CN101108876B - Method for preparing S- protection glutathione by adopting complexation common protection - Google Patents
Method for preparing S- protection glutathione by adopting complexation common protection Download PDFInfo
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- CN101108876B CN101108876B CN2007100245899A CN200710024589A CN101108876B CN 101108876 B CN101108876 B CN 101108876B CN 2007100245899 A CN2007100245899 A CN 2007100245899A CN 200710024589 A CN200710024589 A CN 200710024589A CN 101108876 B CN101108876 B CN 101108876B
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- 238000000034 method Methods 0.000 title claims abstract description 23
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title abstract description 18
- 108010024636 Glutathione Proteins 0.000 title abstract description 9
- 229960003180 glutathione Drugs 0.000 title abstract description 9
- 238000010668 complexation reaction Methods 0.000 title 1
- 229960002989 glutamic acid Drugs 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 235000013878 L-cysteine Nutrition 0.000 claims abstract description 4
- 239000004201 L-cysteine Substances 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 108010016626 Dipeptides Proteins 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- -1 amino-phenyl aldehyde Chemical class 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 239000003637 basic solution Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 9
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003729 cation exchange resin Substances 0.000 abstract description 3
- 239000002244 precipitate Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 20
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- 229910001453 nickel ion Inorganic materials 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 0 C*(C1)CN(Cc2ccccc2)C1C(Nc(cccc1)c1C(*)=O)=O Chemical compound C*(C1)CN(Cc2ccccc2)C1C(Nc(cccc1)c1C(*)=O)=O 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- QTQDDTSVRVWHMO-UHFFFAOYSA-N S-Methylglutathione Natural products OC(=O)CNC(=O)C(CSC)NC(=O)CCC(N)C(O)=O QTQDDTSVRVWHMO-UHFFFAOYSA-N 0.000 description 1
- 108700024212 S-methyl glutathione Proteins 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- QTQDDTSVRVWHMO-BQBZGAKWSA-N S-methylglutathione Chemical compound OC(=O)CNC(=O)[C@H](CSC)NC(=O)CC[C@H](N)C(O)=O QTQDDTSVRVWHMO-BQBZGAKWSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a method adopting the complex common protection to prepare S-protective glutathione, which comprises the following steps: the chiral auxiliary, the divalent metal ion salt and L-glutamic acid are adopted to form complex in the alkaline methanol to realize the common protection of the L-glutamic acid Alpha-carboxyl and the amino; the L-glutamic acid of the complex common protection is connected to the S-protection L-cysteine through the protocol reagent to form the S-protective glutathione of the complex common protection; the S-protective glutathione of the complex common protection is connected to the glycin through the protocol reagent to form the S-protective glutathione of the complex common protection; the S-protective glutathione of the complex common protection is hydrolyzed in the diluted acid to gain the chiral auxiliary precipitate and the mixed solution of the S-protective glutathione and the divalent metal ion; the S-protective glutathione is separated with the divalent metal ion through the cation exchange resin. The invention is simple in operation, high in yield, low in production cost and is convenient for the industrial application.
Description
Technical field
The present invention relates to the method that a kind of employing complex common protection prepares S-protection gsh (1).
Wherein the R group represents it is blocking group to the L-cysteine sulfydryl, can be methyl, benzyl, to methyl-benzyl, diphenyl-methyl, trityl, the tertiary butyl, ethanamide methyl, pivalyl amine methyl, fluorene methyl etc.
Background technology
Gsh is the tripeptides by L-L-glutamic acid, L-halfcystine and glycine be combined into, be belong to contain sulfydryl, the small-molecule peptide material, have antioxygenation and detoxification, the widespread use in field of medicaments gains public acceptance already.
Reported the chemical synthesis process of multiple gsh; Douglas KT has corresponding summary (Glutathione:Chemical; Biochemical and Medical Aspects; Part A.Vol.3:243-279; 1989), in these methods, all need the α-carboxyl and the amino of L-L-glutamic acid are protected respectively; dissociate behind γ-carboxyl, just can connect reactive polypeptide.After connecing the peptide end, L-L-glutamic acid α-carboxyl and amino blocking group need be removed, obtain the finished product.In protection-deprotection process repeatedly, cause phenomenons such as peptide bond rupture, racemization easily, thereby make that yield reduces, optical purity reduces.
α-carboxyl and amino method of carrying out common protection for L-L-glutamic acid also have report, forming Peng oxazoline ketone as employing L-L-glutamic acid such as: Nefkens and trialkylboron reaction protects α-carboxyl and amino (to see Tetrahedron altogether, 39 (18): 2995-2998,1983); Employing N-protected L-L-glutamic acid such as Itoh and polyformaldehyde reaction form 5-Yang oxazoline ketone and protect α-carboxyl and amino (seeing Chem.Pharm.Bull., 17:1679,1969) altogether.Though these methods can realize the α-carboxyl and the amino common protection of L-L-glutamic acid, but still need to consume a large amount of reaction reagents, and not recyclable.
Therefore, find one can realize that the α-carboxyl of L-L-glutamic acid and amino protection altogether and the reusable method of energy be the keys of chemosynthesis gsh.
Summary of the invention
The object of the invention provides a kind of α-carboxyl and amino complex common protection method to L-L-glutamic acid, and then protects L-halfcystine and glycine to connect peptide in proper order by free γ-carboxyl and S-, realizes the chemosynthesis of gsh.
The objective of the invention is to realize by following technical measures:
A kind of method that adopts complex common protection to prepare S-protection gsh, this method comprises the following steps:
(1) L-L-glutamic acid α-carboxyl and amino protection altogether;
Get chiral auxiliary(reagent), divalent-metal ion salt, L-L-glutamic acid and under alkaline condition, react, form complex compound, realize L-L-glutamic acid α-carboxyl and amino protection altogether.
Wherein the chiral auxiliary(reagent) that is adopted in the reaction is 2-(N-benzyl-L-prolyl) amino-benzophenone (2a, n=1, R '=Ph, BPB), 2-(N-benzyl-pyrrole-2-formyl) amino-benzophenone (2b, n=2, R '=Ph, BPyB) and 2-(N-benzyl-L-prolyl) amino-phenyl aldehyde (2c, n=1, R '=H, a kind of in BPBa).
Divalent-metal ion (the M that is adopted in the complex common protection reaction
2+) salt is Cu
2+, Ni
2+, Zn
2+, Co
2+A kind of etc. in hydrochloride, vitriol or the nitrate of divalent transition metal ion.
The alkali that is adopted in the reaction can be a kind of in sodium hydroxide, the potassium hydroxide.
(2) complex common protection L-L-glutamic acid connects S-protection L-halfcystine;
In DMF, add complex common protection L-L-glutamic acid, employing connects peptide reagent and connects S-protection L-halfcystine.This step need not to separate, and can directly carry out next step operation.
The protecting group (R) of the S-that adopted here protection L-cysteine sulfydryl can benzyl, methyl, a kind of in the blocking groups such as methyl-benzyl, diphenyl-methyl, trityl, the tertiary butyl, ethanamide methyl, pivalyl amine methyl, fluorene methyl.The used peptide reagent that connects can be a kind of among DCC/HOBt, DCC/HOSu, the DCC/HOAt.The mol ratio of two materials kept 1: 1 usually in every winding peptide reagent.
(3) complex common protection paddy Guang dipeptides connects glycine;
The employing of back reaction product connects peptide reagent and connects glycine, finishes the synthetic of tripeptides.Reactant is poured in the water, separates out solid, can obtain complex common protection S-protection gsh after the filtration.
(4) complex common protection S-protection gsh mixture hydrolysis;
Complex common protection S-protection gsh is dissolved in the methyl alcohol, and solution slowly is added drop-wise in the acid and is hydrolyzed.Filter chiral auxiliary(reagent), recyclable repeated use.Filtrate steaming removal solvent gets S-protection gsh and divalent-metal ion mixture.
Employed acid can be a kind of in hydrochloric acid, sulfuric acid or sulfuric acid and the hydrochloric acid mixed solution in this step.The volumetric molar concentration of acid can be 3mol/L.
(5) gsh separates with the divalent-metal ion exchange;
Protect gsh mixture hydrolyzed solution to go in the cation exchange resin column of having handled well S-, adopt the ammoniacal liquor wash-out, protect gsh to separate S-with divalent-metal ion.To collect the liquid freeze-drying, get S-protection gsh.The wash-out divalent-metal ion reclaims and uses.
Beneficial effect of the present invention:
Complex common protection method of the present invention prepares S-protection gsh and has compared following advantage with other chemical synthesis process:
1, employing complex common protection method has reduced protection and the deprotection process to alpha-amino group in the L-L-glutamic acid and carboxyl, need not amino and carboxy protective in the back continued access peptide process, has avoided connecing repeated protection and deprotection steps in the reactive polypeptide process, and is simple to operate.
2, after removing complex common protection, can reclaim the complexing auxiliary agent by high yield.Isolate divalent-metal ion by ion-exchange simultaneously, reclaim and reuse.Remove the necessary peptide reagent that connects, consume other reagent hardly, have Atom economy preferably.
Embodiment
Following examples mainly are for a better understanding of the present invention, and can not be regarded as limitation of the scope of the invention.
Synthesizing of embodiment 1:BPB-Ni-Glu title complex
2-(N-benzyl-L-prolyl) amino-benzophenone (2a, n=1, R '=Ph, BPB, 0.005mol), NiCl
26H
2O (0.01mol), Glu (0.025mol) and methyl alcohol 18mL mix, and stir, and are heated to 40-50 ℃.Once add potassium hydroxide aqueous solution (0.08mol), reacted 2 hours, be cooled to room temperature, said mixture is poured in 200 ml waters, standing over night has a large amount of crystal to separate out.Filter, crystal washes with water twice.Vacuum-drying gets red crystals BPB-Ni-Glu complex compound (3a, n=1, R '=Ph, M
2+=Ni
2+) 2.76g, be 97% with respect to the molar yield of BPB.
Synthesizing of embodiment 2:BPyB-Ni-Glu title complex
Reaction process and condition be with embodiment 1, and (R '=Ph is BPyB) with, NiCl for 2b, n=2 to adopt 2-(N-benzyl-pyrrole-2-formyl) amino-benzophenone
26H
2O, Glu reaction gets red crystals BPyB-Ni-Glu complex compound (3b, n=2, R '=Ph, M
2+=Ni
2+) 2.67g, be 92% with respect to the molar yield of BPyB.
Synthesizing of embodiment 3:BPBa-Cu-Glu title complex
Reaction process and condition be with embodiment 1, and (R '=H is BPBa) with, CuSO for 2c, n=1 to adopt 2-(N-benzyl-L-prolyl) amino-phenyl aldehyde
46H
2O, Glu reaction gets yellow solid BPBa-Cu-Glu complex compound (3c, n=1, R '=Ph, M
2+=Cu
2+) 2.29g, be 92% with respect to the molar yield of BPBa.
Synthesizing of embodiment 4:BPB-Ni-(S-benzyl) paddy Guang dipeptides
(3a 0.005mol) adds 20mL DMF to BPB-Ni-Glu, and the stirring at room dissolving adds DCC (0.005mol) and HOBt (0.005mol), reacts 2 hours, removes by filter DCU, gets filtrate, is complex common protection L-L-glutamic acid activated ester solution.
S-benzyl L-halfcystine (0.005mol) is dissolved in 20mL DMF, slowly drops to above-mentioned complex common protection L-L-glutamic acid activated ester solution, and reaction is spent the night.Filter, filtrate includes BPB-Ni-(S-benzyl) paddy Guang dipeptides (4a, n=1, R '=Ph, R=PhCH
2, M
2+=Ni
2+), need not to handle and carry out next step reaction.
Synthesizing of embodiment 5:BPyB-Ni-(S-methyl) paddy Guang dipeptides
Reaction process and condition adopt BPyB-Ni-Glu (3b) and S-methyl L-halfcystine to connect reactive polypeptide with embodiment 4, get BPyB-Ni-(S-methyl) paddy Guang dipeptides (4b, n=2, R '=Ph, R=CH
3, M
2+=Ni
2+) filtrate, need not to handle and can carry out next step reaction.
Synthesizing of embodiment 6:BPBa-Cu-(S-benzyl) paddy Guang dipeptides
Reaction process and condition adopt BPBa-Cu-Glu (3c) and S-benzyl L-halfcystine to connect reactive polypeptide with embodiment 4, get BPyB-Ni-(S-benzyl) paddy Guang dipeptides (4c, n=1, R '=H, R=PhCH
2, M
2+=Cu
2+) filtrate, need not to handle and can carry out next step reaction.
Synthesizing of embodiment 7:BPB-Ni-(S-benzyl) gsh
Filtrate among the embodiment 4 (4a) is stirred, and adds DCC (0.005mol) and HOBt (0.005mol), reacts 2 hours, removes by filter DCU, gets filtrate, is complex common protection S-benzyl L-glutamy L-halfcystine activated ester solution.
Glycine (0.005mol) is dissolved in 20mL DMF, slowly drops in the above-mentioned complex common protection S-benzyl L-glutamy L-halfcystine activated ester solution, and reaction is spent the night.Filter, filtrate is poured in the 100mL water, separates out solid, filters, obtain BPB-Ni-(S-benzyl) gsh 3.19g (5a,, n=1, R '=Ph, R=PhCH
2, M
2+=Ni
2+), be 78% with respect to the molar yield of BPB-Ni-Glu.
Synthesizing of embodiment 8:BPyB-Ni-(S-methyl) gsh
Reaction process and condition adopt (4b) and glycine to connect reactive polypeptide with embodiment 7, obtain BPB-Ni-(S-methyl) gsh 2.79g (5b, n=2, R '=Ph, R=CH
3, M
2+=Ni
2+), be 65% with respect to the molar yield of BPyB-Ni-Glu (2b).
The hydrolysis of embodiment 9:BPB-Ni-(S-benzyl) gsh
BPB-Ni-(S-benzyl) gsh (5a) of preparation among the embodiment 7 is dissolved in the 20mL methyl alcohol, slowly is added drop-wise in the hydrochloric acid soln of 3mol/L, 60 ℃ are stirred hydrolysis.After reaction finishes, filter solid, be chiral auxiliary(reagent) BPB1.31g (2a, yield 90%), reclaim and reuse.Filtrate steaming removal solvent gets S-benzyl gsh (1a, R=PhCH
2) and the nickel ion mixture.
The hydrolysis of embodiment 10:BPyB-Ni-(S-methyl) gsh
Reaction process and condition adopt BPB-Ni-(S-methyl) gsh to be hydrolyzed with embodiment 9, obtain S-Methylglutathione (3b, R=CH
3) and the nickel ion mixture, reclaim chiral auxiliary(reagent) BPyB 1.31g (1b, yield 90%).
Embodiment 11:S-benzyl gsh separates with the nickel ion exchange
The S-benzyl gsh and the nickel ion mixture that obtain among the embodiment 9 are dissolved in the 20mL water, go in H type 731 cation exchange resin columns of having handled well, amount of resin is about 10-15 a times of hydrolyzed solution volume.With mass concentration is 8% ammoniacal liquor drip washing, washes out fully to S-benzyl gsh.The liquid freeze-drying be will collect, S-benzyl gsh 1.24g (1a, R=PhCH got
2, yield 90%).The nickel ion that remains on the Zeo-karb takes off with pickling, reclaims and uses.
Claims (5)
1. adopt complex common protection to prepare the method for S-protection gsh, this method comprises the following steps:
(1). adopt chiral auxiliary(reagent), divalent-metal ion salt and L-L-glutamic acid in basic solution, to form complex compound, realize L-L-glutamic acid α-carboxyl and amino protection altogether;
(2). complex common protection L-L-glutamic acid connects S-protection L-halfcystine by connecing peptide reagent, forms complex common protection S-protection paddy Guang dipeptides;
(3). complex common protection S-protection paddy Guang dipeptides connects glycine by connecing peptide reagent, forms complex common protection S-protection gsh;
(4). the hydrolysis in acid solution of complex common protection S-protection gsh obtains the mixing solutions that chiral auxiliary(reagent) precipitation and S-protect gsh and divalent-metal ion;
(5). separate S-protection gsh and divalent-metal ion by Zeo-karb;
Wherein:
The chiral auxiliary(reagent) that is adopted in the step (1) is a kind of in 2-(N-benzyl-L-prolyl) amino-benzophenone, 2-(N-benzyl-pyrrole-2-formyl) amino-benzophenone or 2-(N-benzyl-L-prolyl) amino-phenyl aldehyde;
In the step (2) protecting group of S-protection L-cysteine sulfydryl be benzyl, methyl, a kind of in methyl-benzyl, diphenyl-methyl, trityl, the tertiary butyl, ethanamide methyl, the fluorene methyl.
2. method according to claim 1 is characterized in that the common protection divalent-metal ion salt that is adopted in the step (1) is Cu
2+, Ni
2+, Zn
2+, Co
2+Vitriol, hydrochloride or nitrate in a kind of.
3. method according to claim 1 is characterized in that the alkali that is adopted in the step (1) is a kind of in sodium hydroxide, the potassium hydroxide.
4. method according to claim 1, the peptide reagent that connects that it is characterized in that being adopted in step (2), (3) is a kind of among DCC/HOBt, DCC/HOSu, the DCC/HOAt.
5. method according to claim 1 is characterized in that employed acid in the step (4) is a kind of in hydrochloric acid, sulfuric acid or sulfuric acid and the hydrochloric acid mixed solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100245899A CN101108876B (en) | 2007-06-25 | 2007-06-25 | Method for preparing S- protection glutathione by adopting complexation common protection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100245899A CN101108876B (en) | 2007-06-25 | 2007-06-25 | Method for preparing S- protection glutathione by adopting complexation common protection |
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| Publication Number | Publication Date |
|---|---|
| CN101108876A CN101108876A (en) | 2008-01-23 |
| CN101108876B true CN101108876B (en) | 2011-02-02 |
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Non-Patent Citations (7)
| Title |
|---|
| MASAYOSHI MURAKI, et al..Use of N, S-Bis-tert-butoxycarbonyl-L-cysteine for Synthesisof Glutathione.CHEMICAL & * |
| MASAYOSHIMURAKI et al..Use of N |
| Noriyoshi Inukai, et al..The Peptide Synthesis. I. Use of the S-EthylmercaptoGroup for the Protection of the Thiol Function of Cysteine.Bulletin of the Chemical Society of Japan40 12.1967,40(12),2913-2918. * |
| Noriyoshi Inukai, et al.The Peptide Synthesis. I. Use of the S-EthylmercaptoGroup for the Protection of the Thiol Function of Cysteine.Bulletin of the Chemical Society of Japan40 12.1967,40(12),2913-2918. |
| PHARMACEUTICAL BULLETIN19 8.1971,19(8),1708-1713. * |
| Yuri N. Belokon, et al..Improved procedures for the synthesis of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone (BPB) and Ni(II)complexes of Schiff＇s bases derived from BPB andaminoacids.Tetrahedron: Asymmetry9 23.1998,9(23),4249-4252. * |
| Yuri N. Belokon, et al.Improved procedures for the synthesis of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone (BPB) and Ni(II)complexes of Schiff＇s bases derived from BPB andaminoacids.Tetrahedron: Asymmetry9 23.1998,9(23),4249-4252. |
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