CN105367477B - A method of synthesis 1- methyl tryptophan - Google Patents
A method of synthesis 1- methyl tryptophan Download PDFInfo
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- CN105367477B CN105367477B CN201410391864.0A CN201410391864A CN105367477B CN 105367477 B CN105367477 B CN 105367477B CN 201410391864 A CN201410391864 A CN 201410391864A CN 105367477 B CN105367477 B CN 105367477B
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Abstract
The present invention provides a kind of direct high-efficiency synthesis methods of 1- methyl tryptophan.More specifically, a kind of method for synthesizing the 1- methyl tryptophan as shown in following formula I, the method includes：In atent solvent, in the presence of alkaline reagent, make tryptophan and methylating reagent CH3X (X is defined as in the description) reaction, is isolated required product 1- methyl tryptophan.The present invention is by using organic solvent as reaction medium, and in the case where suitable alkaline reagent is as dehydrogenating agent, tryptophan reacts with methyl halogenated object, crude product 1- methyl tryptophan of available high-purity by operations such as extraction, washing, recrystallizations.The method of the present invention yield is good, selectivity is strong, easy to operate, safe and easily controllable.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate more specifically to the method for synthesis 1- methyl tryptophan.
Background technique
The diseases for much seriously threatening human health are all weakened with human immune system related, such as cancer cell will be by
The effective immune response of patient is gradually destroyed, the infectious diseases such as HIV and HCV are also in that human immunological competence weakens and causes viral length
Phase retains.In recent years the study found that catalysis tryptophan degradation enzyme indoles amine -2,3- dioxygenase (indoleamine-2,3-
Dioxygenase, IDO) in regulation immunosupress.This enzyme long term activation, activity of this fermentoid in many cancer patient's bodies
Higher, then cancer patient's prognosis is poorer.Preclinical study shows to inhibit IDO that can effectively improve anticarcinogen materialization common at present
Treat therapeutic effect.In vitro experiment it has been confirmed that, 1- methyl tryptophan (1-MT) be IDO competitive inhibitor (Cady,
S.G.；Sono, M., Arch.Biochem.Biophys.1991,291,326-333.), chemical structural formula is：
Recently, 1- methyl tryptophan and a series of chemotherapeutics such as cyclophosphamide for having gone up clinic, cis-platinum, adriamycin, or
Paclitaxel plus uses, and shows splendid synergistic effect, becomes a kind of chemical, immune conjoint therapy drug got a good chance of
(Muller A.J.,Duhadaway J.B.,Donover P.S.,Sutanto-Ward E.,Prendergast G.C.,
Nat.Med.,2005,11,312–9).1- methyl tryptophan is expected to play a significant role in anticancer therapy, its synthetic method
Exploitation will bring advantageous Social benefit and economic benefit.
Japanese scholars Yamada, S.；Shioiri,T.；Itaya,T.；Hara,T.；Matsueda, R. et al. exist
A kind of synthetic method of 1- methyl tryptophan is reported on Chem.Pharm.Bull.1965,13,88.This method metallic sodium exists
Sodamide is made in liquefied ammonia, adds tryptophan and iodomethane reaction, obtains 1- methyl tryptophan by complicated purifying.It is this
Use metallic sodium in method, this substance habitually under easily burn, and general industry product are big bulk again, when reaction
It needs to be shredded under inert gas protection to feed intake.Operation also needs at low temperature, to require production equipment high, operation
Safety of employees is also by very big threat.In addition, the leakage of ammonia is also possible to have extreme influence to surrounding enviroment, industrially very
Hardly possible is realized.
As described above, Japanese scholars Yamada, S.；Shioiri,T.；Itaya,T.；Hara,T.；Matsueda, R. etc.
The method that people reports on Chem.Pharm.Bull. uses metallic sodium, it is also necessary to which special Cryo Equipment wants operating staff
Ask high, risk is big, and the safety of industrialized production is difficult to ensure.In the report of published 1- methyl tryptophan synthetic method
In, the method that does not solve these problems effectively.
Summary of the invention
In view of above-mentioned, that the object of the present invention is to provide yields is good, selectivity is strong, easy to operate, safe and easily controllable
Synthesis 1- methyl tryptophan method.
In one aspect, the present invention provides a kind of method for synthesizing the 1- methyl tryptophan as shown in following formula I,
The method includes：In atent solvent, in the presence of alkaline reagent, make tryptophan and methyl shown in Formula Il
Change reagent C H3X reaction, is isolated required product 1- methyl tryptophan, in the methylating reagent CH3In X, X is indicated
Cl、Br、I、OSO2(OCH3)、OPO(OCH3)2、OSO2CF3Or OSO2C6H4CH3,
Preferably, the atent solvent be toluene, tetrahydrofuran, acetonitrile, acetone, butanol, n,N-Dimethylformamide and
One of dimethyl sulfoxide is a variety of.
Preferably, the alkaline reagent is lithium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, Sodamide, hydrogenation
Lithium, sodium hydride, hydrofining, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds
One of base potassium and butyl lithium are a variety of.
Preferably, the reaction carries out under inert gas protection.
Preferably, the tryptophan：Alkaline reagent：Methylating reagent CH3The molar ratio of X is 1：1~10：0.5~2.5.
Preferably, the separation is included in after completion of the reaction, and reaction is quenched with water, then carries out in recrystallizationization solvent
It recrystallizes and passes through filtering and obtain solid, be finally dried.
It is further preferred that the recrystallizationization solvent is toluene, ether, acetone, methyl phenyl ethers anisole, ethyl alcohol and t-butyl methyl ether
One of or it is a variety of.
It is further preferred that it is described recrystallization -20-5 DEG C at a temperature of carry out.
It is further preferred that being dissolved to form aqueous solution with water by filtering the solid obtained before the drying, and will with acid
The pH of the aqueous solution is adjusted to 5.5~7.5 so that solid is precipitated, and solid be precipitated is obtained by filtering, is carried out after washed
It is dry.
It is further preferred that product obtained is pure 1- methyl tryptophan.
The present invention is by using organic solvent as reaction medium, in the case where suitable alkaline reagent is as dehydrogenating agent, tryptophan
It reacts with methyl halogenated object, crude product 1- methyl of available high-purity by operations such as extraction, washing, recrystallizations
Tryptophan.
Detailed description of the invention
Fig. 1 is the 1- methyl tryptophan of 1 synthesis according to embodiments of the present invention1H-NMR nmr spectrum.
Fig. 2 is the 1- methyl tryptophan of 1 synthesis according to embodiments of the present invention13C-NMR nmr spectrum.
The infrared spectrogram of the 1- methyl tryptophan of Fig. 31 synthesis according to embodiments of the present invention.
Fig. 4 is the mass spectrogram of the 1- methyl tryptophan of 1 synthesis according to embodiments of the present invention.
Specific embodiment
In order to provide the synthesis 1- methyl color ammonia that yield is good, selectivity is strong, easy to operate, safe and easily controllable
The method of acid, the present invention use organic solvent as reaction medium, and suitable alkaline reagent can be with first as dehydrogenating agent, tryptophan
Base halides react, and the 1- methyl tryptophan crude product of generation is by operations such as extraction, washing, recrystallizations, so that it may obtain
The 1- methyl tryptophan of high-purity.
In one embodiment, the present invention provides a kind of method for synthesizing the 1- methyl tryptophan as shown in following formula I,
The method includes：In atent solvent, in the presence of alkaline reagent, make tryptophan and methyl shown in Formula Il
Change reagent C H3X reaction, is isolated required product 1- methyl tryptophan, in the methylating reagent CH3In X, X is indicated
Cl、Br、I、OSO2(OCH3)、OPO(OCH3)2、OSO2CF3Or OSO2C6H4CH3,
Preferably, the atent solvent be toluene, tetrahydrofuran, acetonitrile, acetone, butanol, n,N-Dimethylformamide and
One of dimethyl sulfoxide is a variety of.
Preferably, the alkaline reagent is lithium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, Sodamide, hydrogenation
Lithium, sodium hydride, hydrofining, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds
One of base potassium and butyl lithium are a variety of.In the present invention, it is no longer needed using the alkaline reagent of commercialization without being prepared in situ
Metallic sodium is directly used, as being not necessarily to be prepared in situ if Sodamide with sodium and liquefied ammonia；In addition the present invention is replaced with organic solvent
Liquefied ammonia makees solvent, just so that operation is got up without using low temperature pressure-resistant equipment from equipment more safe and simple, can make to react
It can industrially apply well.
Preferably, the reaction carries out under inert gas protection.
Preferably, the tryptophan：Alkaline reagent：Methylating reagent CH3The molar ratio of X is 1：1~10：0.5~2.5.
Preferably, the separation is included in after completion of the reaction, and reaction is quenched with water, then carries out in recrystallizationization solvent
It recrystallizes and passes through filtering and obtain solid, be finally dried.
It is further preferred that the recrystallizationization solvent is toluene, ether, acetone, methyl phenyl ethers anisole, ethyl alcohol and t-butyl methyl ether
One of or it is a variety of.
It is further preferred that it is described recrystallization -20-5 DEG C at a temperature of carry out.
It is further preferred that being dissolved to form aqueous solution with water by filtering the solid obtained before the drying, and will with acid
The pH of the aqueous solution is adjusted to 5.5~7.5 so that solid is precipitated, and solid be precipitated is obtained by filtering, is carried out after washed
It is dry.
By the above method, the present invention can obtain pure 1- methyl tryptophan product.
In a more particular embodiment, firstly, in reaction vessel such as three-necked flask, 1 parts by weight tryptophan is existed
Suspension in 50-150mL atent solvent is cooling in such as 0 DEG C of ice-water bath at low temperature, later preferably in inert gas such as N2
Under protective atmosphere, the alkaline reagent of 1-10 equivalent part is added portionwise in such as 30-50min.After adding alkaline reagent, preferably
Reaction system is stirred at room temperature 0.5-2 hours, reaction system can be become muddy lilac from clear solution during this period
Solution.After the completion of stirring, then reaction system moved under low temperature in such as 0 DEG C of ice-water bath, by the methylation of 0.5-2.5 equivalent part
Reagent such as iodomethane in 10-50mL atent solvent solution, be added dropwise within reaction system within such as 20-40min, instead
Answering the purple of system can take off gradually, and the turbidity of reaction mixture solution can also reduce.After being added dropwise, then in room temperature
Lower the reaction was continued 2~10h.After completion of the reaction, it by being recrystallized in recrystallizationization solvent, filters later and dries and obtain
To required product.
It is highly preferred that about 2-10mL water is added to quench the reaction after completion of the reaction.Gained mixed liquor is poured into 300-
In for example, about 0 DEG C of recrystallization solvent, a large amount of solids are precipitated 600mL, directly filter.It is further preferred that obtained solid
It is dissolved with 30-100mL water to obtain aqueous solution, the pH of the aqueous solution is adjusted between 5.5~7.5 with sour such as concentrated hydrochloric acid, is analysed
A large amount of solids out filter the solid of precipitation.Resulting solid product is preferably washed with the ice water of 50-200mL again, later optionally
It is washed with 50-200mL in about 0 DEG C of recrystallization solvent.White solid powder product is obtained with anhydrous sodium sulfate drying
8.5g (yield 78%), the specific rotatory power [α] of productD 20+ 7.5 (c=1.0,2M HCl) show that the optical purity of product is protected
It holds.
It is noted that the addition or order by merging of reaction raw materials are not particularly limited in the method for the present invention.For example,
In one embodiment, tryptophan can be first dissolved in atent solvent, be subsequently added into alkaline reagent, finally again with methylation
Reagent reaction.In another embodiment, tryptophan and methylating reagent can be first dissolved in atent solvent, be added again later
Enter alkaline reagent to be reacted.
The following example is for detailed description of the invention, and not limitation is of the invention.
Embodiment 1
In the three-necked flask equipped with ice-water bath, 10.2g tryptophan is added to the tetrahydrofuran (THF) of 100mL, in nitrogen
Under protective condition, within 50min, the Sodamide of 5g commercialization is added portionwise, removes ice-water bath in room after adding Sodamide
(about 25 DEG C) of temperature are stirred 2 hours, and temperature of reaction system is then down to 0 DEG C with ice-water bath.By 7.46g iodomethane in 50mL THF
In solution be added dropwise in above-mentioned mixed solution in 30min with constant pressure funnel, continue to be stirred to react 15 after being added dropwise
Hour.After completion of the reaction, the water of 30mL is added at room temperature to quench reaction.Reaction mixture is poured into 400mL ether, is seen
It has observed a large amount of solids to be precipitated, filtered with Buchner funnel, obtained solid is dissolved to obtain solution, enriching hydrochloric acid with 100mL water
25mL adjusts pH to 6.5, and the solid of precipitation is filtered again and is come out, dry with anhydrous sodium sulfate, obtains white solid powder production
Object, 8.5g (yield 78%, m.p.269 DEG C).
Compound is tested to by the above method product obtained nuclear-magnetism of Bruker400MHz1H-NMR and13C-
NMR spectra, infrared and mass spectral analysis.Fig. 1 to Fig. 4 is respectively the product obtained according to the present embodiment 11H-NMR nuclear magnetic resonance
Spectrogram,13C-NMR nmr spectrum, infrared spectrogram and mass spectral analysis figure.It can be seen from the figure that product obtained1H-NMR nmr spectrum is absorbed with following characteristics：1H-NMR(400MHz,CDCl3):δ=2.96 (t, J=8.8Hz,
1H), 3.73 (s, 3H), 7.02 (d, J=8Hz, 1H), 7.14 (t, J=8Hz, 2H), 7.38 (d, J=8Hz, 1H), 7.57 (d, J
=8Hz, 1H)；13C-NMR nmr spectrum is absorbed with following characteristics：13C-NMR(100MHz,CDCl3) δ (ppm)=
25.3,32.0,52.9,104.6,109.9,118.2,119.1,121.7,126.7,129.4,129.5,136.7,171.3；It is red
Outer spectrogram is absorbed with following characteristics：νmax(KBr)cm-1:3423,3066,2569,2077,1593,1408,1132,918,
732,557；And mass spectral characteristic peak is as follows：217.0973,218.1006.It can be it is clearly noted not only that being obtained from result above
Solid product be 1- methyl tryptophan, purity 100%.
Embodiment 2
By 10.2g tryptophan be added 130mL dimethyl sulfoxide (DMSO), under the conditions of nitrogen protection, in 30min it
It is interior, 5g sodium hydroxide is added portionwise, a hour is stirred at room temperature after adding sodium hydroxide, system temperature is then down to 0 with ice
DEG C, the solution of the 30mL DMSO of 7.46g iodomethane is instilled to the DMSO solution of tryptophan, Sodamide within 30min, is added dropwise
After continue to be stirred to react 15h, react tryptophan completely, system be added 50mL water quench reaction, will reaction mixing
Object pours into 400mL ether, has a large amount of solids to be precipitated, and filters, and obtained solid is dissolved to obtain solution, enriching hydrochloric acid tune pH with water
To between 6~7, the solid of precipitation is filtered out, is dried to obtain white solid powder product 8.7g (yield 80%, m.p.269
℃)。
It is same as Example 1, product obtained is carried out1H-NMR and13C-NMR nuclear magnetic resonance, infrared and mass spectrum point
Analysis.As a result (not shown) shows that solid product obtained is 1- methyl tryptophan, purity 100%.
Embodiment 3
Tryptophan (10.2g) and iodomethane (7.46g) are put into toluene and acetonitrile (1:1,50mL) mixed solvent dissolution,
KOH (8.4g) is added portionwise within 2h, solution becomes sepia, is stirred overnight at room temperature, and solution colour is by brown stain
Colorless cleared solution is added ice water (150mL), and acetonitrile rotation is removed, is extracted with n-butanol (3 × 100mL), will be obtained organic
It is mutually dried overnight with anhydrous sodium sulfate, then filtering is spin-dried for resulting organic phase, obtains the pure 1- methyl tryptophan of white
(7.7g, 71%, m.p.269 DEG C).
It is same as Example 1, product obtained is carried out1H-NMR and13C-NMR nuclear magnetic resonance, infrared and mass spectrum point
Analysis.As a result (not shown) shows that solid product obtained is 1- methyl tryptophan, purity 100%.
The above, the only preferred embodiments of the disclosure, but scope of protection of the present invention is not limited thereto,
Any those skilled in the art are in the technical scope of present disclosure, and any changes or substitutions that can be easily thought of, all answer
It is included within the scope of protection of the present invention, therefore, protection scope of the present invention should be with protection scope defined by claim
Subject to.
Claims (8)
1. a kind of method for synthesizing the 1- methyl tryptophan as shown in following formula I,
The method includes：In inert organic solvents, in the presence of alkaline reagent, make tryptophan and methyl shown in Formula Il
Change reagent C H3X reaction, is isolated required product 1- methyl tryptophan, in the methylating reagent CH3In X, X is indicated
Cl、Br、I、OSO2(OCH3)、OPO(OCH3)2、OSO2CF3Or OSO2C6H4CH3,
Wherein the inert organic solvents are toluene, tetrahydrofuran, acetonitrile, acetone, butanol, N,N-dimethylformamide and diformazan
One of base sulfoxide is a variety of,
The alkaline reagent is lithium carbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, Sodamide, lithium hydride, sodium hydride, hydrogen
Change potassium, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium and butyl lithium
One of or it is a variety of.
2. the method according to claim 1, wherein the reaction carries out under inert gas protection.
3. the method according to claim 1, wherein the tryptophan：Alkaline reagent：Methylating reagent CH3X's
Molar ratio is 1：1~10：0.5~2.5.
4. method according to any one of claim 1-3, which is characterized in that the separation is included in after completion of the reaction,
Reaction is quenched with water, then carry out recrystallizing in recrystallizationization solvent and solid is obtained by filtering, is finally dried.
5. according to the method described in claim 4, it is characterized in that, the recrystallizationization solvent is toluene, ether, acetone, benzene
One of methyl ether, ethyl alcohol and t-butyl methyl ether are a variety of.
6. according to the method described in claim 4, it is characterized in that, it is described recrystallization -20-5 DEG C at a temperature of carry out.
7. according to the method described in claim 4, it is characterized in that, use is water-soluble by filtering the solid obtained before the drying
Solution forms aqueous solution, and the pH of the aqueous solution is adjusted to 5.5~7.5 so that solid is precipitated with acid, is analysed by filtering to obtain
Solid out is dried after washed.
8. the method according to the description of claim 7 is characterized in that product obtained is pure 1- methyl tryptophan.
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| CN110790696A (en) * | 2018-08-03 | 2020-02-14 | 田海滨 | 11Preparation method and preparation system of C- α -methyl-L-tryptophan |
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| CN101121717A (en) * | 2007-05-17 | 2008-02-13 | 四川大学 | Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine |
| CN102167766A (en) * | 2011-03-21 | 2011-08-31 | 北京化工大学 | Vinyl amino acid (ester) polymer and preparation method thereof |
| CN103570603A (en) * | 2012-07-19 | 2014-02-12 | 杭州中肽生化有限公司 | Novel synthetic method of hemiasterlin |
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| CN101121717A (en) * | 2007-05-17 | 2008-02-13 | 四川大学 | Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine |
| CN102167766A (en) * | 2011-03-21 | 2011-08-31 | 北京化工大学 | Vinyl amino acid (ester) polymer and preparation method thereof |
| CN103570603A (en) * | 2012-07-19 | 2014-02-12 | 杭州中肽生化有限公司 | Novel synthetic method of hemiasterlin |
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