CN100473642C - Preparation method of alpha-alkyl-isoserine and byproduct - Google Patents
Preparation method of alpha-alkyl-isoserine and byproduct Download PDFInfo
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Abstract
The present invention discloses a method for synthesizing two enantiomers of 2-alkyl isoserine by utilizing chiral malic acid as raw material through four-step reaction process. Its yield is high, can be up to 52-65% and its selectivity also is high (98%ee).
Description
Technical field
The present invention relates to the amino acid whose method of a kind of preparation, particularly a kind ofly be equipped with the method for alpha-alkyl-isoserine, and adopt similar approach to prepare a kind of by product with the asymmetric synthesis legal system---the method for amino azido-ester.
Background technology
Nonprotein alpha-hydroxyl-beta-aminophenol (isoserine) is one of member important in the beta-amino acids family.Many alpha-hydroxyl-beta-aminophenols itself have fine bio-pharmacology effect, for example the avtive spot that 4-phenyl-2-hydroxy-beta-Gamma Amino Butyric Acid, 5-methyl-2-hydroxy-beta-glycoleucine etc. can the recognition protein enzymes (referring to Hayashi, Y.; Kinoshita, Y.; Hidaka, K.; Kiso, A.; Uchibori, H.J.Org.Chem.2001,66,5537.), they also are the important fragments of the complicated natural product molecule of synthetic multiple biologically active, for example, the Taxol with antitumour activity is (referring to (a) Ha, H.-J.; Park, G.-S.; Ahn, Y.-G.; Lee, G.S.Bioorg.Med.Chem.Lett.1998,8,1619. (b) Review:Nicolaou, K.C.; Dai, W.-M.; Guy, R.K.Angew.Chem., Intl.Ed.Engl.1994,33,15.), suppress the bestatin of aminoprotease (referring to (a) Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H.J.Antibiot.1976,29,600. (b) Pearson, W.H.; Hines, J.V.J.Org.Chem.1989,54,4235.), suppress renin KRI1314 (referring to Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.; Umeyama, H.; Kiso, Y.J.Chem.Soc., Chem.Commun.1989,1678.), have powerful antimicrobial dideoxykanamycin A (referring to Umemura, E.; Tsuchiya, T.; Umezawa, S.J.Antibiot.1988,41,530.), have the KNI-764 that suppresses Hiv-1 proteolytic enzyme (referring to Mimoto, T.; Kato, R.; Takaku, H.; Nojima, S.; Terashima, K.; Misawa, S.; Fukazawa, T.; Ueno, T.; Sato, H.; Shintani, M.; Kiso, Y.; Hayashi.H.J.Med.Chem.1999,42,1789.) etc. all form as core by alpha-hydroxyl-beta-aminophenol.These physiology, pharmacology and physically significant characteristic come from the alpha-hydroxyl-beta-aminophenol particular structure probably---the hydroxyl of free α position.Also just because of the special pharmacological that this compounds had, perhaps physiology, perhaps physical properties makes synthetic alpha-hydroxyl-beta-aminophenol (isoserine) become the focus that the chemosynthesis worker pays close attention to.
So far, the method for asymmetric synthesis of alpha-hydroxyl-beta-aminophenol seldom (referring to Battaglia, A.; Guerrini, A.; Bertucci, C.J.Org.Chem.2004,69,9055.), and, have only the only a few bibliographical information so far about 2-methyl isoserine stereoscopic correspondence method for selective synthesis for the isoserine that alpha-alkyl replaces, and referring to (a) Cativiela, C.; Diaz-de-Villegas, M.D.; Galvez, J.A.Tetrahedron 1996,52,687. (b) Pires, R..; Burger, K.Synthesis 1996,1277. (c) Avenoza, A.; Busto, J.H.; Corzana, F.Tetrahedron:Asymmetry 2004,15, and 131).Wherein productive rate is best, selectivity is the highest be Avenoza research group report in 2004 synthetic method (referring to Avenoza, A.; Busto, J.H.; Corzana, F.Tetrahedron:Asymmetry 2004,15,131), they are from N-methoxyl group-N-methyl-Methacrylamide, elder generation's asymmetric dihydroxylation, dihydroxylation product and thionyl chloride reaction generate cyclic sulfite, again with sodiumazide to the cyclic sulfite nucleophilic ring opening, then, with the concentrated hydrochloric acid neutralization, can obtain the corresponding carboxylic acid derivative again with lithium hydroxide hydrolysis nucleophilic ring opening product, pass through palladium carbon shortening at last, two pairs of enantiomers of optionally having synthesized 2-methyl isoserine simultaneously.
Summary of the invention
The invention provides a kind of new method of comparatively simply synthesizing alpha-alkyl-isoserine.The present invention provides the method for preparing amino azido-ester with the similar way of the present invention simultaneously.
Method of the present invention is the chirality oxysuccinic acid to be carried out non-mapping select protection to obtain 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; again it is carried out the Stereoselective alkylation reaction; again the carboxylic acid in the previous reaction products therefrom is reset with Curtius and changed into amino acid ester; again product is added hydrochloric acid at 110～120 ℃ of sealed reactions; obtain the hydrochloride of alpha-alkyl-isoserine; hydrochloride is dissolved in a spot of ethanol; add an amount of propylene oxide backflow and then obtained an alpha-alkyl isoserine in, the alkyl here refers to: benzyl, perhaps ethyl; perhaps allyl group, perhaps methyl.The process of this method is referring to reaction formula 1.
The 1a:R=benzyl; The 1b:R=ethyl; The 1c:R=allyl group; The 1d:R=methyl
Formula 1
In the method for the invention, adopting diphenyl phosphate azide during the Curtius rearrangement reaction is reagent, and toluene is solvent, and methyl alcohol participates in rearrangement reaction.
Another concrete grammar of the present invention is non-mapping to be selected the oxysuccinic acid of protection; carry out solid and select alkylated reaction; product 1 mmole of getting gained is dissolved in 2 milliliters the dry toluene; the triethylamine that adds 0.28 milliliter of 2 mmole; applying argon gas protection then; the diphenyl phosphate azide that adds 0.202 milliliter of 1 mmole; shake up the back at argon shield and room temperature stirring reaction to the reflux temperature condition; condensing reflux after reaction is finished, the faint yellow oily thing of gained gets Urethylane through column chromatography for separation.
In the method for the present invention; after in aforementioned preparation process, obtaining Urethylane; 50 milligrams Urethylane can be dissolved in 2 milliliter 88% the formic acid; under argon shield, refluxed 4 to 6 hours; boil off solvent and obtain the N-protected alpha-alkyl isoserine that pivalyl aldehyde is protected, further hydrolysis just can obtain the alpha-alkyl isoserine that we need in the NaOH of 6M HCl or the 1M aqueous solution again.
Can adopt following method to handle for the Urethylane that obtains: will add the hydrochloric acid of 2mL 6M in the 50mg Urethylane; charge into argon gas; 110-120 ℃ of reaction 1 hour; go the pivalyl aldehyde protecting group; cooling, the pressure reducing and steaming solvent is dissolved in it in hydrochloric acid of 2mL 6M again; under the argon shield; 110-120 ℃ was reacted 10 hours, and postcooling is used ethyl acetate extraction to room temperature behind the adding 2mL water; with the water layer evaporated under reduced pressure; add the 1mL dehydrated alcohol, the propylene oxide that the dissolving back adds 0.5mL refluxes and stirred 1 hour; cooling back pressure reducing and steaming solvent gets Alpha-hydroxy-alpha-alkyl-beta-amino acids.
The another kind of method for preparing alpha-alkyl-isoserine is the chirality oxysuccinic acid to be carried out non-mapping select protection to obtain 2-[(2R among the present invention; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; 2-[(2R with 290 milligrams of 1 mmoles; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate carries out three-dimensional selecting product behind the alkylated reaction to be dissolved in 2 milliliters the dry toluene; the triethylamine that adds 0.14 milliliter of 1 mmole; shake up; applying argon gas protection then; the diphenyl phosphate azide that adds 0.202 milliliter of 1 mmole; under argon shield, stir; normal-temperature reaction adds under argon gas atmosphere after one hour and is dissolved in 3 milliliters of benzylalcohol 0.95 mmoles among the DMF; CuCl (the 5mg that adds catalytic amount again; 5%mmol); continue reaction under the room temperature to complete; add 10 ml water termination reactions; use ethyl acetate extraction (10mL * 3) after filtering removal CuCl; merge organic phase; use salt solution; wash respectively with distilled water; anhydrous magnesium sulfate drying; filter, the pressure reducing and steaming solvent obtains faint yellow solid, gets benzyl carbamate through column chromatography for separation; benzyl carbamate is dissolved in 2 milliliter 88% the formic acid again and goes the pivalyl aldehyde protecting group, palladium carbon hydrogenation is sloughed benzyl and is changed into alpha-alkyl-isoserine then.Equally, the alkyl here refers to: benzyl, perhaps ethyl, perhaps allyl group, perhaps methyl.
The unexpected preparation method who has found amino azido-ester in the experimentation of the present invention.This method is the benzyl 2-[(2R with 290 milligrams of 1 mmoles; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or benzyl 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate is dissolved in 2 milliliters the dry toluene; the triethylamine that adds 0.28 milliliter of 2 mmole; shake up; applying argon gas protection then; the diphenyl phosphate azide that adds 0.404 milliliter of 2 mmole; at argon shield and room temperature stirring reaction to the reflux temperature condition; reaction is finished postcooling to room temperature, and pressure reducing and steaming is removed toluene, gets faint yellow oily thing it is dissolved in 15 milliliters of methylene dichloride; use saturated aqueous common salt again; saturated sodium carbonate solution and distilled water wash respectively; anhydrous magnesium sulfate drying is handled, and filters, and the pressure reducing and steaming methylene dichloride gets flaxen solid; after a small amount of methylene dichloride dissolving, get amino azido-ester through column chromatography for separation.And the azido-of amino azido-ester can change into tetrazolium, 1,2,3-triazoles and amino.According to the report of relevant document, this type of compound also has certain application prospect at field of medicaments.
The present invention utilizes the chirality oxysuccinic acid to be raw material, through four-step reaction, and two kinds of enantiomers of having synthesized 2-alkyl isoserine of high yield (52-65%) highly selective (98% ee).What wherein, 2-ethyl, benzyl, allyl group replaced does not see that as yet report is arranged synthesizing of isoserine.
Embodiment
It below is related embodiment of the present invention.
In the embodiment of this invention; at first need the chirality oxysuccinic acid is carried out the cis-selectivity protection; obtain 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-and the 2-tertiary butyl-5-oxygen-1,3-dioxolane-4-yl] acetate, carry out the Stereoselective alkylation reaction then.Its reaction process is referring to reaction formula 2.
A, pivalyl aldehyde (1.5 equivalent), catalytic amount tosic acid, dense H
2SO
4/ pentane refluxes
B, i) HMDS (2.1 equivalent)/THF, n-BuLi (hexane solution) (2.0 equivalent), 0 ℃, 20 minutes
Ii) RX/THF, 5 minutes, heats-23 ℃, 6 hours (RX=EtI is-5 ℃ of droppings) gradually by-78 ℃; Iii) 1M HCl.
The 4a:R=benzyl; The 4b:R=ethyl; The 4c:R=allyl group; The 4d:R=methyl
Formula 2
1) specific practice of oxysuccinic acid cis-selectivity protection is: (20g 232mmol) is dissolved in 300 milliliters of Skellysolve As, adds 2 gram tosic acid and 3 vitriol oils, and (20g 150mmol), sees in the following formula 2 to add the chirality oxysuccinic acid with pivalyl aldehyde.The control oil bath temperature was 45-50 ℃ of backflow, stirring 36 hours.Be cooled to room temperature, filter, the solid that obtains is dissolved in 200 milliliters of methylene dichloride, use 20 milliliter 8% phosphoric acid washing twice again, use anhydrous magnesium sulfate drying, boil off methylene chloride after the filtration and obtain white solid 3 (29.7g, 98%), do not carry out purifying and promptly carry out next step reaction.
The synthetic principle of Seebach ' s " SRS ", highly selective (98% de) are well followed in this reaction
26Made up the required chiral centre of our final product.Document Seebach, D.; Naef, R.and Calderari, G.Tetrahedron, 1984,40,1313. reports, (2R is 4S)-4 with (2R's difference isomer 4R)-4 exists
1Have than big-difference on the HNMR, thus the reaction selectivity de value can by
1HNMR measures, and we find when detecting
1The peak that only occurs the simplification compound in the HNMR spectrogram.Corresponding compound (2R, 4R)-4 with (2S, 4S)-4
1H NMR,
13C NMR, fusing point are identical, and optically-active size equidirectional is opposite and conform to bibliographical information.
About the cis-selectivity protection of oxysuccinic acid, can be referring to Seebach, D.; Naef, R.and Calderari, G.Tetrahedron, 1984,40,1313. and Seebach, D.; Sting, A.R.; Hoffmann, M.Angew.Chem., Int.Ed.Engl.1996,35,2708..People such as Seebach studied the reaction of selectivity alpha-alkyl alpha hydroxy acid in 1984.A tree name report is used pivalyl aldehyde, all kinds of alpha hydroxy acid of the protection of cis-selectivity well, and in alkylated reaction subsequently its stereoselectivity also very good (〉 95% de).This part work provides theoretical basis for the synthetic principle (" Self-Regeneration of Stereocenters " synthesis principle) of Seebach ' s " SRS " that he proposed in 1996.
2) Stereoselective alkylation reaction
Under 0 ℃, with the 2-[(2R of 440 μ L (2.1mmol), 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; perhaps 2-[(2S, 4S)-the 2-tertiary butyl-5-oxygen-1,3-dioxolane-4-yl] acetate joins and uses in argon shield and the exsiccant 25mL round-bottomed flask; add the 2.0mL anhydrous tetrahydro furan then; after 5 minutes, add 1.43mL (1.4mol/L, n-Butyl Lithium 2.0mmol); 0 ℃ of reaction 20 minutes, freezing more standby to-78 ℃.
Alkylated reaction: in 25 milliliters of exsiccant round-bottomed flask with long necks, under the argon shield with 3 (202mg, 1.0mmol) be dissolved in 8 milliliters of anhydrous tetrahydro furans, after 10 minutes, above-mentioned homemade LHMDS is added drop-wise to (2 minutes) in the reaction system with syringe lentamente along the bottle wall-78 ℃ of coolings; Add the close electric alkylating reagent halohydrocarbon RX (1.5mmol) that is dissolved in 2 milliliters of anhydrous tetrahydro furans lentamente along the bottle wall after 5 minutes; React and after 30 minutes temperature is raised to-23 ℃ (tetracol phenixin-liquid nitrogen) continuation reaction 6 hours (during iodoethane, then temperature being elevated to again-5 ℃ of reactions 10 hours).Afterwards, the hydrochloric acid with 4mL 1M will react cancellation.Separatory washs upper organic phase to the pH=2 with saturated aqueous common salt 2 milliliters * 2, distilled water 2 milliliters * 2, uses anhydrous magnesium sulfate drying, and the pressure reducing and steaming solvent obtains the head product of 4 (following identical) in the formula 2; Lower layer of water is merged back ethyl acetate extraction 10 milliliters * 3 mutually, the organic phase that merges extraction, wash to the pH=2 with saturated aqueous common salt 5 milliliters * 2, distilled water 5 milliliters * 2, use anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent obtains another part head product of 4.Merge above crude product,, obtain compound 4 by column chromatography (sherwood oil: ethyl acetate, 8: 1～1: 1) purifying.Compound (2R, 4R)-4 (2S, 4S)-4 except that optically-active was opposite, spectrum data was all identical for enantiomer.
Among the present invention, in obtaining reaction formula 2, behind the compound 4, utilize the Curtius rearrangement reaction to change carboxyl into amino acid ester again.
The Curtius rearrangement reaction is one of reaction the most frequently used in the organic reaction in reported first (referring to Curtius, Ber.1890,23,3023) in 1890, usually can use in natural product complete synthesis.This is reflected at can be well with carboxylic acid under the comparatively gentle situation of condition, and carboxylic acid ester compound is converted into the amino compound of few carbon.
The Curtius rearrangement reaction at first will be converted into carboxylic acid the nitrine acid amides, its method commonly used be (referring to (a) Joseph, W.J.Org.Chem.1961,26,3511. (b) Jellimann, C.; Mathe-Allainmat, M.; Andrieux, J.; Kloubert, S.; Boutin, J.A.; Nicolas, J.-P.; Bennejean, C.; Delagrange, P.; Langlois, M.J.Med.Chem.2000,43,4051. (c) Reichelt, A.; Gaul, C.; Frey, R.R.; Kennedy, A.; Martin, S.F.J.Org.Chem.2002,67,4062. (d) Pellicciari, R.; Marinozzi, M.; Camaioni, E.; Del Carmen Nunez, M.; Costantino, G.; Gasparini, F.; Giorgi, G.; Macchiarulo, A.; Subramanian, N.J.Org.Chem.2002,67,5497. (e) Lisowski, V.; Leonce, S.; Kraus-Berthier, L.; Sopkova-de Oliveira Santos, J.; Pierre, A.; Atassi, G.; Caignard, D.-H.; Renard, P.; Rault, S.J.Med.Chem.2004,4,1448.): substrate is generated the mixed acid anhydride activated carboxyl with Vinyl chloroformate in equivalent triethylamine condition, add as sodium azide aqueous solution by N again
3 -Nucleophilic attack activatory carboxyl obtains corresponding nitrine acid amides.Then, heating allows its rearrangement in the solvent of dry non-activity proton, or adding alcohol strong acid at last just can obtain carbamate or ammonia.But we are difficult to obtain purer rearrangement precursor nitrine acid amides with this method, if purifying is not with regard to rearrangement reaction then productive rate is very low and complicated being difficult to of system separates.
Through relevant result of experiment and analysis, the present invention has improved the Curtius rearrangement reaction.Promptly use diphenyl phosphate azide (DPPA) can solve this contradiction as azide reagent.This way can be avoided separating and be reset precursor nitrine acid amides, and the nitrine acid amides is reset the side reaction of the nucleophile participation that does not have other in the system of back.Correlated response is referring to reaction formula 3.Use methyl alcohol in the related experiment respectively, different reagent such as benzylalcohol and uncle's butyric acid are tested, go forward side by side to be about to substrate and in exsiccant alcohol, to reflux earlier, or the different treatment that earlier substrate is refluxed in different solvent such as benzene or toluene test, to obtain optimal conditions.The optimal conditions of its reaction sees Table 1.
5a:R=benzyl R '=Me; The 5b:R=ethyl; R '=Me;
The 5c:R=allyl group; R '=Me; The 5d:R=methyl; R '=Me
5a (B): R=benzyl R '=Bn; 5a ': R=benzyl R '=t-Bu;
Formula 3
The condition optimizing of table 1.Curtius rearrangement reaction
As seen the experimental data that provides from table 1 directly refluxes (batch 1-3) in the exsiccant alcoholic solution, can obtain the expection product of moderate yield during with methyl alcohol or benzylalcohol, and accident obtains amino azido-ester during with the trimethyl carbinol
346a '.Referring to formula 4.
Formula 4
Experiment also shows, adds alcohol (batch 4-9) again if substrate is refluxed to reset earlier in solvent, and productive rate obviously improves, the toluene better effects if.And be amino azido-ester with batch 1 a same primary product when adding the trimethyl carbinol.We think it may is that the nucleophilicity of the trimethyl carbinol is not enough, thereby and its each other steric hindrance when the attack isocyanic ester be difficult to carry out greatly, like this isocyanic ester may with N
3 -Thereby reaction obtains amino azido-ester primary product.In order to confirm this supposition, we are increased to 2 equivalents (batch 10) with the amount of DPPA, obtain the amino azido-ester 6a ' of 76% productive rate, and therefore N in experiment has been described
3 -Can with isocyanate reaction, its reactive behavior is greater than the trimethyl carbinol.
In addition, find also in the experiment that the very approaching more difficult purifying of the polarity of product and benzylalcohol is referring to the 11st in table 1.The product benzyl carbamate with palladium carbon shortening to slough benzyl, obtain alpha-alkyl-isoserine, and Urethylane just can obtain ammonia smoothly under strong acid or highly basic condition, and product is the quaternary carbon chiral centre, can racemization under strongly-acid or highly basic condition.
To sum up, we finally select toluene as solvent, and methyl alcohol participates in rearrangement reaction.Optimum experimental condition and the results are shown in Table 2, we have further optimized Curtius rearrangement reaction condition, and its test-results sees Table 2.By table 2 as seen; substrate is dissolved in the exsiccant toluene; argon shield adds TEA (2.0 equivalent) down; DPPA (1.0 equivalent); refluxed 30 minutes or normal temperature down reaction add five normal anhydrous methanols after 1 hour, refluxing to obtain ideal rearrangement product Urethylane in 16 hours again.
The condition optimizing of the further rearrangement reaction of table 2 Curtius
Utilize the rearrangement condition of above-mentioned optimization; with other acid 4; be R type or S type oxysuccinic acid; after carrying out non-mapping selection protection; four kinds of alkyl carry out the product behind the three-dimensional selection alkylated reaction; can obtain corresponding Urethylane 5 by high productivity through rearrangement reaction, formula 5 is seen in its reaction, and reaction result sees Table 3.
The 5a:R=benzyl; The 5b:R=ethyl; The 5c:R=allyl group; The 5d:R=methyl
Formula 5
Table 3 Curtius resets the result
The detailed process of above-mentioned test is as follows:
The preparation of Urethylane 5:
Acid in the formula 24 (1mmol) is dissolved in the dry toluene of new processing (2mL), add triethylamine (0.28mL, 2mmol); shake up, fill argon shield with, add DPPA (0.202mL; 1mmol), stirring reaction added that reflux condensing tube refluxes after 1 hour under argon shield.React after 16 hours, some plate detection reaction is complete, termination reaction.After the reaction system cool to room temperature, pressure reducing and steaming toluene obtains faint yellow oily thing.Column chromatography (PE:EtOAc=20:1～2:1) separate Urethylane 5.By identical method, and in the modus ponens 2 (2R, 4R)-4a, perhaps (2R, 4R)-4b, perhaps (2R, 4R)-4c, perhaps (2R, 4R)-4d, perhaps (2S, 4S)-4a, perhaps (2S, 4S)-4b, perhaps (2S, 4S)-4c, perhaps (2S 4S)-4 reacts, and can obtain corresponding Urethylane respectively.
In the present invention benzyl carbamate (2R, 4R)-the concrete preparation process of 5a (R=Bn) is as follows:
With acid in the formula 2 (2R, 4R)-(290mg 1mmol) is dissolved in the dry toluene of new processing (2mL) 4a (R=Bn); (0.14mL 1mmol), shakes up to add triethylamine; charge into argon shield, and adding DPPA (0.202mL, 1mmol); add reflux condensing tube; stir under argon shield, normal-temperature reaction one hour adds benzylalcohol (0.95mmol) solution that is dissolved in DMF (3ml) under argon atmospher; add again catalytic amount CuCl (5mg, 5%mmol).It is complete that the plate detection reaction is put in the continuation reaction under the room temperature after 2 hours, adds entry (10mL) termination reaction.Filter, use ethyl acetate extraction (10mL * 3) behind the elimination CuCl, merge organic phase, with salt solution (3 * 3mL), with distilled water (3 * 3mL) respectively the washing, anhydrous magnesium sulfate drying filters, and the pressure reducing and steaming solvent obtains faint yellow solid, column chromatography (PE:EtOAc=5:1～1:1) separate obtain the white solid benzyl carbamate (2R, 4R)-5a (B).
By identical method, and in the modus ponens 2 (2R, 4R)-4b, perhaps (2R, 4R)-4c, perhaps (2R, 4R)-4d, perhaps (2S, 4S)-4a, perhaps (2S, 4S)-4b, perhaps (2S, 4S)-4c, perhaps (2S, 4S)-4d reacts, and can obtain corresponding benzyl carbamate respectively.
Synthesizing of alpha-alkyl-isoserine
The Curtius rearrangement product 5 that obtains is above added 6M hydrochloric acid 110-120 ℃ of reaction 11h in sealed tube, obtain Alpha-hydroxy-β-alkyl-beta-amino acids hydrochloride with good productive rate and selectivity, hydrochloride is dissolved in a spot of ethanol, adds an amount of propylene oxide backflow and then obtained free Alpha-hydroxy-alpha-alkyl-beta-amino acids (alpha-alkyl isoserine) in one hour.Reaction is referring to formula 5
The 1a:R=benzyl; The 1b:R=ethyl; The 1c:R=allyl group; The 1d:R=methyl
A.i) 6M HCl, tube sealing, 110-120 ℃; Ii) propylene oxide/Et0H refluxes
Formula 6
Wherein (R) with (S)-fusing point of Alpha-Methyl-isoserine (R=Me), optically-active are respectively mp.225-227 ℃ (dec), [α] 18D-11.5 ° of (c1.0, H
2O) [lit.
23aMp.228 ℃ (dec), [α] 18D-11.2 ° of (c1.0, H
2O)]; [α] 18D+11.2 ° of (c1.0, H
2O) [lit.
23bMp.228 ℃ (dec), [α] 18D+11.3 ° of (c1.0, H
2O)]; Consistent with bibliographical information, and its
1H NMR also with the conforming to of bibliographical information.And other-alkyl-isoserine do not seen bibliographical information, but consider that each operation after the highly selective alkylation can not influence their change of configuration, therefore can think that height has selectively obtained corresponding alpha-alkyl-isoserine.
In experiment of the present invention, also find; after having obtained Curtius rearrangement product Urethylane 5; Urethylane 5 is dissolved in the analytical pure formic acid (88%); argon shield refluxed 4 to 6 hours down, boiled off the N-protected alpha-alkyl-isoserine that solvent can obtain the pivalyl aldehyde protection.Therefore, this also is the method for a synthetic alpha-alkyl isoserine Urethylane, and its reaction formula is seen formula 7.Further hydrolysis just can obtain the alpha-alkyl isoserine that we need in 6M HCl or 1M NaOH.
Formula 7
And Urethylane 5 pivalyl aldehyde protecting group under strong acid hydrochloric acid condition also is unsettled, therefore, we next step reaction of hydrochloric acid condition obtain must the alpha-alkyl isoserine.Experiment is found; under 6M HCl condition, 110-120 ℃ was reacted 11 hours in sealed tube, can almost quantitatively obtain de-protected hydrochloride; at last with propylene oxide in ethanol, handle with regard to high yield obtained free alpha-alkyl isoserine, see reaction formula 6.Its result such as following table 4:
Table 4: the preparation result of free alpha-alkyl isoserine
Annotate: optically-active is to test in the aqueous solution
More than Shi Yan specific practice is:
Claim the Curtius rearrangement product 5 (50mg); in in the 10mL round-bottomed flask; add 2mL formic acid (88%); load onto reflux condensing tube; under argon shield backflow 4-6 hour, cooling, pressure reducing and steaming solvent; dry, promptly obtain Alpha-hydroxy-alpha-alkyl-beta-amino acids Urethylane (alpha-alkyl-isoserine Urethylane).
Another kind of facture is:
Claim Curtius rearrangement product 5 (50mg) in sealed tube; the hydrochloric acid that adds 2mL 6M; charge into argon gas,, go the pivalyl aldehyde protecting group 110-120 ℃ of reaction 1 hour; cooling; the pressure reducing and steaming solvent is dissolved in it in hydrochloric acid of 2mL 6M, under the argon shield again; 110-120 ℃ was reacted 10 hours; postcooling is to room temperature, add behind the 2mL water with ethyl acetate extraction three times (2 * 3mL), with the water layer evaporated under reduced pressure; add the 1mL dehydrated alcohol; the propylene oxide that the dissolving back adds 0.5mL refluxes and stirred 1 hour, cooling back pressure reducing and steaming solvent; dry, get the Alpha-hydroxy-alpha-alkyl-beta-amino acids (alpha-alkyl-isoserine) of white solid.
From above given example as seen; the present invention sets out with two kinds of commercially available enantiomerism chirality oxysuccinic acid; set up chiral centre according to synthetic principle highly-solid selectively protection of Seebach ' s " SRS " and highly-solid selectively alkylation (98% de); again through a Curtius rearrangement reaction and a step protective reaction; totally four steps are with overall yield 52% (R=Et) or about 64% (R=allyl group; Bn Me) has synthesized corresponding two kinds of optically pure alpha-alkyl-isoserines respectively.Its synthetic method is more simple than prior art.Wherein, synthetic α-benzyl-isoserine, α-ethyl-isoserine, the α-allyl group-isoserine of selectivity is reported first.This method can also be used for asymmetric synthesis α, β-two alkyl-isoserine.
The preparation of amino azido-ester 6:
With the acid in the formula 2 (2R, 4R)-(290mg 1mmol) is dissolved in the dry toluene of new processing (2mL) 4a (R=Bn); (0.28mL 2mmol), shakes up to add triethylamine; charge into argon shield; (0.404mL 2mmol), adds reflux condensing tube to add DPPA; under argon shield, stir; reflux, react that to put the plate detection reaction after 24 hours complete, termination reaction.After the reaction system cool to room temperature, pressure reducing and steaming toluene, obtain faint yellow oily thing, it is dissolved in methylene dichloride (15mL), and saturated aqueous common salt (2mL), saturated sodium carbonate solution (3mL), usefulness distilled water (3mL) wash anhydrous magnesium sulfate drying respectively, filter, the pressure reducing and steaming methylene chloride obtains faint yellow solid, with a small amount of methylene dichloride dissolving back column chromatography (PE:EtOAc=20:1～2:1) separate obtain the amino azido-ester of white solid (2R, 4R)-6
a(azido-can change into tetrazolium, 1,2,3-triazoles and amino)
By identical method, and in the modus ponens 5 (2R, 4R)-4b, perhaps (2R, 4R)-4c, perhaps (2R, 4R)-4d, perhaps (2S, 4S)-4a, perhaps (2S, 4S)-4b, perhaps (2S, 4S)-4c, perhaps (2S 4S)-4 reacts, and can obtain corresponding amino azido-ester respectively.
Claims (7)
1; alpha-substitution-preparation method of isoserine; it is characterized in that the chirality oxysuccinic acid is carried out non-mapping selects protection to obtain 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; again it is carried out the stereoselectivity conversion reaction; generate the 2-[(2R that 4-replaces; 4R)-and the 2-tertiary butyl-5-oxygen-1,3-dioxolane-4-yl] 2-[(2S that replaces of acetate or 4-, 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; again the carboxylic acid in the previous reaction products therefrom is carried out Curtius with diphenyl phosphate azide and resets and to change amino acid ester into, again product is added hydrochloric acid at 110～120 ℃ of sealed reactions, obtain alpha-substitution-hydrochloride of isoserine; hydrochloride is dissolved in a spot of ethanol; add an amount of propylene oxide reflux obtained in one hour alpha-substitution-isoserine, the substituting group here refers to: benzyl, perhaps ethyl; perhaps allyl group, perhaps methyl.
2, alpha-substitution according to claim 1-preparation method of isoserine, adopting toluene when it is characterized in that carrying out the Curtius rearrangement reaction is solvent, and adds methyl alcohol in reaction, participates in rearrangement reaction.
3; alpha-substitution according to claim 2-preparation method of isoserine; it is characterized in that 1 mmole 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] product after the stereoselectivity conversion reaction of acetate is dissolved in 2 milliliters of dry toluenes; the triethylamine that adds 0.28 milliliter of 2 mmole; applying argon gas protection then; the diphenyl phosphate azide that adds 0.202 milliliter of 1 mmole; shake up the back at argon shield and room temperature stirring reaction to the reflux temperature condition; condensing reflux after reaction is finished, the faint yellow oily thing of gained gets Urethylane through column chromatography for separation.
4; according to claim 2 or 3 described alpha-substitution-preparation method of isoserine; it is characterized in that and to add the hydrochloric acid of 2mL 6M in the 50mg Urethylane; charge into argon gas; 110-120 ℃ of reaction 1 hour, go the pivalyl aldehyde protecting group, cooling; the pressure reducing and steaming solvent; it is dissolved in the hydrochloric acid of 2mL 6M, under the argon shield, 110-120 ℃ was reacted 10 hours again; postcooling is to room temperature; use ethyl acetate extraction after adding 2mL water,, add the 1mL dehydrated alcohol the water layer evaporated under reduced pressure; the dissolving back adds the propylene oxide of 0.5mL; reflux to stir 1 hour, cooling back pressure reducing and steaming solvent, Alpha-hydroxy-alpha-substitution-beta-amino acids.
5; alpha-substitution-preparation method of isoserine; it is characterized in that the chirality oxysuccinic acid is carried out non-mapping selects protection to obtain 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate; with 1 mmole 2-[(2R; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] acetate carries out solid and selects conversion reaction; generate the 2-[(2R that 4-replaces; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] 2-[(2S that replaces of acetate or 4-; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-yl] product behind the acetate is dissolved in 2 milliliters the dry toluene; the triethylamine that adds 0.14 milliliter of 1 mmole; shake up; applying argon gas protection then; the diphenyl phosphate azide that adds 0.202 milliliter of 1 mmole; under argon shield, stir; normal-temperature reaction adds under argon gas atmosphere after one hour and is dissolved in 3 milliliters of benzylalcohol 0.95 mmoles among the DMF; the 5mg CuCl that adds catalytic amount again; continue reaction under the room temperature to complete; add 10 ml water termination reactions; after filtering removal CuCl; with ethyl acetate extraction 3 times; each 10mL ethyl acetate of using; merge organic phase; use salt solution; wash respectively with distilled water; anhydrous magnesium sulfate drying; filter; the pressure reducing and steaming solvent obtains faint yellow solid; get benzyl carbamate through column chromatography for separation, benzyl carbamate is dissolved in 2 milliliter 88% the formic acid again and goes the pivalyl aldehyde protecting group, palladium carbon hydrogenation sloughs that benzyl changes into that a-replaces-isoserine then; the substituting group here refers to: benzyl; perhaps ethyl, perhaps allyl group, perhaps methyl.
6; the method for preparing amino azido-ester; it is characterized in that 290 milligrams of 2-[(2R of 1 mmole; 4R)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-benzyl-4-yl] acetate or 2-[(2S; 4S)-the 2-tertiary butyl-5-oxygen-1; 3-dioxolane-4-benzyl-4-yl] acetate is dissolved in 2 milliliters the dry toluene; the triethylamine that adds 0.28 milliliter of 2 mmole; shake up; applying argon gas protection then adds the diphenyl phosphate azide of 0.404 milliliter of 2 mmole, at argon shield and room temperature stirring reaction to the reflux temperature condition; reaction is finished postcooling to room temperature; pressure reducing and steaming is removed toluene, gets faint yellow oily thing, and it is dissolved in 15 milliliters of methylene dichloride; use saturated aqueous common salt again; saturated sodium carbonate solution and distilled water wash respectively; anhydrous magnesium sulfate drying is handled, and filters, and the pressure reducing and steaming methylene dichloride gets flaxen solid; after a small amount of methylene dichloride dissolving, get amino azido-ester through column chromatography for separation.
7,, it is characterized in that the azido-in the amino azido-ester is converted into tetrazyl, 1,23 triazolyls or amino according to the method for claim 6.
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| (S)-异丝氨酸的合成. 陈立功等.化学通报，第2期. 2001 |
| (S)-异丝氨酸的合成. 陈立功等.化学通报，第2期. 2001 * |
| new synthesis of enantiopure 2-methyl isoseines. alberto avenoza et al.tetrahedron:asymmetry,No.15. 2004 |
| new synthesis of enantiopure 2-methyl isoseines. alberto avenoza et al.tetrahedron:asymmetry,No.15. 2004 * |
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