CN103204868A - One-pot method for synthesizing chiral amino boronate intermediate - Google Patents

One-pot method for synthesizing chiral amino boronate intermediate Download PDF

Info

Publication number
CN103204868A
CN103204868A CN 201210196091 CN201210196091A CN103204868A CN 103204868 A CN103204868 A CN 103204868A CN 201210196091 CN201210196091 CN 201210196091 CN 201210196091 A CN201210196091 A CN 201210196091A CN 103204868 A CN103204868 A CN 103204868A
Authority
CN
China
Prior art keywords
preparation
add
chiral
amino
copper
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN 201210196091
Other languages
Chinese (zh)
Inventor
张明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHENGDU AIQUN TECHNOLOGY Co Ltd
Original Assignee
CHENGDU AIQUN TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CHENGDU AIQUN TECHNOLOGY Co Ltd filed Critical CHENGDU AIQUN TECHNOLOGY Co Ltd
Priority to CN 201210196091 priority Critical patent/CN103204868A/en
Publication of CN103204868A publication Critical patent/CN103204868A/en
Pending legal-status Critical Current

Links

Abstract

The invention discloses a one-pot method for preparing a chiral amino boronate intermediate. According to the invention, three components of a chiral amine source, an aldehyde source and a boron source are subjected to a one-step reaction under the effect of a dehydration agent and a catalyst, such that a chiral alpha-amino boronate intermediate is obtained. With a simple de-protection treatment, a series of chiral alpha-amino boronate with various structures can be rapidly prepared. According to the chiral alpha-amino boronate preparation method disclosed by the invention, an unstable imine compound is not required to be prepared in advance; operation steps are simplified; production cost is low; operation is simple; and the method is suitable for industrialized productions.

Description

The method of one kettle way synthesis of chiral aminoboronic acid ester intermediate
Technical field:
The present invention relates to the method for a kind of " one kettle way " synthesis of chiral alpha-amino boronic acid ester intermediate.
Background technology:
Boric acid compound is an extremely important compounds in the organic compound, because its particular structure feature possesses good biological activity and pharmacological action, is widely used in synthetic potential enzyme inhibitors and feedback control drug transport polymkeric substance.And alpha-amino boronic acid more is considered to the pharmacophore of serpin, this class inhibitor can occupy to reversibility the space of enzyme and substrate-function, proteolytic ferment can not be combined and the corresponding peptide bond of hydrolysis with the substrate polyprotein, thereby be made into to comprise zymoplasm, the inhibitor (as compd E) of multiple protein enzymes such as endopeptidase and dipeptidyl peptidase.And serine protease can also be regulated in the cell and extracellular proteolysis enzyme level, be again carrier and the conditioning agent of a kind of free-radical scavengers and many cytokines simultaneously, so the alpha-amino boronic acid analogue also has anti-AIDS and antineoplastic activity (as compd A, B, C and D).Based on above-mentioned pharmacology widely and biological activity, in recent years, alpha-amino boronic acid has caused the extensive concern of domestic and international biochemist and Pharmaceutical Chemist.
Figure BDA00001766546600011
At present, the method for synthesis of chiral alpha-amino boronic acid ester structure fragment mainly contains following two kinds of synthesis strategies:
First kind: synthesize (R)-1-amino-3-methyl butyl boric acid pinane diol ester (B) based on Matteson rearrangement reaction strategy: Chinese patent CN200580017645, WO2009004350 and WO2009036281 have all reported based on synthetic (the R)-1-amino of Matteson rearrangement reaction-3-methyl butyl boric acid pinane diol ester and have been used for the synthetic of Velcade.There is important disadvantages in this synthetic method: needs four step chemical conversions, processing step is loaded down with trivial details, some processing condition require relatively harsher, there is two-step reaction all need under ultralow temperature (subzero 50 to subzero 60 degrees centigrade), carry out, so when this key intermediate of industrial mass production was used for Velcade synthetic, production capacity will be subjected to great restriction.
Figure BDA00001766546600012
Second kind: the connection boric acid ester is to the asymmetry catalysis addition reaction of the two keys of imines C=N, and a step makes up chirality alpha-amino boronic acid ester structure fragment:
Reported among the Chinese patent CN101812026 that the connection boric acid pinacol ester (2) of copper catalysis is to R-(+)-N-(3-methyl butylidene)-addition reaction of 1-phenylethylamine (1); pass through R-(+)-the chiral induction effect of 1-phenylethylamine synthetic (3); compound (3) is under the atmosphere of hydrogen; by the blocking group of palladium carbon catalytic eliminating amino, thereby make up key intermediate---chirality alpha-amino boronic acid ester ((the R)-1-amino-3-methyl butyl boric acid pinacol ester) structure fragment (4) that synthesizes Velcade.But; this patent is not reported the stereochemistry data (ee value) of this key intermediate; and; the connection boric acid ester of mantoquita catalysis need just can be finished under the condition of solvent reflux the asymmetric reduction reaction of the two keys of imines C=N; next step method that removes the amido protecting group is just can finish under the catalysis of palladium carbon; increase cost and the potential safety hazard of conversion unit, be unfavorable for the enforcement of suitability for industrialized production.
Figure BDA00001766546600021
Reported 1 among the Chinese patent CN101781326; 3-dicyclohexyl imidazoles fork trimethyl carbinol copper (6) catalysis connection boric acid ester (7) addition N-(sulfinyl) isovaleric aldehyde imines (5) generates N-substituted chiral alpha-amino boronic acid ester structure fragment (8), and this fragment can generate chirality alpha-amino boronic acid (9) by deprotection under acidic conditions.CN101812026 is the same with Chinese patent, the document is not reported concrete stereochemistry data (ee value), and, the catalyzer 1 that uses, the preparation condition of 3-dicyclohexyl imidazoles fork trimethyl carbinol copper (6) is extremely harsh, need the anhydrous of strictness, the operating environment of anaerobic, and also this catalyzer is preserved also trouble; The another one aspect, connection boric acid ester compound (7) needs that relate to use in this patent prepare in advance, do not have ready-made industrialization product, have increased obstacle for the further industrial applications of this patented technology undoubtedly.
Figure BDA00001766546600022
Document (J.Am.Chem.Soc.2008; 130; 6910-6911) reported a kind of 1; 3-dicyclohexyl imidazoles fork trimethyl carbinol copper (6) catalysis connection boric acid pinacol ester (2) addition N-(tertiary butyl sulfinyl) isovaleric aldehyde imines (10) generates N-substituted chiral alpha-amino boronic acid ester structure fragment (11); this fragment is under acidic conditions, and room temperature reaction can generate chirality alpha-amino boronic acid ester (4) by deprotection.But, with the same reason of Chinese patent CN101781326, because the preparation catalyzer---the condition of 1,3-dicyclohexyl imidazoles fork trimethyl carbinol copper (6) is extremely harsh, the operational condition that needs anhydrous and oxygen-free still becomes a big bottleneck of the industrial applications prospect of this method.
Figure BDA00001766546600023
So; we sum up Chinese patent CN101812026 and Chinese patent CN101781326 reported method has its fatal defective (for example: need the hydrogen catalyzed deprotection of palladium carbon; crucial feedstock production complex process; there is not existing industrialization product, crucial Preparation of Catalyst and preservation condition harshness).Yet; document (J.Am.Chem.Soc.2008; 130; 6910-6911) pointed out that is produced a Velcade key intermediate---(R)-method of 1-amino-3-methyl butyl boric acid pinacol ester; use tertiary butyl sulfinyl as the chirality assistant agent; induce the connection boric acid ester to the addition of imines; the de value satisfactory (98:2) of the key intermediate that generates; amino protecting group (tertiary butyl sulfinyl) is easy to remove (can remove under the acidic conditions); but; because the catalyzer of the key of its use---1; 3-dicyclohexyl imidazoles fork trimethyl carbinol copper (6); need be in strictness anhydrous, prepare in the operating environment of anaerobic, be unfavorable for the industrial applications of this catalyzer.
By above analysis, we sum up present existing method and prepare chirality alpha-amino boronic acid ester and also have following shortcoming:
(1), severe reaction conditions.(for example patent CN200580017645, WO2009004350 and WO2009036281, subzero 50～60 ° of C);
(2), potential safety hazard is big.(for example patent CN101812026 reported method needs the hydrogenation condition, requires high to the device security performance);
(3), the catalyzer that uses is difficult for preparation, its preservation and working conditions harshness.(for example patent CN101781326 and document J.Am.Chem.Soc.2008 report among 130, the 6910-6911 that the catalyzer that uses need be anhydrous, prepare in the inert environments of anaerobic, use and preservation condition are also relatively harsher, and this catalyzer is very easily rotten, thereby has a strong impact on the effect of catalyzed reaction.）
(4), need the unsettled imine intermediate of preparation property in advance.(patent CN101812026 for example, CN101781326 and document J.Am.Chem.Soc.2008,130, in the documents such as 6910-6911, need prepare group with imine moiety in advance---(R)-2-methyl-N-(3-methyl butylidene) propane-2-sulfinyl amine, increased the experimental implementation operation like this, increased cost, and imine compound character instability is difficult for standing storage.）
Summary of the invention:
The object of the invention is to prepare at existing method many not parts of chirality alpha-amino boronic acid ester, provides a kind of " one kettle way " quick, the method for the intermediate of easy preparation alpha-amino boronic acid ester.This synthetic method used raw material is simple and easy to, and is simple to operate, and production unit is not had special requirement, and production cost reduces greatly, is fit to very much suitability for industrialized production.
Specifically, the present invention has announced a kind of suc as formula the alpha-amino boronic acid of chirality shown in I ester intermediates preparation:
Figure BDA00001766546600031
Wherein, the carbon of asterisk (*) position is chiral carbon, is R or S configuration; R 1, R 2Independently be the alkyl of C1～C6, perhaps R 1And R 2Be connected to
Figure BDA00001766546600032
R 3Be the alkane of C1～C8, aromatic hydrocarbons, Aux is the chiral induction group, is selected from:
Figure BDA00001766546600033
The compound I preparation method that the present invention announces is characterized in that in certain solvent under certain temperature, under the effect of catalyzer and dewatering agent, with compound I I, III and IV react, and obtain I:
Wherein, the carbon of asterisk (*) position is chiral carbon, is R or S configuration; R 1, R 2Independently be the alkyl of C1～C6, perhaps R 1And R 2Be connected to
Figure BDA00001766546600035
R 3Be the alkane of C1～C8, aromatic hydrocarbons, Aux is the chiral induction group, is selected from:
Figure BDA00001766546600036
The compound I preparation method that the present invention announces, it is characterized in that: described solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in the fragrant alkanes; Described solvent preferentially is selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in the dimethylbenzene;
The compound I preparation method that the present invention announces is characterized in that: described temperature of reaction is-30～100 ° of C; Preferred range is-10～80 ° of C.
The compound I preparation method that the present invention announces, it is characterized in that: described catalyzer is that organocopper compound is organic copper catalyzer or inorganic copper catalyst, is preferably three fluosulfonic acid copper, propionic acid copper, copper sulfate, cuprous chloride, cuprous bromide, 1,3-dicyclohexyl imidazoles fork uncle fourth oxygen is cuprous.
The compound I preparation method that the present invention announces, it is characterized in that: described dewatering agent is anhydrous magnesium sulfate, anhydrous sodium sulphate, cesium carbonate, copper sulfate, sal enixum, tetrabutyl titanate, tetraethyl titanate, titanium isopropylate, molecular sieve.
The present invention is quick by one kettle way; obtain the various chirality alpha-amino boronic acid ester intermediate of a series of structures easily; this class intermediate is handled through simple deprotection owing to be the product of amino sulfinyl protection, both can obtain corresponding chirality alpha-amino boronic acid ester compound.Corresponding sulfinyl deprotection method can be referring to document: " Synthesis and Applications of tert-Butanesulfinamide " Chem.Rev.2010,110,3600 – 3740.
In a word, beneficial effect of the present invention:
(1) raw material of the present invention's use is the domestic market cheapness, the industrial chemicals that is easy to get.On the one hand the present invention's " one kettle way " of announcing prepare the equal market Chemicals on sale at home of raw material of the method use of chirality alpha-amino boronic acid ester intermediate, all raw materials are all cheap and easy to get, can prepare the chirality alpha-amino boronic acid with relatively low cost like this.
(2) the present invention avoids preparing in advance group with imine moiety, makes operation become simpler.Patent CN101812026, CN101781326 and document J.Am.Chem.Soc.2008,130, the processing method that adopts in the documents such as 6910-6911 all needs a large amount of technological operation step preparation property and the unsettled group with imine moiety of process in advance, and this class group with imine moiety in a humid environment, can be degraded into corresponding aldehyde and amine very soon, the preservation condition of group with imine moiety is also relatively harsher, has increased the cost of equipment undoubtedly, is unfavorable for carrying out of suitability for industrialized production." one kettle way " that the present invention adopts be synthesis of chiral alpha-amino boronic acid ester intermediate fast, need not prepare group with imine moiety in advance, under the effect of dewatering agent, aldehyde and amine are after condensation changes into imines in reaction process, can under the effect of catalyzer, participate in next step addition reaction immediately, the step of simplification and technological operation is fit to carrying out of industrialized production very much like this.
(3) all preparation process conditions of the present invention all carry out under the temperature of reaction of room temperature, and conversion unit is not had special requirement.Reaction in the preparation chirality alpha-amino boronic acid ester disclosed by the invention is all carried out under the room temperature reaction condition; unlike patent CN200580017645; the reactions steps of key such as WO2009004350 and WO2009036281 need be carried out under the condition of subzero 50～60 ° of C; and need to use the method for hydrogenation to deviate from amino blocking group among the patent CN101812026; this preparation technology requires highly to production unit, has increased the manufacturing cost of product undoubtedly.The chirality alpha-amino boronic acid ester intermediate that the present invention adopts " one kettle way " to prepare both can obtain chirality alpha-amino boronic acid ester through simple amino deprotection processing.
Embodiment:
Embodiment 1:
Add (R)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid DOPCP 2.71g(12mmol); add 50ml t-butyl methyl ether dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add anhydrous magnesium sulfate 2g; three fluosulfonic acid copper 329mg(1mmol); finish; allow reaction mixture room temperature reaction 48 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1N NaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound R-N-(R-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP (2.18g; productive rate 72%, the de value〉98:2). 1HNMR(600MHz,CDCl 3):δ3.60(s,1H),3.18(m,1H),2.90(m,1H),1.76~1.71(m,1H),1.53~1.46(m,2H),1.17(s,9H),0.95(s,6H),0.90(s,3H),0.89(s,3H)； 13C?NMR(150M?Hz,CDCl 3):δ?21.8,24.5,24.8,25.4,31.7,42.8,55.8,72.1。
Embodiment 2:
Figure BDA00001766546600051
Add (S)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid DOPCP 2.71g(12mmol); add 50ml methylene dichloride dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add anhydrous sodium sulphate 2g; propionic acid copper 180mg(1mmol); finish; allow reaction mixture 0 ° of C reaction 48 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1NNaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound S-N-(S-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP (2.12g; productive rate 70%, the de value〉98:2).ESI-MS：304.2[M+H] +。
Embodiment 3:
Figure BDA00001766546600052
Add (R)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid (2-methyl-2; the 4-pentanediol) ester 3.04g(12mmol); add 50ml tetrahydrofuran (THF) dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add cesium carbonate 2g; cuprous chloride 100mg(1mmol); finish; allow reaction mixture room temperature reaction 48 hours, the process of TLC monitoring reaction is after question response is finished; add the 50ml ethyl acetate and disperse reaction solution, add 1N NaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound R-N-(R-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid (2-methyl-2; the 4-pentanediol) ester (2.79g, productive rate 88%, de value〉98:2). 1H?NMR(600MHz,CDCl 3):δ4.19~4.13(m,1H),3.22(d,J=6.0Hz,1H),2.85~2.83(m,1H),1.85~1.71(m,2H),1.55~1.35(m,3H),1.25(s,6H),1.21(d,J=6.0Hz,3H),1.16(s,9H),0.89~0.87(m,6H)； 13C?NMR(150MHz,CDCl 3):δ?22.5,22.8,25.4,27.8,31.0,32.8,42.8,45.7,55.8,65.1,71.2；HR-ESI-MS:340.2105[(M+Na) +,340.2094?calculated?for?C 15H 32BNNaO 3S],318.2318[(M+H) +,318.2274?calculated?for?C 15H 33BNO 3S]。
Embodiment 4:
Figure BDA00001766546600053
Add (S)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and the connection boric acid (2; 4-dimethyl-2; the 4-pentanediol) ester 3.38g(12mmol); add 50ml ethyl acetate dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add copper sulfate 2g; cuprous bromide 150mg(1mmol), finishes, allow reaction mixture-10 ° of C reactions 72 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1NNaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate, the organic phase concentrating under reduced pressure namely gets compound S-N-(S-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid (2,4-dimethyl-2; the 4-pentanediol) ester (2.25g; productive rate 68%, the de value〉98:2), ESI-MS:332.6[M+H] +
Embodiment 5:
Figure BDA00001766546600061
Add (R)-p-methylphenyl sulfinyl amine 1.55g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid DOPCP 2.71g(12mmol); add 50ml t-butyl methyl ether dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add tetrabutyl titanate 1g; 1; the cuprous 369mg(1mmol of 3-dicyclohexyl imidazoles fork uncle's fourth oxygen); finish; allow reaction mixture room temperature reaction 48 hours, the process of TLC monitoring reaction is after question response is finished; add the 50ml ethyl acetate and disperse reaction solution, add 1N NaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound R-N-(R-p-methylphenyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP (2.62g; productive rate 78%, the de value〉98:2).
Embodiment 6:
Figure BDA00001766546600062
Add (S)-p-methylphenyl sulfinyl amine 1.55g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid pinacol ester 3.04g(12mmol); add 50ml toluene dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add sal enixum 2g; cuprous bromide 150mg(1mmol); finish; allow reaction mixture 80 ° of C reactions 12 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1N NaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound S-N-(S-p-methylphenyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP (2.46g; productive rate 70%, the de value〉98:2), ESI-MS:352.4[M+H] +
Embodiment 7:
Figure BDA00001766546600063
Add (R)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); isovaleric aldehyde 1.03g(12mmol) and connection boric acid pinacol ester 3.04g(12mmol); add 50ml t-butyl methyl ether dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add molecular sieve 2g; cuprous chloride 97mg(1mmol); finish; allow reaction mixture room temperature reaction 48 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1N NaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound R-N-(R-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP (2.85g; productive rate 90%, the de value〉98:2). 1H?NMR(600MHz,CDCl 3):δ?3.01~2.97(m,2H),1.66~1.62(m,1H),1.49~1.47(m,1H),1.45~1.42(m,1H),1.17(s,6H),1.16(s,6H),1.10(s,9H),0.83?(d,J=6.0Hz,6H); 13C?NMR(150M?Hz,CDCl 3):δ83.7,55.8,42.5,25.4,24.8,24.4,22.6,22.5,22.4;HR-ESI-MS:340.2094[(M+Na) +,340.2094?calculated?for?C 15H 32BNNaO 3S],318.2271[(M+H) +,318.2274?calculated?for?C 15H 33BNO 3S]。
Embodiment 8:
Figure BDA00001766546600071
Add (S)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); phenylacetic aldehyde 1.44g(12mmol) and connection boric acid DOPCP 3.04g(12mmol); add 50ml ethyl acetate dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add tetraethyl titanate 1g; three fluosulfonic acid copper 329mg(1mmol); finish; allow reaction mixture 50 ° of C reactions 36 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1NNaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound S-N-(S-tertiary butyl sulfinyl)-1-amino-2-phenyl-1-boric acid DOPCP (1.69g; productive rate 50%, the de value〉98:2), ESI-MS:338.6[M+H] +
Embodiment 9:
Figure BDA00001766546600072
Add (R)-tertiary butyl sulfinyl amine 1.21g(10mmol in the 100ml reaction flask); phenyl aldehyde 1.27g(12mmol) and connection boric acid pinacol ester 3.04g(12mmol); add 50ml t-butyl methyl ether dispersed with stirring mixing then; under the atmosphere of nitrogen protection; add titanium isopropylate 1g; cuprous bromide 150mg(1mmol); finish; allow reaction mixture room temperature reaction 48 hours; the process of TLC monitoring reaction; after question response is finished, add the 50ml ethyl acetate and disperse reaction solution, add 1NNaHCO then 33 liters of washings of the aqueous solution once; upper organic phase saturated common salt water washing three times; telling water discards; organic phase stirs dry with an amount of anhydrous sodium sulphate; the organic phase concentrating under reduced pressure namely gets compound R-N-(R-tertiary butyl sulfinyl)-1-amino-1-phenyl-1-boric acid DOPCP (2.43g; productive rate 72%, the de value〉98:2), ESI-MS:338.5[M+H] +
Embodiment 10:
Figure BDA00001766546600073
Add R-N-(R-tertiary butyl sulfinyl)-1 Amino 3 methyl butane-1-boric acid DOPCP 2.66 grams (8.8mmol) in the round-bottomed flask of 100ml in advance; add the 20ml dioxane then and disperse stirred for several minute; behind the complete mixing of question response raw material; add 10ml methyl alcohol; under room temperature condition, slowly drip the saturated dioxane 20ml of 4M hydrogen chloride gas; after dropwising; reaction solution is at the about 30min of room temperature reaction; the process of TLC monitoring reaction; after question response is finished; the concentrating under reduced pressure reaction solution namely has a large amount of white solids to separate out to small volume, adds the continuous agitator treating of mixing solutions 40ml of normal hexane/t-butyl methyl ether (2:1) then; filter; be drying to obtain whitening compound (R)-1 Amino 3 methyl butane-1-boric acid neopentyl glycol ester hydrochloride (1.90g, productive rate 96%, ee value〉99%). 1H?NMR(600MHz,CDCl 3):δ7.90(br.s,3H),3.65(s,4H),2.84(br.s,1H),1.92(br.s,1H),1.74(br.s,1H),1.61(br.s,1H),0.97(s,6H),0.95(m,6H)； 13CNMR(150M?Hz,CDCl 3):δ22.0,24.3,24.7,25.1,31.8,38.9,72.3。

Claims (6)

1. one kind suc as formula the alpha-amino boronic acid of chirality shown in I ester intermediates preparation:
Figure FDA00001766546500011
Wherein, the carbon of asterisk (*) position is chiral carbon, is R or S configuration; R 1, R 2Independently be the alkyl of C1～C6, perhaps R 1And R 2Be connected to
Figure FDA00001766546500012
R 3Be the alkane of C1～C8, aromatic hydrocarbons, Aux is the chiral induction group, is selected from:
Figure FDA00001766546500013
2. the preparation method of compound I as claimed in claim 1 is characterized in that in certain solvent, and under certain temperature, under the effect of catalyzer and dewatering agent, with compound I I, III and IV react, and obtain I:
Figure FDA00001766546500014
Wherein, the carbon of asterisk (*) position is chiral carbon, is R or S configuration; R 1, R 2Independently be the alkyl of C1～C6, perhaps R 1And R 2Be connected to
Figure FDA00001766546500015
R 3Be the alkane of C1～C8, aromatic hydrocarbons, Aux is the chiral induction group, is selected from:
Figure FDA00001766546500016
3. preparation method as claimed in claim 2, it is characterized in that: described solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in the fragrant alkanes; Described solvent preferentially is selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in the dimethylbenzene.
4. preparation method as claimed in claim 2, it is characterized in that: described temperature of reaction is 30～100 ° of C; Preferred range is-10～80 ° of C.
5. preparation method as claimed in claim 2, it is characterized in that: described catalyzer is that organocopper compound is organic copper catalyzer or inorganic copper catalyst, is preferably three fluosulfonic acid copper, propionic acid copper, copper sulfate, cuprous chloride, cuprous bromide, 1,3-dicyclohexyl imidazoles fork uncle fourth oxygen is cuprous.
6. preparation method as claimed in claim 2, it is characterized in that: described dewatering agent is anhydrous magnesium sulfate, anhydrous sodium sulphate, cesium carbonate, copper sulfate, sal enixum, tetrabutyl titanate, tetraethyl titanate, titanium isopropylate, molecular sieve.
CN 201210196091 2012-01-14 2012-06-14 One-pot method for synthesizing chiral amino boronate intermediate Pending CN103204868A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201210196091 CN103204868A (en) 2012-01-14 2012-06-14 One-pot method for synthesizing chiral amino boronate intermediate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201210011209.9 2012-01-14
CN201210011209 2012-01-14
CN 201210196091 CN103204868A (en) 2012-01-14 2012-06-14 One-pot method for synthesizing chiral amino boronate intermediate

Publications (1)

Publication Number Publication Date
CN103204868A true CN103204868A (en) 2013-07-17

Family

ID=48752297

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201210196091 Pending CN103204868A (en) 2012-01-14 2012-06-14 One-pot method for synthesizing chiral amino boronate intermediate

Country Status (1)

Country Link
CN (1) CN103204868A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702235A (en) * 2012-05-11 2012-10-03 武汉人福医药集团股份有限公司 Catalyst and application thereof
CN112174993A (en) * 2020-11-27 2021-01-05 郑州萃智医药科技有限公司 Preparation method of 2, 6-dimethylpyridine-3-boric acid

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702235A (en) * 2012-05-11 2012-10-03 武汉人福医药集团股份有限公司 Catalyst and application thereof
CN102702235B (en) * 2012-05-11 2015-06-03 人福医药集团股份公司 Catalyst and application thereof
CN112174993A (en) * 2020-11-27 2021-01-05 郑州萃智医药科技有限公司 Preparation method of 2, 6-dimethylpyridine-3-boric acid

Similar Documents

Publication Publication Date Title
CN108840838B (en) A method of preparing 1,1- diarylethane class compound
CN102372657B (en) Synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir
CN103204867B (en) Chiral aminoboronic acid ester and preparation method and its application in bortezomib synthesizes
CN104610355B (en) Indole framework based center chirality sulfonamides monophosphine ligand and preparation method
CN104169265B (en) Use acetate alkyl ammonium to prepare the new method of AcHMF
JP6487568B2 (en) Kinetic resolution by catalytic asymmetric hydrogenation of racemic δ-hydroxy ester and its application
CN109704926B (en) Anticancer active molecular skeleton 1, 4-eneyne compound and preparation method and application thereof
CN110483561A (en) A kind of synthetic method of ene boric acid ester type compound
Sun et al. Deep eutectic solvent promoted hydrothiocyanation of alkynoates leading to Z-3-thiocyanatoacrylates
Gong et al. Sulfur-containing amino acid-derived ionic liquid as a halogen-free catalyst for CO 2 mild transformation into cyclic carbonates
CN103204868A (en) One-pot method for synthesizing chiral amino boronate intermediate
Xie et al. Ligand-Controlled NiH-Catalyzed Regiodivergent and Enantioselective Hydroamination of Alkenyl Amides
CN103204902A (en) Aqueous-phase synthesis of novel key intermediate used for preparation of bortezomib and application of key intermediate in synthesis of bortezomib
Han et al. Chiral N‐phosphonyl imine chemistry: asymmetric additions of ester enolates for the synthesis of β‐amino acids
CN105001159A (en) Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid
JP2017530956A (en) Asymmetric catalytic synthesis of nitropyrazole amide compounds
CN101848916A (en) Titanium compound and process for asymmetric cyanation of imines
CN104860975B (en) A kind of preparation method of bortezomib synthetic intermediate
JP2016537420A (en) Method for synthesizing ester and catalyst for the synthesis
CN103665038B (en) A kind of carbon phosphorus chirality dialkyl phosphine oxide and synthetic method thereof
CN102166530B (en) Bi-chiral organic small molecular catalyst and preparation method thereof
CN103450072A (en) Pyrrole derivative of R-proline with cyclopropane structure and preparation method of pyrrole derivative
CN111393476B (en) Chiral bidentate nitrogen phosphine ligand Rong-Phos and preparation method and application thereof
CN103435535A (en) Preparation method of R-proline having cyclopropane structure
CN102329320B (en) Method for synthesizing natural product (+/-)-folicanthine and intermediate product thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C05 Deemed withdrawal (patent law before 1993)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20130717