Preferred X is a chlorine;
The chemical name of said catalyzer is anhydrous lithium bromide, Lithium chloride (anhydrous), anhydrous lithium iodide;
Said solvent is selected from ether, THF, 1, one or more in 4-dioxane, toluene, benzene, YLENE, sherwood oil, the methyltetrahydrofuran;
The mol ratio of part and compound (3) is 0.01～0.1: 1.
2. method according to claim 1 is characterized in that, the reaction times of step (1) is 1～6 hour, and temperature of reaction is-10～30 ℃.
3. method according to claim 1 is characterized in that, said solvent is selected from ether, THF, 1, one or more in 4-dioxane, toluene, benzene, YLENE, sherwood oil, the methyltetrahydrofuran.
4. method according to claim 1, the mol ratio that it is characterized in that part and compound (3) is 0.01～0.1: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109851522A (en) * | 2018-12-10 | 2019-06-07 | 万华化学集团股份有限公司 | N- ethyl-is new-the menthyl formamide configuration reversal method for preparing N- ethyl-L- menthyl formamide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516819A (en) * | 2006-09-12 | 2009-08-26 | 吉里德科学公司 | Process and intermediates for preparing integrase inhibitors |
| CN102531885A (en) * | 2011-12-20 | 2012-07-04 | 上海灏翔生物科技有限公司 | Method for synthesizing L-peppermint carboxylic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516819A (en) * | 2006-09-12 | 2009-08-26 | 吉里德科学公司 | Process and intermediates for preparing integrase inhibitors |
| CN102531885A (en) * | 2011-12-20 | 2012-07-04 | 上海灏翔生物科技有限公司 | Method for synthesizing L-peppermint carboxylic acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109851522A (en) * | 2018-12-10 | 2019-06-07 | 万华化学集团股份有限公司 | N- ethyl-is new-the menthyl formamide configuration reversal method for preparing N- ethyl-L- menthyl formamide |
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