CN105061289B - A kind of method for preparing pharmaceutical grade L tryptophans - Google Patents
A kind of method for preparing pharmaceutical grade L tryptophans Download PDFInfo
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- CN105061289B CN105061289B CN201510460051.7A CN201510460051A CN105061289B CN 105061289 B CN105061289 B CN 105061289B CN 201510460051 A CN201510460051 A CN 201510460051A CN 105061289 B CN105061289 B CN 105061289B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of technique for preparing pharmaceutical grade L tryptophans, the technique includes dissolving, decolourizes, adjusts the steps such as pH, filtering washing, drying.Wherein dissolving is by L tryptophan dissolving crude products in solvent, with weight ratio meter, solvent：Crude product is 100:50‑60.Present invention process is simple, and refined rear L tryptophans meet 2010 editions Chinese Pharmacopoeia standards.The refined production of L tryptophans high-volume can be realized using present invention process, solves that L tryptophans subtractive process consumption solvent amount is excessive, and crystallisation concentration is relatively low, it is difficult to the shortcomings that large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation method for preparing medicinal grade amino acid, and in particular to a kind of refined side of L-Trp
Method, it is prepared into pharmaceutical grade L-Trp.
Background technology
The entitled tryptophane of tryptophan chemistry, separates and obtains for 1902 from casein.Isomery during tryptophan has 3
Body, respectively L-type, D types and raceme DL types.Tryptophan is a kind of important nutritional necessary amino acid, can only have microorganism or
Induction biosynthesis.L-Trp therein is one of 8 kinds of amino acid needed by human, and humans and animals itself can not synthesize, Zhi Nengcong
Absorbed in food.D-trp is hardly metabolized in human body, also non-toxic, therefore human body is not required to supplement.L-Trp
As a kind of essential amino acid, it is widely used in medicine, food and feed etc. at present.L-Trp structural formula is：
L-Trp medically has important application.In vivo, L-Trp metabolic conversion can produce serotonin,
The physiological activators such as heteroauxin, niacin, epiphysin, pigment, alkaloid, coenzyme, plant hormone, and tryptophan metabolism loses
Tune can cause diabetes or mentally deranged.L-Trp is medically widely used to treat bark favus treatment, schizophrenia
Disease treatment, nutrient amino acids piece etc..Therefore the demand of pharmaceutical grade L-Trp is just growing day by day.
L-Trp belongs to heat-sensitive substance, long-time heating or illumination easy coloring, easy decomposed metamorphic, so in extraction work
Protein Hydrolyze method, chemical synthesis, enzyme law catalysis are commonly used in skill research or directly carries out fermenting and producing L-Trp.Generally this
L-Trp made from a little methods is because color is deep (being often lark), and it is water-soluble with other to contain other amino acid impurity of part
Property albumen etc., light transmittance, content and specific rotation are difficult to reach standards of pharmacopoeia, are only capable of reaching feed grade amino acid standard.Some documents
The process for purification of L-Trp is reported, but distinct disadvantage be present, or subtractive process is excessive using solvent, can not scale metaplasia
Production, or it is refined after L-Trp be unable to reach standards of pharmacopoeia.
The process for purification of L-Trp, relevant report are as follows：
CN200810019958.X (Publication No. CN101531626A) discloses biological fermentation process industrialized production L- colors
The process for purification of propylhomoserin, comprises the following steps：Crude product is added in 60 DEG C of pure water of 20 times of weight under agitation, be warming up to 75 DEG C
Dissolving, alum is added by crude product weight 0.1%；303# activated carbons are added by the 30% of crude product weight, 75 DEG C decolourize 15 minutes；It is de-
Color liquid is cooled to 5-15 DEG C, 15% adds the industrial acetic acid of concentration 80% by volume, 5 ± 3 DEG C of stirring insulation crystallizes 4 hours；Knot
The separation of brilliant liquid centrifuge, frozen water elution, at 80 DEG C vacuum drying 4-6 hours obtain fine work.The shortcomings that this method maximum is using molten
Matchmaker's amount is too big.Because solubility of the L-Trp in pure water is very small, therefore make L- at high temperature using the water of 20 times of weight
Less than 5%, this technology has highlighted L-Trp highly finished product and has been difficult to high-volume life the refined concentration of tryptophan dissolved clarification, i.e. L-Trp
The shortcomings that production.
CN201010560069.1 (Publication No. CN102030698A), which is disclosed, utilizes organic film separation and Extraction fermentation L-
The method of tryptophan, first the pH of zymotic fluid is adjusted to certain value, then carries out micro-filtration-ultrafiltration system batch can and carry out membrane filtration,
PH value is adjusted again, is concentrated, and alcohol crystallization, is produced.This invention provides the method from broth extraction L-Trp crude product, not
The process for purification of L-Trp is provided, the L-Trp of preparation is difficult to the quality standard for reaching pharmaceutical grade L-Trp.
CN 200910065010.2 (Publication No. CN101565396A) discloses a kind of process for refining of L-Trp.
Specific method is using water and propanol solvent mixture as solvent, by L-Trp dissolving crude product, reacts 100- after 50-80 DEG C of dissolving
120min, the clarified solution after filtering crystallize to obtain L-Trp highly finished product.With weight ratio meter, the wherein dosage of solvent is solvent：
Crude product=100:20-30.Obtained L-Trp light transmittance >=90%, optical activity are -30.0-32.5 degree, yield about 85%.Should
Solvent has used the mixed solvent of water and alcohol in invention, adds the solubility of L-Trp, but solvent usage amount is still larger,
Solvent usage amount is 4-5 times of L-Trp crude product weight, and product light transmittance be difficult to reach as defined in standards of pharmacopoeia >=
95.0%, also illustrate that the decolorizing effect of the L-Trp in the mixed solvent of alcohol and water is not ideal.This technological invention can not
Stably produce pharmaceutical grade L-Trp.
So far, pertinent literature report is not had also to solve to refine L-Trp using lesser amount of solvent with further,
And reach the technological invention of pharmaceutical grade standard.
The content of the invention
It is an object of the invention to provide a kind of effective process for purification, and feed grade L-Trp is refined into pharmaceutical grade L- colors
Propylhomoserin.Simultaneously solve in L-Trp subtractive process consume solvent it is excessive, crystallisation concentration is relatively low, can not realize large-scale industrial
The shortcomings that production.
A kind of method for preparing pharmaceutical grade L-Trp provided by the invention, this method comprise the following steps：
1) dissolve：By feed grade L-Trp dissolving crude product in solvent, with weight ratio meter, solvent：Crude product is 100:50-
60；
2) decolourize：The dissolved clarification liquid of above-mentioned L-Trp is added into activated carbon decolorizing, filtering, obtains achromaticity and clarification filtrate；
3) pH is adjusted：Filtrate after decolouring is adjusted into pH to 5.4-6.4, obtains L-Trp crystal；
4) filtering washing：After L-Trp crystal is centrifuged, damp product are washed with water, and centrifuge out crystal；
5) dry：By L-Trp crystal vacuum drying, produce.
In above-mentioned process for purification：
In step 1)：
The content of L-Trp should be not less than 95% in the feed grade L-Trp.
The solvent is aqueous sodium carbonate or sodium hydrate aqueous solution, and its concentration is 5-8%, preferably 5%-8% hydrogen
Aqueous solution of sodium oxide；
Solution temperature is controlled at 50-60 DEG C；
In step 2)：
The dosage of activated carbon is the 5% of L-Trp crude product weight；
Bleaching time is 0.5-1h；
In step 3)：
Filtrate adjusts pH value temperature control at 40-50 DEG C；
PH adjusting agent is the hydrochloric acid that concentration is 10%；
In step 4)：
During centrifugation, rotating speed 1500-2000rpm, time 15-30min, it is preferable that rotating speed 1700rpm, when
Between be 20min；
In step 5)：
Vacuum drying temperature and time are respectively 50-70 DEG C, 10h, and vacuum is -0.09MPa--0.1MPa.
Preferably, the described method comprises the following steps：
1) dissolve：
By feed grade L-Trp dissolving crude product in solvent, wherein solvent is 5%-8% sodium carbonate or sodium hydroxide
The aqueous solution, solution temperature is 50-60 DEG C, with weight ratio meter, solvent：Crude product is 10:5-6；
2) decolourize：
The activated carbon decolorizing 0.5h of L-Trp crude product weight 5% will be added under the dissolved clarification liquid insulation of above-mentioned L-Trp,
After filtering while hot, achromaticity and clarification filtrate is obtained；
3) pH is adjusted：
By at 40-50 DEG C of filtrate after decolouring, pH=5.4-6.4 then is adjusted with hydrochloric acid, obtains L-Trp crystal；
4) filtering washing：
The solution centrifugal of the crystal containing L-Trp is separated, obtains L-Trp tide product, after being washed with water 2 times, centrifugation point
Separate out crystal；
5) dry：
At 50-70 DEG C of L-Trp crystal after vacuum drying 10h, vacuum is -0.09MPa~-0.1MPa, vacuum packaging
Closed preservation.
Process for purification provided by the invention has advantages below：
1st, few using solvent, the solvent that the present invention uses is molten compared to patent CN101565396A and CN101531626A
Matchmaker's dosage substantially reduces, and identical equipment can produce more pharmaceutical grade L-Trps.Because solvent dosage is few, also reduce
The energy consumption of heating process consumption, saves cost.
2nd, method disclosed in patent CN 101565396A, its mixed solvent used can not recycling, it is and of the invention
Can be with co-producing sodium chloride byproduct.
3rd, the present invention can effectively remove the impurity such as other protein and increase L-Trp through alkali tune and heating stepses exists
Solubility in water, light transmittance can be effectively improved by bleaching process, can be realized in high yield by reducing solvent dosage, profit
With vacuum packaging it is possible to prevente effectively from L-Trp is oxidized in atmosphere.Therefore the present invention can prepare pharmaceutical grade with high yield
L-Trp.
4th, the technical solution adopted by the present invention is that the feed grade L-Trp of the solubility very little in water is water-soluble in alkalescence
Dissolved in liquid, the sodium salt of the larger L-Trp of production solubility.Again by medicinal carbon decoloring, remove pigment and other albumen are miscellaneous
Matter, the L-Trp sodium-salt aqueous solution clarified after filtering.Then it is difficult with the isoelectric point of salt acid for adjusting pH value to L-Trp
The L-Trp of dissolubility separates out crystal.Centrifuge, then wash and remove remaining salt, drying and packaging after centrifugation.
5th, process for purification provided by the invention, its yield is more than or equal to 90%, specific rotation -30.0-32.5 degree, and light transmittance >=
95.0%, content >=99.0%, product index meets standards of pharmacopoeia.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Feed grade L-Trp produces for Anhui Fengyuan Fermentation Technology Engineering Research Co., Ltd. in following examples, content
>=95.0%.
Embodiment 1
1) dissolve：Take feed grade L-Trp crude product 50kg to put into 200L enamel stills, add 5% sodium hydroxide water
Solution 100kg (solvents：The weight ratio of crude product is 10：5), stir, be heated to 60 DEG C of insulated and stirreds, make L-Trp whole
Dissolving.
2) decolourize：Activated carbon 2.5kg (equivalent to the 5% of feed grade L-Trp crude product weight) is added after dissolved clarification, 60
Decolouring 0.5h is incubated at DEG C, filters to 200L crystallized in enamel still through 0.22 μm of stud while hot, obtain achromaticity and clarification filtrate.
3) pH is adjusted：Filtrate after decolouring is cooled to 50 DEG C, then adjusts filtrate with the hydrochloric acid that concentration is 10%
PH6.0, produce a large amount of L-Trp white crystals.
4) filtering washing：Step 3) is obtained into the decline of crystal stirring to warm to room temperature, centrifuges 20min (centrifuges
Rotating speed 1700rpm), L-Trp tide product white crystal is obtained, with purified water 10kg, is washed 2 times, centrifuges 20min (centrifugations
Machine rotating speed 1700rpm), obtain L-Trp highly finished product.
5) dry：At 60 DEG C after vacuum drying 10h, closed preservation is vacuum-packed.
Embodiment 2
1) dissolve：Take feed grade L-Trp crude product 60kg to put into 200L enamel stills, add 5% sodium hydroxide water
Solution 100kg (solvents：The weight ratio of crude product is 10：6), stir, be heated to 50 DEG C of insulated and stirreds, make L-Trp whole
Dissolving.
2) decolourize：Activated carbon 3kg (equivalent to the 5% of feed grade L-Trp crude product) is added after dissolved clarification, is protected at 50 DEG C
Warm decolouring 0.5h, filter to 200L crystallized in enamel still through 0.22 μm of stud while hot, obtain achromaticity and clarification filtrate.
3) pH is adjusted：Filtrate after decolouring is cooled to 45 DEG C, is then 6.4 with the pH of 10% hydrochloric acid regulation filtrate,
Produce a large amount of L-Trp white crystals.
4) filtering washing：Step 3) is obtained into the decline of crystal stirring to warm to room temperature, centrifuges 20min (centrifuges
Rotating speed 1700rpm), L-Trp tide product white crystal is obtained, with purified water 12kg, is washed 2 times, centrifuges 20min (centrifugations
Machine rotating speed 1700rpm), obtain L-Trp highly finished product.
5) dry：At 50 DEG C after vacuum drying 10h, closed preservation is vacuum-packed.
Embodiment 3
1) dissolve：Take feed grade L-Trp crude product 60kg to put into 200L- enamel stills, add 8% sodium hydroxide
Aqueous solution 100kg (solvents：The weight ratio of crude product is 10：6), stir, be heated to 55 DEG C of insulated and stirreds, make L-Trp complete
Dissolve in portion.
2) decolourize：Activated carbon 3kg (equivalent to the 5% of feed grade L-Trp crude product weight) is added after dissolved clarification, at 55 DEG C
Lower insulation decolouring 0.5h, filter to 200L crystallized in enamel still through 0.22 μm of stud while hot, obtain achromaticity and clarification filtrate.
3) pH is adjusted：Filtrate after decolouring is cooled to 40 DEG C, then adjusts filtrate with the hydrochloric acid that concentration is 10%
PH5.4, produce a large amount of L-Trp white crystals.
4) filtering washing：Step 3) is obtained into the decline of crystal stirring to warm to room temperature, centrifuges 20min (centrifuges
Rotating speed 1700rpm), L-Trp tide product white crystal is obtained, with purified water 12kg, is washed 2 times, centrifuges 20min (centrifugations
Machine rotating speed 1700rpm), obtain L-Trp highly finished product.
5) dry：At 70 DEG C after vacuum drying 10h, closed preservation is vacuum-packed.
Comparative example 1
Refined using process for refining disclosed in CN 101565396A.
Experimental example 1：Comparison on yield, product index
Embodiment 1-3 and comparative example 1 method are compared, concrete outcome is shown in Table 1：
Table 1：L-Trp refines
The result of table 1 is shown：Embodiment 1-3 yield is not less than 91%, and purity is not less than 99%, its printing opacity of the product of preparation
Degree and specific rotation are also superior to comparative example 1.As a result show：The process for purification of L-Trp of the present invention, product yield is high, molten
Matchmaker's dosage is few, and product index can reach pharmaceutical grade standard.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (5)
- A kind of 1. method for preparing pharmaceutical grade L-Trp, it is characterised in that comprise the following steps：1) dissolve：By feed grade L-Trp dissolving crude product in solvent, with weight ratio meter, solvent：Crude product is 100:50-60； The solvent is the sodium hydrate aqueous solution that mass concentration is 5-8%；The content of L-Trp in the feed grade L-Trp 95% should be not less than；Temperature control during dissolving is at 50-60 DEG C；2) decolourize：The dissolved clarification liquid of above-mentioned L-Trp is added into activated carbon decolorizing, bleaching time 0.5-1h, filtering, obtains nothing Color clear filtrate；The dosage of activated carbon is the 5% of L-Trp crude product weight；3) pH is adjusted：Filtrate after decolouring is adjusted into pH to 5.4-6.4, obtains L-Trp crystal；4) filtering washing：After L-Trp crystal is centrifuged, damp product are washed with water, and centrifuge out crystal；5) dry：By L-Trp crystal vacuum drying, produce.
- 2. according to the method for claim 1, it is characterised in that when the step 4) centrifuges, rotating speed 1500- 2000rpm, time 15-30min.
- 3. according to the method for claim 1, it is characterised in that pH adjusting agent is the salt that concentration is 10% in the step 3) Acid.
- 4. according to the method for claim 1, it is characterised in that filtrate adjusts pH value temperature control in 40- in the step 3) 50℃。
- 5. according to the method described in claim any one of 1-4, it is characterised in that the described method comprises the following steps：1) dissolve：By feed grade L-Trp dissolving crude product in solvent, the sodium carbonate or sodium hydroxide that wherein solvent is 5%-8% are water-soluble Liquid, solution temperature is 50-60 DEG C, with weight ratio meter, solvent：Crude product is 10:5-6；2) decolourize：By the lower activated carbon decolorizing for adding feed grade L-Trp crude product weight 5% of the dissolved clarification liquid insulation of above-mentioned L-Trp 0.5h, after filtering while hot, obtain achromaticity and clarification filtrate；3) pH is adjusted：It is 5.4-6.4 by pH is adjusted at 40-50 DEG C of filtrate after decolouring, obtains L-Trp crystal；4) filtering washing：The solution of the crystal containing L-Trp is down to room temperature, is then centrifuged for separating, obtains L-Trp tide product, is washed with water 2 times Afterwards, centrifuge again, isolate crystal；5) dry：At 50-70 DEG C of L-Trp crystal after vacuum drying 10h, vacuum is -0.09MPa~-0.1MPa, and vacuum packaging is closed Preserve.
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| CN105481750B (en) * | 2015-12-10 | 2018-02-27 | 河南巨龙生物工程股份有限公司 | A kind of process for extracting high-purity medicine rank tryptophan |
| CN111410627A (en) * | 2020-04-03 | 2020-07-14 | 石家庄市冀荣药业有限公司 | production method of pharmaceutical-grade L-tryptophan |
| CN113354569A (en) * | 2021-06-04 | 2021-09-07 | 无锡晶海氨基酸股份有限公司 | Method for purifying tryptophan |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531626A (en) * | 2008-03-14 | 2009-09-16 | 江苏诚意药业有限公司 | Refining method for producing L-tryptophan in industrial way by using biofermentation method |
| CN101550101A (en) * | 2009-01-20 | 2009-10-07 | 福建省建阳武夷味精有限公司 | Method for clean purifying L-tryptophan by utilizing fermented liquid |
| CN102146052A (en) * | 2010-12-24 | 2011-08-10 | 山东鲁抗医药股份有限公司 | Method for preparing tryptophan |
| CN102304077A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Method for purifying tryptophan |
-
2015
- 2015-07-28 CN CN201510460051.7A patent/CN105061289B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531626A (en) * | 2008-03-14 | 2009-09-16 | 江苏诚意药业有限公司 | Refining method for producing L-tryptophan in industrial way by using biofermentation method |
| CN101550101A (en) * | 2009-01-20 | 2009-10-07 | 福建省建阳武夷味精有限公司 | Method for clean purifying L-tryptophan by utilizing fermented liquid |
| CN102146052A (en) * | 2010-12-24 | 2011-08-10 | 山东鲁抗医药股份有限公司 | Method for preparing tryptophan |
| CN102304077A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Method for purifying tryptophan |
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