CN103554005A - Novel simple synthesis method of L-5-hydroxytryptophan - Google Patents
Novel simple synthesis method of L-5-hydroxytryptophan Download PDFInfo
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- CN103554005A CN103554005A CN201310592943.3A CN201310592943A CN103554005A CN 103554005 A CN103554005 A CN 103554005A CN 201310592943 A CN201310592943 A CN 201310592943A CN 103554005 A CN103554005 A CN 103554005A
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- 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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Abstract
The invention relates to a novel synthesis method of L-5-hydroxytryptophan. The method is characterized by comprising the following steps: by taking 5-bromoindole and 3-bromo-2-hydroximino-propionate as raw materials, connecting a side chain of 2-hydroximino-propionate to a 3-site of the indole through a Michael addition reaction, and preparing the L-5-hydroxytryptophan through a reduction reaction, a hydrolysis reaction and resolution. The method has the advantages of short synthetic route, readily available raw materials, mild reaction conditions, high product yield, low cost and the like, and the problems of long synthetic route, low product yield, high production cost and severe environmental pollution in a traditional method for chemically synthesizing the L-5-hydroxytryptophan are solved. The method has high application prospects.
Description
technical field:
The invention belongs to natural organic chemistry field, it relates to a kind of short-cut method of being prepared levo-5-hydroxytryptophan by 5-bromo indole and the bromo-2-hydroxyl of 3-imido grpup-propionic ester.
background technology:
Levo-5-hydroxytryptophan (L-5-hydroxytryptophan is abbreviated as 5-HTP) is the precursor that in human body, a kind of Serotonin of crying Hall covers, and the mankind need take in the relative equilibrium of this He Ermeng of a certain amount of 5-HTP guarantee.5-HTP is also the precursor substance of important inhibition neurotransmitters varies (5-HT), this varies is distributed widely in the positions such as human body brain, thrombocyte, stomach, central nervous system, is that brain controls the emotion, the important chemical substance of behavior, appetite, sleep, impulsion.In addition, varies can promote mood, neural health, can depress appetite, reduce fat picked-up, and reduce anxiety, control the emotion, promote sleep.At present domestic can stably manufactured healthcare products, such as " excellent speed reaches " etc., quality product has obtained the approval of the country such as American-European.
5-HTP traditional method is mainly to extract acquisition from the dry seed of mesquite plant Ghana cereal Griffonia simplicifolia.And this wild plant is born in the west African states such as African Ghana, the Ivory Coast and Togo, resource is very limited, so expensive.For example patent (CN101648900) has been reported a kind of method that Africa produces the supercritical extraction that Ghana's seed is raw material of take: first by Ghana's seed oil removing, then the mixing solutions of comminuting matter water and alcoholic solvent extracts 3～5 times, gained extracting solution, after ultrafiltration, again through ion exchange resin absorption, wash-out, vacuum concentration, low temperature crystallization step obtains highly purified 5-HTP dry powder.This technique is to have extraction conditions to stablize, and pollutes product purity advantages of higher without hazardous solvent.But the method raw materials for production place one's entire reliance upon output and the collection period of Ghana's seed, year produces unstable, and production cost is higher.
Chemosynthesis is the effective way of obtaining more cheap 5-HTP.At present the main synthetic method of report has three kinds: first method is that (patent CN101323586) to take tryptophane and oxyacetic acid be raw material, in autoclave, carry out hydroxylation reaction and obtain poly-hydroxy tryptophane, then under the catalysis of tryptophanase, alkaline condition hydrolysis obtains 5-HTP product.The method reactions steps is many, obtains the conditional instability of 5-HTP, need strict resolving and purifying condition, and in reaction process, energy consumption is huge, therefore fails to accomplish scale production always.Second method is exactly that (patent CN 102351775A) take L-Trp as starting raw material, through over-churning, N-acetylize, reduction, oxidation, rearrangement and Deprotection six-step process, has synthesized left-handed 5-hydroxytryptophan.Last crude product is again through crystallisation by cooling, and mother liquor has obtained left-handed 5-hydroxytryptophan crystal by steps such as macroporous resin column absorption, wash-out, concentrated, cooling crystallizations.The method has the advantages such as raw material is cheap and easy to get, simple to operate, productive rate is high, quality good, environmental pollution is less, but it also exists reactions steps many, the low deficiency (45% left and right) that waits of total recovery.The third is that (CN102212028A) is with 3-methyl-4-nitrophenols or take 3-methylphenol as raw material; through hydroxyl protection, N, the condensation of N-diformamide dimethyl formal, hydrogenation, Mannich reaction, diethyl acetamido docking, hydrolysis reaction, enzyme split and deprotection reaction 9 step reactions obtain product.But the method exists reactions steps many, the low deficiency that waits of total recovery.Utilize biotechnology to prepare 5-HTP and seek one of more efficient, safe production 5-HTP direction.For example, patent CN101864466 has reported the method that biotechnology is produced 5-HTP, the method has been utilized engineering strain BL21-DE3 and rabbit Oryctolagus cuniculus tryptophan hydroxylase gene, build the secondary metabolism fermentation of recombinant expression vector, in thalline, tryptophan transfer is turned to 5-HTP, then obtained 5-HTP product through steps such as bacteriolyze, separation and purification, vacuum concentration, crystallizations.There is following shortcoming in the method: expression amount is not high; Gene is at cell inner expression.Cause on the one hand the waste of raw material tryptophane, cause on the other hand 5-HTP finished product purity not high.In addition due to the complicacy of bacterial metabolism, the impurity that often has other to produce due to thalline self metabolism except 5-HTP in product.Need to carry out complicated separation and purification to product and could obtain and reach product, can not meet large-scale production requirement.
This seminar has successfully developed a kind of chemosynthesis in conjunction with the novel method of preparation 5-HTP through studying for many years.It is raw material that the method be take 5-bromo indole and the bromo-2-hydroxyl of 3-imido grpup-ethyl propionate, splits three key steps prepared 5-HTP through condensation reaction, reduction and basic hydrolysis, and the method reactions steps is few, and yield is high, environmentally friendly, is suitable for large-scale production.
summary of the invention:
In order to solve above-mentioned plant extraction process, prepare 5-HTP raw material and be subject to the impacts such as season, region; Existing chemical synthesis process synthesis step is long, and yield is low; Biotechnology method is produced the problems such as complicated.The object of the present invention is to provide in a kind of reactions steps, simple to operate, raw material is easy to get, be easy to industrialization, aftertreatment is easy, productive rate is high, environmental pollution is little, the preparation method of left-handed 5-hydroxytryptophan.This invention is achieved through the following technical solutions: a kind of preparation method of left-handed 5-hydroxytryptophan.The method is reacted with the bromo-2-hydroxyl of 3-imido grpup-ethyl propionate by 5-bromine, 2-hydroxyl imido grpup ethyl propionate is connected on indoles 3-position, oximido reduction is obtained, it is 2-amino-pyruvic acid ester group indoles, and then its hydrolysis is obtained to DL-5-hydroxytryptophan, finally fractionation, purifying obtain 5-HTP product.
1. 5-HTP synthetic route of the present invention is as shown in Figure 1:
2. in said synthesis route, the reaction process condition of each step is as follows:
1) condensation reaction of Compound I I and III.Get compound III and be dissolved in halohydrocarbon, preferred solvent is methylene dichloride, and consumption is 15～20 times of compound III weight.Then add 1.05～1.2 times of compound III to Compound I I (mol ratio) and 5～8 times to the medium tenacity alkali of Compound I I, preferred reagent is Na
2cO
3or K
2cO
3(mol ratio), then stirring reaction 24 hours at room temperature.By a short silicagel column filtering solid, and with ethyl acetate washing, collect filtrate, concentrating under reduced pressure, silicagel column on resistates, wash-out (gradient solvent is that 30:70 is to ethyl acetate/normal hexane of 50:50), evaporating solvent, obtains a kind of white crystal compound IV.Fusing point is 175-176 oC after tested.
2) reduction of compound VI.Compound VI is a kind of oxime compounds, and direct-reduction obtains aminated compounds.This step reaction solvent can be methyl alcohol, ethanol etc., and reductive agent can be magnesium powder-ammonium acetate, zinc powder-formic acid etc.The mol ratio of compound VI and reductive agent is 1:8～10; Solvent load and compound weight ratio can be 1:15～25, react for back flow reaction 3-4 hour.After having reacted, decompression and solvent recovery, resistates adds 5% Na
2cO
3solution, then extracts three times by ethyl acetate, and concentrated, crystallization obtains compound V.This melting point compound is 127-128 oC.
3) hydrolysis of compound V.Compound V is dissolved with a certain proportion of alcoholic solvent, then join 15 ~ 30% strong base solution, preferred reagent is sodium hydroxide and potassium hydroxide, hydrolysis reaction.The consumption of solvent is advisable with complete dissolved compound V, the consumption of alkali is target compound 8 ~ 10 times.Temperature of reaction is 65～85 oC, and the reaction times is 3～4 hours.After having reacted, with glacial acetic acid, regulating PH, is 4～5.5, has solid to separate out, and filters, and collects solid, with 70% ethyl alcohol recrystallization, obtains DL-5-hydroxytryptophan.
4) fractionation of DL-5-hydroxytryptophan.This step utilizes the tartrate Split Method of comparative maturity to split DL body.Resolution solvent is: utilize methanol/acetone (3:1) mixed solvent that DL-5-hydroxytryptophan is dissolved in methanol/acetone mixed solvent, temperature remains on 25～30 ℃, add tartrate, the tartaric molar ratio of DL-5-hydroxytryptophan and D-is about 1:1.05～1.2 in batches, stirs, be cooled to 15 ℃ of left and right, stirring and crystallizing, filters solid drying, obtain Compound I, i.e. L-5-hydroxytryptophan.Product fusing point is 270 oC.
The present invention compares and has the following advantages and outstanding effect with existing L-5-hydroxytryptophan chemical synthesis process:
1) levo-5-hydroxytryptophan chemical synthesis process route of the present invention is short, and step is few, and raw material is easy to get, and cost is low.The problems such as the raw material of traditional chemical synthetic method is expensive, and step is many, and production cost is higher have been overcome.
2) each step of this inventive method is simple to operate, and reaction conditions is gentle, and in each intermediate product treating processes, refuse is few, and environmental pollution is extremely low.
accompanying drawing explanation:
Fig. 1 is the synthetic route chart of 5-HTP
embodiment:
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
embodiment 1
Condensation reaction: take 30 g compound III (142 mmol) and be dissolved in the methylene dichloride of 500 ml, then add 56 g Compound I I (28.4 mmol) and 110 g sodium carbonate (1.04 mol), form a kind of suspended substance, this mixture at room temperature, stirring reaction 24 hours.Through a short silicagel column, filter, and wash solid (80 ml ' 3) by ethyl acetate, collect filtrate, decompression and solvent recovery, silicagel column on residuum, with ethyl acetate-normal hexane gradient elution (ethyl ester-normal hexane: 30:70; 50:50), collect elutriant, concentrating under reduced pressure, the cooling crystallization that obtains compound IV.Fusing point is 126～127 ℃, yield 92%.
embodiment 2
Reduction reaction: above-mentioned resulting compound is a kind of oxime compounds, can obtain aminated compounds through reduction.Get 300 ml dissolve with methanol for compound IV 11 g, add 81 g ammonium acetates, stirring and dissolving at 35 ℃, then adds 52 g magnesium powder marks batch, after magnesium powder adds, continues stirring reaction 30 min.After having reacted, filter, filtrate decompression is concentrated, and residuum adds the Na of 50 ml 5%
2cO
3solution, extracts 3 times by 100 ml ethyl acetate heating for dissolving, and united extraction liquid is concentrated, separates out coarse-grain.Coarse-grain obtains crystal 9 g with 70% ethyl alcohol recrystallization.Yield 82%.Product fusing point 127～128 oC.
embodiment 3
Hydrolysis reaction: get 50 ml dissolve with ethanol for 10 g, be then added dropwise in the three bottleneck reaction flasks that fill 230 ml10%KOH solution, stirring reaction is 3.5 hours at 75 ℃, continues reaction half an hour after ethanol evaporation.Cooling, with glacial acetic acid, regulate pH to 5.0, standing have crystal to separate out, and coarse-grain obtains compound V7.8 g with 70% alcohol recrystallization.Efficiency of pcr product is 78%.
embodiment 4
Mesotomy: add above-mentioned raceme 5 g in there-necked flask, methanol-acetone mixed solvent (3:1) 70 ml, stirring and dissolving, temperature remains on 25～30 ℃, add 3.7 g D-tartrate in batches, stirring reaction 30 minutes, is cooled to 15 ℃ of left and right, crystallization, filter, solid drying, obtains Compound I, i.e. L-5-hydroxytryptophan.Product fusing point is 270 oC.
Claims (7)
1. the object of the invention is to develop a kind of simple synthesis of (L)-5HTP, it is characterized by that to take 5-bromo indole and the bromo-2-hydroxyl of 3-imido grpup-propionic ester be starting raw material, through the method for synthetic (the L)-5HTP of condensation, reduction, hydrolysis and fractionation four-step reaction.
2. according to right 1, require described method, its synthetic route is as shown in Figure of description 1.
3. according to right 2, require in described synthetic route, compound III, compound IV and compound V molecular structure R can be methyl and ethyl.
4. according to right 1, require described method, the preparation of compound IV is realized by 5-bromo indole (Compound I I) and the bromo-2-hydroxyl of 3-imido grpup-propionic ester (compound III) condensation reaction, it is characterized in that solvent system used is halohydrocarbon, preferred reagent is methylene dichloride, used catalyst is alkaline carbonate, is preferably Na
2cO
3or K
2cO
3, reaction conditions is stirring at room reaction 24 hours.
5. according to right 1, require described method, the preparation of compound V is obtained by compound IV reduction reaction, it is characterized in that this step reaction solvent is the alcoholic solvents such as methyl alcohol, ethanol, reductive agent is magnesium powder-ammonium acetate or zinc powder-formic acid system, and the mol ratio of compound VI and reductive agent is 1:8～10; Solvent load and compound weight ratio are 1:15～25; Reaction conditions is back flow reaction 3-4 hour under normal pressure.
6. according to right 1, require described method, the preparation of Compound I is obtained by compound V hydrolysis reaction, this response feature is hydrolysis reaction in the strong base solution 15 ~ 30% by compound V, preferably highly basic is sodium hydroxide and potassium hydroxide, agents useful for same is alcoholic solvent, and the consumption of solvent is advisable with complete dissolved compound V, the consumption of alkali is target weight 8 ~ 10 times, temperature of reaction is 65～85 oC, and the time is 3～4 hours.
7. according to right 1, require described synthetic method, the fractionation of DL-5-hydroxytryptophan DL body is to utilize the tartrate Split Method of comparative maturity to carry out, specific features is that resolution solvent is methanol/acetone (3:1) mixed solvent, DL-5-hydroxytryptophan is dissolved in methanol/acetone mixed solvent, and temperature remains on 25～30 ℃, adds D-tartrate in batches, the tartaric molar ratio of DL-5-hydroxytryptophan and D-is about 1:1.05～1.2, stir, be cooled to 15 ℃ of left and right, stirring and crystallizing.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019148087A1 (en) | 2018-01-29 | 2019-08-01 | Duke University | Compositions and methods of enhancing 5-hydroxytryptophan bioavailability |
| US11752107B2 (en) | 2021-07-30 | 2023-09-12 | Evecxia Therapeutics, Inc. | 5-hydroxytryptophan gastroretentive dosage forms |
| US11779567B2 (en) | 2021-10-14 | 2023-10-10 | Evecxia Therapeutics, Inc. | Method for optimizing 5-hydroxytryptamine function in the brain for therapeutic purposes |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094345A2 (en) * | 2000-06-07 | 2001-12-13 | Lilly Icos Llc | Derivatives of 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione |
| US20060160884A1 (en) * | 2004-12-28 | 2006-07-20 | Wyeth | Alkynyl-containing tryptophan derivative inhibitors of tace/matrix metalloproteinase |
| CN1876631A (en) * | 2006-07-17 | 2006-12-13 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tryptophan using asymmetric conversion method |
| CN102212028A (en) * | 2010-04-06 | 2011-10-12 | 上海恩翊医药科技有限公司 | Preparation method of (L)-5-hydroxytryptophan |
| CN103333098A (en) * | 2013-07-24 | 2013-10-02 | 马鞍山德鸿生物技术有限公司 | D-tryptophan |
-
2013
- 2013-11-22 CN CN201310592943.3A patent/CN103554005A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094345A2 (en) * | 2000-06-07 | 2001-12-13 | Lilly Icos Llc | Derivatives of 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione |
| US20060160884A1 (en) * | 2004-12-28 | 2006-07-20 | Wyeth | Alkynyl-containing tryptophan derivative inhibitors of tace/matrix metalloproteinase |
| CN1876631A (en) * | 2006-07-17 | 2006-12-13 | 安徽省恒锐新技术开发有限责任公司 | Method for preparing D-tryptophan using asymmetric conversion method |
| CN102212028A (en) * | 2010-04-06 | 2011-10-12 | 上海恩翊医药科技有限公司 | Preparation method of (L)-5-hydroxytryptophan |
| CN103333098A (en) * | 2013-07-24 | 2013-10-02 | 马鞍山德鸿生物技术有限公司 | D-tryptophan |
Non-Patent Citations (2)
| Title |
|---|
| KAAPJOO PARK，等: "Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-a converting enzyme (TACE) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》, 22 April 2009 (2009-04-22), pages 3587 - 3865 * |
| 刘平，等: "吲哚5位和3位取代化合物的合成研究", 《长沙理工大学硕士学位论文》, 3 September 2012 (2012-09-03) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019148087A1 (en) | 2018-01-29 | 2019-08-01 | Duke University | Compositions and methods of enhancing 5-hydroxytryptophan bioavailability |
| US11752107B2 (en) | 2021-07-30 | 2023-09-12 | Evecxia Therapeutics, Inc. | 5-hydroxytryptophan gastroretentive dosage forms |
| US11779567B2 (en) | 2021-10-14 | 2023-10-10 | Evecxia Therapeutics, Inc. | Method for optimizing 5-hydroxytryptamine function in the brain for therapeutic purposes |
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Application publication date: 20140205 |