CN100584821C - A kind of method for preparing optically pure t-leucine - Google Patents
A kind of method for preparing optically pure t-leucine Download PDFInfo
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- CN100584821C CN100584821C CN 200710044378 CN200710044378A CN100584821C CN 100584821 C CN100584821 C CN 100584821C CN 200710044378 CN200710044378 CN 200710044378 CN 200710044378 A CN200710044378 A CN 200710044378A CN 100584821 C CN100584821 C CN 100584821C
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Abstract
The invention provides a kind of method for preparing optically pure t-leucine, it is characterized in that, comprise step: the acid resolving agent of bright acid amides of (1) racemization uncle and optical purity is reacted in resolution solvent and salts out; (2) according to specific rotation, described salt through the diluted acid replacement Treatment, use organic solvent extraction directly or through behind the recrystallization in water, and the acquisition organic phase is with mutually inorganic; (3) stir described inorganic phase, after alkali lye is adjusted to alkaline pH, separate out a large amount of solids again, the described solid of washing and drying promptly gets described optically pure t-leucine; (4) dry, concentrated described organic phase reclaims the acid resolving agent of described optical purity.The present invention is easy and simple to handle, quick, product yield is high, production cost is greatly reduced.
Description
Technical field
The present invention relates to Terleu, be specifically related to the Terleu preparation method, be meant a kind of method for preparing optically pure t-leucine especially.
Background technology
The Terleu of optical purity is a kind of non-protein amino acid, and Chang Zuowei chirality instrument is used for asymmetric synthesis and biostats and peptide etc.Because its importance, the preparation method of report also has much at present, mainly contains Split Method and asymmetric synthesis method and biological enzyme synthesis method.Traditional method for splitting particularly for the preparation of chiral acid and amine, owing to the simplicity and the operability of scale operation, be suitable for characteristics such as batch production, still is widely adopted.
In 1934, the Terleu of optical purity is prepared (Physiol.Chem.1934 first by the N-formyl radical-Terleu that splits racemization with brucine, 228), again successively reported: split Terleu methyl esters or ethyl ester (Chem.Ber with dibenzoyl tartaric acid thereafter, 1964,97﹠amp; J.Am.Chem.Soc, 1979,101); Split N-thiobenzoyl-Terleu (J.Am.Chem.Soc, 1979,101) with brucine; Split N-benzene methoxy acyl group-Terleu (Bull.Chem, Soc.Jpn, 1979,52) with quinine or quinidine; Split a lot of methods such as N-ethanoyl-Terleu with cinchonidine; but these a methods all common shortcoming need earlier exactly with racemization Terleu derivatize; and then split with resolving agent; used resolving agent all costs an arm and a leg; and it is not high to split purity; need repeatedly recrystallization, yield is very low.
Nineteen sixty-eight, the method that T.Tanabe etc. split with tartrate the preceding step raw material uncle acid acid amides in traditional synthetic Terleu technology, its technology is: uncle's acid acid amides and optical purity tartrate is soluble in water, place in the refrigerator and spend the night, filter next day, gained salt is behind recrystallization repeatedly, be dissolved in the bright acid amides of uncle of isolating resolving agent tartrate and optical purity behind the hydrochloric acid by ion exchange resin column, split overall yield and be about 20% (Bull.Chem, Soc.Jpn, 1968,41 (9), 2178～2179).This method is compared with aforesaid method, has saved the trouble of derivatize, and used resolving agent price is also cheaper; Purity is very low but still there is fractionation in it, needs repeatedly recrystallization, and yield is low, and operational condition requires high, defectives such as separation difficulty.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings at above existence, and a kind of method for preparing optically pure t-leucine is provided, this method split purity height, easy and simple to handle, quick, product yield is high, production cost is greatly reduced.
To achieve these goals, the technical scheme of employing of the present invention is as follows:
A kind of method for preparing optically pure t-leucine is characterized in, comprises step:
(1) the acid resolving agent of bright acid amides of racemization uncle and optical purity is reacted in resolution solvent and salts out;
(2) according to specific rotation, described salt through the diluted acid replacement Treatment, use organic solvent extraction, acquisition organic layer and inorganic layer directly or through behind the recrystallization in water;
(3) lesser temps stirs described inorganic layer down, after alkali lye is adjusted to alkaline pH, separates out a large amount of solids again, and the described solid of washing and drying promptly gets described optically pure t-leucine.
Preferably, the acid resolving agent of described optical purity is that optical pure mandel, optical purity are to methyldiphenyl formyl tartrate (hereinafter to be referred as DTTA) or optical purity dibenzoyl tartaric acid (hereinafter to be referred as DBTA).Generally, the mol ratio of bright acid amides of described racemization uncle and described optical pure mandel is 1: 0.5～1: 1; With the mol ratio of DTTA be 1: 0.25～1: 1; With the mol ratio of DBTA be 1: 0.25～1: 1.
Preferably, described resolution solvent is the lower alcohol of C1～C4, the lower alcohol of C1～C4 and the mixed solvent of water, lower ketones or the lower ketones of C3～C4 and the mixed solvent of water of C3～C4.
Preferably, described organic solvent is an ethers, ester class, aromatics or haloalkane hydro carbons.
The above-mentioned method for preparing optically pure t-leucine can also comprise step: (4) dry described organic layer, and filter the back and concentrate, dry, reclaim the acid resolving agent of described optical purity.
Preferably, the concentration＞0mol/L of described diluted acid and≤2mol/L.Described diluted acid is strongly-acid reagent such as hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid.
Preferably, the temperature of described stirring is 10 ℃～50 ℃.
Preferably, described alkaline pH is 7～8.
So, the present invention relates to a kind of to split the method that the bright acid amides of starting raw material racemization uncle prepares optically pure t-leucine, by the bright acid amides of starting raw material racemization uncle being split the resolving agent salt that obtains optical purity with the acid resolving agent of optical purity, then this salt is dissolved in the acidic aqueous solution, add organic solvent extraction and go out resolving agent, the water heating continues hydrolysis, just obtains optically pure t-leucine; To extract solvent and concentrate the dried high efficiente callback resolving agent that gets final product.
Resolution reaction mild condition of the present invention splits the bright acid amides resolving agent of gained uncle salt optical purity height, does not need recrystallization or only needs a recrystallization just to can be used for going on foot down feeding intake, and the resolution yield height is not less than 34%; The salt that splits gained separates by the two-phase extraction method with resolving agent after the acidity displacement, and is simple and convenient, do not need ion exchange column; Only need that water is continued hydrolysis and promptly get optically pure t-leucine, organic phase is concentrated just and can high yield high purity reclaim resolving agent, whole process fractionation purity height, easy and simple to handle, quick, product yield is high, production cost is greatly reduced.
Embodiment
Technological line figure of the present invention is as follows:
At first the bright acid amides of raw material racemization uncle (formula I) is dissolved in the resolution solvent, add the acid resolving agent of optical purity, after one hour, reaction system is warming up to the dissolving clarification, crystal is separated out in cooling, arrive room temperature crystallization one hour in 0 ℃, filter, the gained crystal does not need recrystallization or only needs a recrystallization according to the result of survey specific rotation, can obtain the salt of high-optical-purity, resolution yield is not less than 34%, then gained salt is dissolved in the acidic aqueous solution, displaces resolving agent, and separate with organic solvent extraction, water is the acidic aqueous solution of the bright acid amides of optical purity uncle (formula IIA or formula IIB), after continuing acidic hydrolysis, in and crystallization, the bright amino acid of optical purity uncle (formula III A or formula III B); Organic phase is concentrated solvent after super-dry, can reclaim resolving agent by high yield.
The normal method that adopts of general amino amides hydrolysis has alkaline water solution and sour water solution, and according to the difference of the hydrolysis difficulty or ease of raw material, required acid, the intensity of alkali and hydrolysis temperature be difference to some extent also.Through a large amount of experiments, we determine under the acidic conditions of low concentration, acid reagent concentration≤2mol/L, 10 ℃～50 ℃ of lesser tempss, the bright acid amides of the uncle of hydrolysis optical purity after the hydrolysis fully, goes out the Terleu crystal of optical purity with alkaline reagents neutralization reaction liquation.
The present invention compares with technology in the past, and advantage is: (1) splitting condition gentleness, required time are also short; (2) split products obtained therefrom optical purity height, do not need repeatedly recrystallization; (3) the resolution yield height is not less than 34%; (4) separation of gained salt is succinctly convenient, does not need ion exchange resin; (5) resolving agent reclaims conveniently, rate of recovery height, and quality is good, can apply mechanically.
Content for a better understanding of the present invention is described further below in conjunction with specific embodiment.
Embodiment 1
Split: the bright acid amides of input racemization uncle in a 2000ml four-hole bottle (available from South Asia, Zhejiang chemical industry, lot number: 070401) 150g (1.15mol), acetone 1200ml, water 300ml stirs molten clearly, adds (+)-amygdalic acid 175g (1.15mol), reflux 1h is cooled to 40 ℃, separates out crystal, continue to be cooled to 10 ℃, stirring and crystallizing 1h filters, filter cake washs with small amount of acetone, in 60 ℃ of oven dry 6h, gets white crystal 130g, yield 40%, specific rotation=+ 79 ° (20 ℃, 1g/10ml water).
Recrystallization: get step gained crude product 130g, add 600ml acetone, 150ml water, be heated to reflux molten clear after, be cooled to 45 ℃, have crystal to separate out, continue to be cooled to 5 ℃, stirring and crystallizing 1h filters, filter cake washs with small amount of acetone, in 60 ℃ of oven dry 6h, gets white crystal 110.5g, yield 85%, specific rotation=+ 80.5 ° (20 ℃, 1g/10ml water), more than two the step total recoverys 34%.
Separate: get above-mentioned recrystallization salt 110g, be dissolved in the 300ml 2N hydrochloric acid, stir 0.5h, add t-butyl methyl ether 200ml and extract layering, water layer continues to extract with the 150ml*2 t-butyl methyl ether.Merge organic layer, anhydrous magnesium sulfate drying filters, and mother liquor is evaporated to dried, residual solids with a small amount of petroleum ether after, dry 5h in 50 ℃, promptly get and reclaim (+)-amygdalic acid 160g, the rate of recovery 91%.
Hydrolysis: above-mentioned water layer is heated to 40-50 ℃, and after 12h was stirred in hydrolysis, reaction solution was evaporated to dried.Add dehydrated alcohol 250ml in the residue, stir 1h, remove by filter inorganic salt impurity such as ammonium chloride, mother liquor is concentrated into 1/3 of original volume, adds entry 120ml, stirs, regulate pH value 7～8 with 40% alkali aqueous solution, separate out a large amount of solids, be cooled to 5 ℃, filter, a small amount of cold water washing of filter cake promptly gets L-Terleu 43.5g in 80 ℃ of oven dry 12h, yield 85%, specific rotation=+ 7.5 ° (20 ℃, 1g/10ml 6N HCl), with document J.Am.Chem.Soc, 1988, V110 (2), the optical value unanimity of P651-2, HNMR (DMSO+TFA) δ 1.02 (s, 9H), and δ 3.6 (s, 1H), δ 8.17 (br s, 2H).
Embodiment 2
Split: the input racemization bright acid amides 65g of uncle (0.5mol) in a 500ml four-hole bottle (available from South Asia, Zhejiang chemical industry, lot number: 070401), dehydrated alcohol 390ml, water 65ml stirs molten clearly, adds (-)-amygdalic acid 76g (0.5mol), be warming up to the molten clear 1h that refluxes, solid is separated out in cooling, is cooled to 15 ℃, insulation 0.5h filters a small amount of absolute ethanol washing of filter cake, in 60 ℃ of oven dry 6h, get white crystal 59g, yield 42%, specific rotation=-78.5 ° (20 ℃, 1g/10ml water).
Recrystallization: get step gained crude product 59g, add the 195ml dehydrated alcohol, 33ml water, it is molten clear to be heated to backflow, finishes, and cooling has crystal to separate out, continue to be cooled to 5 ℃, stirring and crystallizing 1h filters, filter cake with a small amount of absolute ethanol washing after, in 60 ℃ the oven dry about 6h, white crystal 49g, yield 83.5%, specific rotation=-80.8 ° (20 ℃, 1g/10ml water), more than two the step total recoverys 35%.
Separate: get above-mentioned recrystallization salt 45g, be dissolved in the 130ml water, add the vitriol oil (concentration 98%) 32g, stir 0.5h, add ethyl acetate 100ml and extract layering, water layer continues to use the 80ml*2 ethyl acetate extraction.Merge organic layer, anhydrous magnesium sulfate drying filters, and mother liquor is evaporated to dried, residual solids with a small amount of petroleum ether after, dry 5h in 50 ℃, promptly get and reclaim (-)-amygdalic acid 23g, the rate of recovery 95%.
Hydrolysis: above-mentioned water layer is heated to 40-50 ℃, and after 6h was stirred in hydrolysis, reaction solution was evaporated to 1/2 of original volume.Add dehydrated alcohol 25ml in the residue, stir, regulate pH value 7～8, separate out a large amount of solids with 40% alkali aqueous solution, be cooled to 5 ℃, filter, a small amount of cold water washing of filter cake promptly gets D-Terleu 17g in 80 ℃ of oven dry 12h, yield 81%, specific rotation=-7.5 ° (20 ℃, 1g/10ml 6N HCl) are with document J.Am.Chem.Soc, 1988, V110 (2), the optical value unanimity of P651-2, HNMR (DMSO+TFA) δ 1.02 (s, 9H), δ 3.6 (s, 1H), and δ 8.17 (br s, 2H).
Embodiment 3
In the four-hole bottle of a 1000ml, and the bright acid amides of uncle of input racemization (available from South Asia, Zhejiang chemical industry, lot number: 070401) 78g (0.6mol), methyl alcohol 780ml stirs molten clearly, adds D-DBTA 107g (0.3mol), be warming up to the backflow salify 2 hours, and be cooled to 0-5 ℃ and separate out solid, stir 0.5h, filter, filter cake washs back 50 ℃ of vacuum drying 5h with a small amount of cold methanol, gets white solid 66.6g, yield 36%, specific rotation=-37 ° (20 ℃, 1g/10ml water).
Separate: get above-mentioned gained salt 60g, be dissolved in the 230ml water, add methylsulfonic acid 40g, stir 0.5h, add isopropyl acetate 150ml and extract layering, water layer continues to extract with the 100ml*2 isopropyl acetate.Merge organic layer, anhydrous magnesium sulfate drying filters, and mother liquor is evaporated to dried, residual solids with a small amount of petroleum ether after, dry 5h in 50 ℃, promptly get and reclaim D-DBTA 33g, the rate of recovery 95%.
Hydrolysis: after 12h was stirred in above-mentioned water layer room temperature (25 ℃) hydrolysis, reaction solution was evaporated to 1/3 of original volume.Add dehydrated alcohol 40ml in the residue, stir, regulate pH value 7～8, separate out a large amount of solids with 40% alkali aqueous solution, be cooled to 5 ℃, filter, a small amount of cold water washing of filter cake promptly gets D-Terleu 20.8g in 80 ℃ of oven dry 12h, yield 80%, specific rotation=-7.2 ° (20 ℃, 1g/10ml 6N HCl) are with document J.Am.Chem.Soc, 1988, V110 (2), the optical value unanimity of P651-2, HNMR (DMSO+TFA) δ 1.02 (s, 9H), δ 3.6 (s, 1H), and δ 8.17 (br s, 2H).
Embodiment 4
In the four-hole bottle of a 1000ml, and the bright acid amides of uncle of input racemization (available from South Asia, Zhejiang chemical industry, lot number: 070401) 65g (0.5mol), ethanol 590ml, water 60ml stirs molten clear, add D-DTTA 193g (0.5mol), be warming up to the backflow salify 2 hours, be cooled to 20-25 ℃ and separate out solid, stir 0.5h, filter, filter cake with a small amount of cold washing with alcohol after 50 ℃ of vacuum drying 5h, get white solid 90.3g, yield 35%, specific rotation=-41 ° (20 ℃, 1g/10ml water).
Separate: get above-mentioned gained salt 90g, be dissolved in the dilute hydrochloric acid of 300ml 1N, stir 0.5h, add t-butyl methyl ether 200ml and extract layering, water layer continues to extract with the 150ml*2 isopropyl acetate.Merge organic layer, anhydrous magnesium sulfate drying filters, and mother liquor is evaporated to dried, residual solids with a small amount of petroleum ether after, dry 5h in 50 ℃, promptly get and reclaim D-DTTA 62g, the rate of recovery 92%.
Hydrolysis: above-mentioned water layer is after 12h is stirred in 10 ℃ of hydrolysis, and reaction solution is evaporated to 1/3 of original volume.Add dehydrated alcohol 40ml in the residue, stir, regulate pH value 7～8, separate out a large amount of solids with 40% alkali aqueous solution, be cooled to 5 ℃, filter, a small amount of cold water washing of filter cake promptly gets D-Terleu 19.5g in 80 ℃ of oven dry 12h, yield 85%, specific rotation=-7.2 ° (20 ℃, 1g/10ml 6N HCl) are with document J.Am.Chem.Soc, 1988, V110 (2), the optical value unanimity of P651-2, HNMR (DMSO+TFA) δ 1.02 (s, 9H), δ 3.6 (s, 1H), and δ 8.17 (br s, 2H).
In sum, the method for preparing optically pure t-leucine of the present invention split the purity height, easy and simple to handle, quick, product yield is high, production cost is greatly reduced.
Need to prove, all quote in this application as a reference, just quoted as a reference separately as each piece document at all documents that the present invention mentions.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read above-mentioned teachings of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (7)
1. a method for preparing optically pure t-leucine is characterized in that, comprises step:
(1) bright acid amides of racemization uncle and optical pure mandel, optical purity are reacted in resolution solvent methyldiphenyl formyl tartrate or optical purity dibenzoyl tartaric acid and salt out;
(2) according to specific rotation, described salt through the diluted acid replacement Treatment, use organic solvent extraction directly or through behind the recrystallization in water, and the acquisition organic phase is with mutually inorganic;
(3) stir described inorganic phase, after alkali lye is adjusted to alkaline pH, separate out a large amount of solids again, the described solid of washing and drying promptly gets described optically pure t-leucine.
2. the method for preparing optically pure t-leucine as claimed in claim 1, it is characterized in that described resolution solvent is the lower alcohol of C1～C4, the lower alcohol of C1～C4 and the mixed solvent of water, lower ketones or the lower ketones of C3～C4 and the mixed solvent of water of C3～C4.
3. the method for preparing optically pure t-leucine as claimed in claim 1 is characterized in that, described organic solvent is ethers, ester class, aromatics or haloalkane hydro carbons.
4. the method for preparing optically pure t-leucine as claimed in claim 1 is characterized in that, also comprises step: (4) dry, concentrated described organic phase, reclaim the acid resolving agent of described optical purity.
5. the method for preparing optically pure t-leucine as claimed in claim 1 is characterized in that, the concentration＞0mol/L of described diluted acid and≤2mol/L.
6. the method for preparing optically pure t-leucine as claimed in claim 1 is characterized in that, the temperature of described stirring is 10 ℃～50 ℃.
7. the method for preparing optically pure t-leucine as claimed in claim 1 is characterized in that, described alkaline pH is 7～8.
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| CN101875615A (en) * | 2009-04-30 | 2010-11-03 | 复旦大学 | Method for preparing tert-leucine with high selectivity |
| IT1398044B1 (en) * | 2010-01-29 | 2013-02-07 | Archimica Srl | PROCESS FOR THE PREPARATION OF LACOSAMIDE |
| CN101886110A (en) * | 2010-06-28 | 2010-11-17 | 浙江树人大学 | New method for splitting photoactive tert-leucine |
| CN102533888B (en) * | 2010-12-29 | 2015-07-15 | 浙江九洲药物科技有限公司 | Continuous enzymatic method for producing L-tert-leucine |
| US8835676B2 (en) * | 2011-03-21 | 2014-09-16 | Divi's Laboratories Ltd. | Process for the preparation of enantiomerically pure tert-leucine |
| CN103159647B (en) * | 2011-12-15 | 2016-06-01 | 浙江九洲药业股份有限公司 | A kind of preparation method of N-methoxycarbonyl group-S-Leucine |
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| 构型转换与拆分技术在制备D-氨基酸中的应用. 漆剑等.化学与生物工程，第No.4期. 2005 |
| 构型转换与拆分技术在制备D-氨基酸中的应用. 漆剑等.化学与生物工程，第No.4期. 2005 * |
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