CN115160153A - L-menthylamine, D-neomenthylamine and preparation method thereof - Google Patents
L-menthylamine, D-neomenthylamine and preparation method thereof Download PDFInfo
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- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
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- C07C29/128—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by alcoholysis
- C07C29/1285—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by alcoholysis of esters of organic acids
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07C2601/14—The ring being saturated
Abstract
The invention relates to the technical field of synthesis and preparation of menthol, in particular to chiral menthylamine with two configurations and a preparation method thereof. The method takes L-menthol as a raw material, generates an alcohol ester intermediate with reversed configuration through a Mitsunobu reaction, hydrolyzes to obtain D-neomenthol, obtains a menthimide intermediate through the Mitsunobu reaction of the L-menthol, and obtains chiral menthylamine with two configurations through hydrazinolysis. The synthetic method has the advantages of novel route and simple experimental operation, and provides a proper tool molecule for discovery of the freshener and catalysis of asymmetric reaction.
Description
Technical Field
The invention relates to the technical field of menthol synthesis and preparation, in particular to L-menthylamine, D-neomenthylamine and preparation methods thereof.
Background
Menthol (also known as menthol) is a compound with cooling property, has inconsistent cooling effects of different configurations, is optimal as L-menthol, and is widely applied to the industries of food, tobacco, medicine, daily chemicals and the like. However, the L-menthol has obvious defects of difficult water dissolution, strong volatility and heavy mint flavor, and further use space of the L-menthol is influenced. In order to overcome the limitations of conventional menthol, compounds derived from the basic skeleton of menthol have been developed into new cooling agents, such as menthyl esters, menthyl ethers, menthane amides, etc., wherein amine derivatives based on chiral menthane amine as a molecular structure are currently less researched and have a larger development space.
In addition, chiral menthylamine has a six-membered ring structure with three chiral centers, and is widely used as a chiral induction source in catalytic asymmetric synthesis, such as N-menthyl alpha-bromophenylacetamide prepared by taking chiral menthylamine as a raw material in the King Shih sea and used as a chiral initiator for atom transfer radical polymerization of achiral monomer methacrylic acid-1-phenyl dibenzosuberyl alcohol ester. Zhouyilong selects chiral menthylamine to be condensed with various amino acids to obtain a series of chiral secondary diamine ligands with novel structures for catalyzing asymmetric Henry reaction and Michael addition reaction.
The current synthesis route of chiral menthylamine is mainly to oxidize menthol into menthone through ketoxime conversion, and then react with hydroxylamine hydrochloride to obtain menthone oxime, kozlov converts menthone oxime into chiral menthylamine by using a platinum black-glacial acetic acid system and a raney nickel-methanol system, but the product is complex, the diastereomer yield is close to 60%, and Schopohl et al adopts large equivalent of metallic sodium (sodium) (i.e., (II)>20 fold) reduction of menthone oxime in anhydrous ethanol, demidava et Al in Au/Al 2 O 3 As a carrier, gold is usedThe (1R, 2R, 5R) -chiral menthylamine ([ alpha ] can be obtained with higher selectivity by catalyzing hydrogen to reduce menthone oxime by rice particles] D 20 = -35.7 °). In the above-mentioned route, chromium reagent and a large amount of transition metal are used for catalytic reaction, so that the pollution and experimental danger are high, and in addition, only one configuration of chiral menthylamine can be obtained, so that there is a certain limitation.
Disclosure of Invention
In order to solve the problems of great pollution and experimental risk and single product configuration existing in the synthesis route of chiral menthylamine in the prior art, the invention aims to provide a preparation method of L-menthylamine.
In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of L-menthylamine comprises the following steps:
step 1, taking L-menthol, p-nitrobenzoic acid and triphenylphosphine into a reaction bottle, adding tetrahydrofuran to dissolve, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, transferring to room temperature to react for 8-12h after dropwise adding, wherein the mass ratio of the L-menthol to the p-nitrobenzoic acid, the triphenylphosphine and the diethyl azodicarboxylate is 1.5;
step 2, dissolving the D-neomenthol ester in the formula (1 a) in methanol, adding potassium carbonate in batches, wherein the mass ratio of the D-neomenthol ester to the potassium carbonate is 1;
step 3, adding D-neomenthol, phthalimide and triphenylphosphine in the formula (2 a) into tetrahydrofuran for dissolving, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, wherein the mass ratio of the D-neomenthol, the phthalimide, the triphenylphosphine and the diethyl azodicarboxylate is 1.5;
step 4, taking the L-menthyl imide intermediate in the formula (3 a), adding methanol to dissolve, adding 80wt% of hydrazine hydrate solution at room temperature, wherein the mass ratio of the L-menthyl imide intermediate to the hydrazine hydrate in the hydrazine hydrate solution is 1;
the invention also aims to provide the L-menthylamine prepared by the preparation method.
The invention also aims to provide a preparation method of D-neomenthylamine.
In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of D-neomenthylamine comprises the following steps:
step 1, adding L-menthol, phthalimide and triphenylphosphine into tetrahydrofuran for dissolving, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, wherein the mass ratio of L-menthol to phthalimide to triphenylphosphine to diethyl azodicarboxylate is 1.5;
step 2, taking the D-neomenthyl imide intermediate in the formula (3 c), adding methanol for dissolving, adding 80wt% of hydrazine hydrate solution at room temperature, wherein the mass ratio of the D-neomenthyl imide intermediate to the hydrazine hydrate in the hydrazine hydrate solution is 1;
the fourth purpose of the invention is to provide D-neomenthylamine prepared by the preparation method.
The fifth purpose of the invention is to provide a preparation method of D-neomenthylamine.
In order to realize the purpose, the invention adopts the following technical scheme: the preparation method of the D-neomenthylamine comprises the following steps:
step 1: adding L-menthol and triphenylphosphine into tetrahydrofuran for dissolving, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, reacting for half an hour, adding diphenyl azidophosphate, and transferring to room temperature for reacting for 8-12 hours, wherein the mass ratio of L-menthol to diphenyl azidophosphate to triphenylphosphine to diethyl azodicarboxylate is 1.5;
step 2, adding the D-neomenthyl azide intermediate of the formula (3 e) and 15wt% of palladium carbon into a reaction bottle, adding methanol for dissolving, reacting for 24 hours under 1-2 atmospheric pressures of hydrogen, filtering the mixture by using kieselguhr, washing by using methanol, and concentrating to obtain colorless liquid, namely D-neomenthyl amine in the formula (4 c);
the invention also aims to provide the D-neomenthylamine prepared by the preparation method.
Compared with the prior art, the invention has the beneficial effects that:
1) The traditional synthetic route of chiral menthylamine is as follows:
the method comprises the steps of oxidizing menthol into menthone through ketoxime conversion, then reacting with hydroxylamine hydrochloride to obtain menthone oxime, and then using the menthone oxime to prepare chiral menthamine. In the prior art, chromium reagents and a large amount of transition metals are used for catalytic reaction in the process of preparing chiral menthylamine by using menthone oxime, so that the pollution and the experimental risk are high, in addition, only one configuration of chiral menthylamine can be obtained, and certain limitation exists.
The Mitsunobu reaction (Mitsunobu reaction) is a bimolecular nucleophilic substitution reaction (SN) 2 Reaction), under the catalysis of triphenylphosphine and diethyl azodicarboxylate, the hydroxyl of a secondary alcohol is replaced by different nucleophiles, and the configuration of the carbon atom connected with the hydroxyl is reversed. The method is based on a molecular structure design principle, L-menthol which is easily obtained in the market is used as a raw material, the L-menthol and p-nitrobenzoic acid react through Mitsunobu to generate an alcohol ester intermediate with reversed configuration, D-neomenthol is obtained through hydrolysis, then the L-menthol and the L-menthol are combined through Mitsunobu reaction and phthalimide again to obtain a menthyl imide intermediate with reversed configuration, finally hydrazinolysis is carried out to obtain L-menthol and D-neomenthol, or the L-menthol is used as a raw material, the L-menthol and diphenyl azide phosphate react through Mitsunobu to generate an azide intermediate with reversed configuration, and then palladium carbon is reduced to obtain the D-neomenthol.
The method for preparing the two chiral menthamines has the advantages of novel method, simple experimental operation and environmental friendliness. One to two Mitsunobu reactions are used to ingeniously realize the functional group conversion from hydroxyl to amino, and the chiral menthylamine with a determined configuration is obtained due to the characteristic of the inversion of the Mitsunobu reaction configuration. Compared with the traditional method which can only obtain chiral menthylamine with one configuration, the method disclosed by the invention can be used for preparing two chiral menthylamines with determined configurations at one time, so that the application range of the chiral menthylamines is expanded; the reaction conditions are mild, all the reaction temperatures do not exceed 60 ℃, nitrogen protection is not needed, and compared with the traditional method, the method avoids using reagents with high pollution and high experimental risk such as chromium, metallic sodium and the like.
2) The two chiral menthamines prepared by the invention have the advantage of wide application range. As an initial tool molecule, the chiral amine derivatives with different configurations can be synthesized by amide condensation, reductive amination, nucleophilic substitution and the like, and can be used for the research and development of subsequent coolants and the catalysis of asymmetric reactions.
Drawings
FIG. 1 is a calculated ECD spectrum for the compound of formula 3a, an experimental ECD spectrum for formula 3a prepared in example 1, and an experimental ECD spectrum for enantiomer 3b of 3 a.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail with reference to the following embodiments, and all other embodiments obtained by a person of ordinary skill in the art without making creative efforts based on the embodiments of the present invention belong to the protection scope of the present invention.
Main instruments and reagents
An AVANCE type III 400MH NMR spectrometer (Bruker, switzerland); BC-R202B rotary evaporator (Shanghai Beikai Biochemical engineering Equipment Co., ltd.); 1260/6460 liquid chromatography tandem triple quadrupole mass spectrometry (agilent technologies, ltd); JASCO P-2000 polarimeter (JASCO corporation of Japan)
L-menthol, p-nitrobenzoic acid, phthalimide, triphenylphosphine, diethyl azodicarboxylate, diphenyl phosphorazidate, 80wt% hydrazine hydrate, tetrahydrofuran, ethyl acetate, methanol, acetone, sodium chloride, potassium carbonate, and anhydrous magnesium sulfate (all available from Agents, inc., brands, such as Mecanne and Aladdin).
Example 1
The embodiment provides a preparation method of L-menthylamine, which includes the following steps:
step 1,1a synthesis. Weighing 10.0g (0.064 mol) of L-menthol, 10.7g (0.064 mol) of p-nitrobenzoic acid and 25.1g (0.096 mol) of triphenylphosphine into a 250ml reaction bottle, adding 40ml of tetrahydrofuran for dissolving, slowly dropwise adding 16.8ml (0.096 mol) of diethyl azodicarboxylate under stirring in ice bath, transferring to room temperature for reaction for 12h after dropwise adding, and monitoring the reaction completion by TLC.
And (3) after the reaction is completed, washing the reaction liquid by using a saturated sodium bicarbonate aqueous solution, extracting by using dichloromethane, and concentrating to obtain a semi-solid. Suspending the semi-solid in 100ml of diethyl ether, adding 40ml of n-hexane, stirring for half an hour, performing suction filtration, and concentrating the filtrate to obtain a yellow oily substance, namely D-neomenthol ester of formula 1 a;
step 2, synthesis of 2a. 8.0g (0.026 mol) of D-neomenthol ester of formula 1a were weighed out and dissolved in 20ml of methanol, 7.2g (0.052 mol) of potassium carbonate were added in portions, stirred at room temperature for 2h and the reaction was monitored by TLC for completion. Filtering the reaction solution, washing with water, extracting with dichloromethane, concentrating, and purifying by silica gel column chromatography (PE: EA = 5;
step 3, synthesis of 3 a. 2.5g (0.016 mol) of D-neomenthol of formula 2a, 2.4g (0.016 mol) of phthalimide and 6.3g (0.024 mol) of triphenylphosphine were weighed into a 100ml reaction flask, dissolved by adding 10ml of tetrahydrofuran, slowly added dropwise with 4.2ml (0.024 mol) of diethyl azodicarboxylate under stirring in an ice bath, transferred to room temperature for reaction for 12h after the dropwise addition, and the completion of the reaction was monitored by TLC. Concentrating the reaction solution to obtain a crude product, and purifying by silica gel column chromatography (PE: EA =20:1,V/V) to obtain an L-menthyl imide intermediate of a formula 3 a;
synthesis of step 4,4a. Weighing 1.0g (0.0035 mol) of L-menthyl imide intermediate into a 25ml reaction bottle, adding 5ml of methanol for dissolving, adding 0.3ml of 80wt% hydrazine hydrate solution at room temperature, then heating to 50 ℃ for reacting for 6h until a large amount of white solid is separated out, filtering, adding dilute hydrochloric acid into the filtrate to adjust the pH value to acidity, diluting with ethyl acetate, adding water for extraction, adding sodium hydroxide solution into the water layer to adjust the pH value to alkalinity, extracting the water layer in batches with ethyl acetate, combining the organic layers, and spin-drying to obtain colorless liquid, namely L-menthylamine of the formula 4 a.
(4a) L-menthylamine
A colorless oily liquid. 1 H NMR(400MHz,CDCl 3 )δ2.52-2.41(m,1H),2.15-2.00(m,1H),1.80-1.71(m,1H),1.67-1.52(m,2H),1.43-1.30(m,1H),1.10(s,2H),0.87(d,J＝7.2Hz,3H),0.84(d,J＝6.8Hz,3H),0.96-0.70(m,4H),0.72(d,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ51.7,50.7,46.1,35.0,32.2,26.1,23.4,22.5,21.3,15.6.ESI-MS:156[M+H]+,[α]D 20 ＝-33.2°(c＝1.4in CHCl3)
The yield of the above example was calculated to be 38.6% and the purity of chiral menthylamine was calculated to be 95%.
Example 2
This example provides a method for preparing D-neomenthylamine, including the following steps:
step 1, synthesis of 3 c. Weighing 2.5g (0.016 mol) of L-menthol, 2.4g (0.016 mol) of phthalimide and 6.3g (0.024 mol) of triphenylphosphine into a 100ml reaction flask, adding 10ml of tetrahydrofuran for dissolving, slowly dropwise adding 4.2ml (0.024 mol) of diethyl azodicarboxylate under the stirring of ice bath, transferring to room temperature for reaction for 12h after dropwise adding, and monitoring the reaction completion by TLC. Concentrating the reaction solution to obtain a crude product, and purifying by silica gel column chromatography (PE: EA =20:1,V/V) to obtain a D-neomenthylimide intermediate of a formula 3 c;
step 2,4c synthesis. Weighing 1.0g (0.0035 mol) of D-neomenthylimide intermediate of formula 3c in a 25ml reaction bottle, adding 5ml methanol for dissolving, adding 0.3ml 80wt% hydrazine hydrate solution at room temperature, heating to 50 ℃ for reacting for 6h until a large amount of white solid is separated out, filtering, adding dilute hydrochloric acid into the filtrate to adjust the pH to acidity, adding water for extraction after diluting with ethyl acetate, adding sodium hydroxide solution into the water layer to adjust the pH to alkalinity, extracting the water layer in batches with ethyl acetate, combining the organic layers, and spin-drying to obtain colorless liquid, namely D-neomenthylamine of formula 4 c.
(4c) D-neomenthylamine
Colorless oily liquid 1 H NMR(400MHz,CDCl 3 )δ＝2.85-2.83(m,1H),1.68-1.53(m,4H),1.39-1.30(m,1H),1.15-1.02(m,2H),0.95(s,2H),0.87(d,J＝6.4Hz,3H),0.85(d,J＝6.4Hz,3H),0.84-0.80(m,1H),0.78(d,J＝6.4Hz,3H),0.80-0.75(m,1H)； 13 C NMR(100MHz,CDCl3)δ48.1,47.5,43.5,35.5,29.4,25.8,24.0,22.7,21.4,20.8.ESI-MS:156[M+H]+,[α] D 20 ＝+10.3°(c＝1.0in CHCl 3 )。
The yield of the above example was calculated to be 50.6% and the purity of chiral menthylamine was calculated to be 95%.
Example 3
This example provides a method for preparing D-neomenthylamine, including the following steps:
step 1, synthesis of 3 e. 2.5g (0.016 mol) of L-type menthol and 12.6g (0.048 mol) of triphenylphosphine are weighed into a 100ml reaction bottle, 10ml of tetrahydrofuran is added for dissolution, 8.4ml (0.048 mol) of diethyl azodicarboxylate is slowly dropped under stirring in an ice bath, 2.5g (0.024 mol) of diphenyl phosphorazidate is added after reaction for half an hour, the reaction solution is transferred to room temperature for reaction for 8-12h, and the completion of the reaction is monitored by TLC. Concentrating the reaction solution to obtain a crude product, and purifying by silica gel column chromatography (PE: EA =40:1,V/V) to obtain a D-neomenthyl azide intermediate of a formula 3 e;
and (5) synthesizing steps 2 and 4 c. 1.0g (0.0056 mol) of D-neomenthyl azide intermediate and 0.15g of palladium on carbon were weighed into a reaction flask, dissolved in methanol, reacted under 1-2 atmospheres of hydrogen for 24h, and the completion of the reaction was monitored by TLC. And (3) filtering the reaction solution by using kieselguhr, washing the reaction solution by using methanol for 3 to 4 times, combining the methanol and concentrating to obtain colorless liquid, namely the D-neomenthylamine of the formula (4 c).
The yield of the above example was calculated to be 38.0% and the purity of chiral menthylamine was calculated to be 95%.
In order to confirm whether the absolute configuration of the synthesized chiral menthylamine is correct, the Electronic Circular Dichroism (ECD) method is adopted to compare the similarity degree of ECD spectra of two enantiomers in calculation and experiment so as to confirm the configuration. Because the ECD test requires that the chiral compound has ultraviolet absorption, and no chromophore exists in the final product, namely, the menthylamine structure, the requirement is difficult to meet, the compound 3a in the previous step of hydrazinolysis and the enantiomer 3b (a benzene ring exists in the molecular structure, see fig. 1) of the compound 3a are selected as objects of configuration analysis, wherein the compound 3b is prepared by other methods and is used for assisting in judging the absolute configurations of the compound 3a and the subsequent compound 4 a.
Recording an experimental ECD spectrum by using a JASCO J-810 circular dichroism spectrometer at room temperature, wherein a solvent is chromatographic grade ethanol, the concentration is controlled to be 0.2mg/ml-0.5mg/ml, the spectrum is recorded at a scanning speed of 100nm/min, the response time is 0.5s, accumulating at least three times of scanning, and correcting a background by using the same solvent and test conditions to obtain the experimental ECD spectrum of the compound.
Using compound 3a as an example, the conformation of compound 3a was analyzed using Discovery Studio 4.0 to obtain a reasonable set of low energy conformations, which were then further optimized at the B3LYP/6-31G (d) level by Density Functional Theory (DFT) using the Gaussian 09 package, including geometric optimization and solvent effect from ethanol. The optimized conformations were then energy calculated using time-density functional theory (TDDFT) under the same basis set. According to the obtained relevant data by calculation, specDis is used for fitting the SpecDis into a Gaussian curve, the Gaussian curve is added into the calculated ECD spectrum of each conformation to obtain a Boltzmann weighted average ECD spectrum, and finally, the maximum absorption peak of the ultraviolet-visible spectrum obtained by experiments is used for correcting the displacement value of the calculated ECD spectrum to obtain the ECD spectrum of the compound 3a theory.
As shown in FIG. 1, when Origin 8.5 is used to compare the calculated ECD spectrum of compound 3a with the experimental ECD spectra of 3a and 3b, the experimental spectra of 3a and 3b have a relatively obvious symmetrical shape and can be considered as a pair of enantiomers, while the calculated ECD spectrum of 3a is substantially consistent with the experimental spectrum of 3a in terms of wavelength and a Cotton effect, a positive Cotton effect exists at 210nm, a negative Cotton effect exists at 235nm, a negative Cotton effect exists in the calculated ECD spectrum near 290nm, and the experimental spectrum does not have a significant Cotton effect, which is probably caused by the fact that the chiral carbon of the compound is far away from the chromophore. Since the hydrazinolysis reaction does not generally cause a change in chiral configuration and the configuration of 4a is identical to that of 3a, it was confirmed that the absolute configuration of compound 4a is (1R, 2R, 5R), and similarly, the absolute configuration of 4c is (1S, 2R, 5R) in the same reaction system.
In conclusion, the L-menthol is used as a raw material, the chiral menthamines with two configurations are synthesized through one to two Mitsunobu reactions, the synthetic method has a novel route and simple experimental operation, and suitable tool molecules are provided for discovery of novel coolants and catalysis of asymmetric reactions.
It should be understood by those skilled in the art that the foregoing is only illustrative of several embodiments of the invention, and not of all embodiments. It should be noted that many variations and modifications are possible to those skilled in the art, and all variations and modifications that do not depart from the gist of the invention are intended to be within the scope of the invention as defined in the appended claims.
Claims (6)
1. The preparation method of the L-menthylamine is characterized by comprising the following steps:
step 1, taking L-menthol, p-nitrobenzoic acid and triphenylphosphine to a reaction bottle, adding tetrahydrofuran to dissolve, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, transferring to room temperature to react for 8-12h after dropwise adding, wherein the mass ratio of the L-menthol to the p-nitrobenzoic acid, the triphenylphosphine and the diethyl azodicarboxylate is 1.5;
step 2, dissolving the D-neomenthol ester in the formula (1 a) in methanol, adding potassium carbonate in batches, wherein the mass ratio of the D-neomenthol ester to the potassium carbonate is 1;
step 3, adding D-neomenthol, phthalimide and triphenylphosphine in the formula (2 a) into tetrahydrofuran for dissolving, and slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, wherein the mass ratio of the D-neomenthol, phthalimide, triphenylphosphine and diethyl azodicarboxylate is 1.5;
step 4, taking the L-menthyl imide intermediate in the formula (3 a), adding methanol to dissolve, adding 80wt% of hydrazine hydrate solution at room temperature, wherein the mass ratio of the L-menthyl imide intermediate to the hydrazine hydrate in the hydrazine hydrate solution is 1, heating to 50-60 ℃, reacting for 4-6h until a large amount of white solid is separated out, filtering, adjusting the pH of the filtrate to be acidic, diluting with ethyl acetate, adding water for extraction, adjusting the pH of the water layer to be alkaline, extracting the water layer in batches with ethyl acetate, combining the organic layers, and spin-drying to obtain colorless liquid, namely L-menthylamine in the formula (4 a);
2. l-menthylamine prepared by the preparation method of claim 1.
3. A preparation method of D-neomenthylamine is characterized by comprising the following steps:
step 1, adding L-menthol, phthalimide and triphenylphosphine into tetrahydrofuran for dissolving, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, wherein the mass ratio of L-menthol to phthalimide to triphenylphosphine to diethyl azodicarboxylate is 1.5;
step 2, taking the D-new menthyl imide intermediate in the formula (3 c), adding methanol for dissolving, adding 80wt% of hydrazine hydrate solution at room temperature, wherein the mass ratio of the D-new menthyl imide intermediate to the hydrazine hydrate solution is 1;
4. d-neo-menthylamine prepared by the preparation method of claim 3.
5. A preparation method of D-neomenthylamine is characterized by comprising the following steps:
step 1: adding L-menthol and triphenylphosphine into tetrahydrofuran for dissolving, slowly dropwise adding diethyl azodicarboxylate under an ice bath condition, reacting for half an hour, adding diphenyl azidophosphate, and transferring to room temperature for reacting for 8-12h, wherein the mass ratio of L-menthol to diphenyl azidophosphate to triphenylphosphine and diethyl azodicarboxylate is 1.5;
step 2, adding the D-new menthyl azide intermediate of the formula (3 e) and 15wt% of palladium carbon into a reaction bottle, adding methanol for dissolving, reacting for 24 hours under 1-2 atmospheric pressures, filtering the mixture by using kieselguhr, washing by using methanol, and concentrating to obtain colorless liquid, namely D-new menthyl amine in the formula (4 c);
6. d-neomenthylamine prepared by the preparation method of claim 5.
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| CN202210803926.9A Pending CN115160153A (en) | 2022-07-07 | 2022-07-07 | L-menthylamine, D-neomenthylamine and preparation method thereof |
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