CN100429223C - Process for producing cyclo (D-phenylpropyl-D-group) dipeptide - Google Patents
Process for producing cyclo (D-phenylpropyl-D-group) dipeptide Download PDFInfo
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- CN100429223C CN100429223C CNB2004100140022A CN200410014002A CN100429223C CN 100429223 C CN100429223 C CN 100429223C CN B2004100140022 A CNB2004100140022 A CN B2004100140022A CN 200410014002 A CN200410014002 A CN 200410014002A CN 100429223 C CN100429223 C CN 100429223C
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- Prior art keywords
- phenylalanine
- carbobenzoxy
- histidine
- phe
- ester
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- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 18
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 230000032050 esterification Effects 0.000 claims abstract description 7
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 11
- -1 D-Histidine ester Chemical class 0.000 claims description 10
- TVENQUPLPBPLGU-OAQYLSRUSA-N (4-nitrophenyl) (2r)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)[C@H](NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 TVENQUPLPBPLGU-OAQYLSRUSA-N 0.000 claims description 8
- 229930195721 D-histidine Natural products 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 claims description 5
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- KLCUXBQGZRJLHZ-XBZODAKZSA-N methyl (2r)-2-amino-3-(1h-imidazol-5-yl)propanoate;(2r)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical class COC(=O)[C@H](N)CC1=CNC=N1.C([C@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 KLCUXBQGZRJLHZ-XBZODAKZSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- 229940077476 2,5-piperazinedione Drugs 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 229930182832 D-phenylalanine Natural products 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- RRONHWAVOYADJL-OAHLLOKOSA-N (2r)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-OAHLLOKOSA-N 0.000 claims 2
- 238000004904 shortening Methods 0.000 claims 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 abstract description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract 1
- 210000004899 c-terminal region Anatomy 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- OHUXOEXBXPZKPT-STQMWFEESA-N Phe-His Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)C1=CC=CC=C1 OHUXOEXBXPZKPT-STQMWFEESA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VEEIFXWJNCAVEQ-FYZOBXCZSA-N methyl (2r)-2-amino-3-(1h-imidazol-5-yl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CC1=CNC=N1 VEEIFXWJNCAVEQ-FYZOBXCZSA-N 0.000 description 2
- VEEIFXWJNCAVEQ-RGMNGODLSA-N methyl (2s)-2-amino-3-(1h-imidazol-5-yl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CNC=N1 VEEIFXWJNCAVEQ-RGMNGODLSA-N 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- XWKAVQKJQBISOL-SSDOTTSWSA-N (2r)-2-anilinopropanoic acid Chemical compound OC(=O)[C@@H](C)NC1=CC=CC=C1 XWKAVQKJQBISOL-SSDOTTSWSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000003519 ventilatory effect Effects 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Peptides Or Proteins (AREA)
Abstract
Phenylalanine is protected by N-terminal benzyloxycarbonyl under the condition of solid alkali, histidine is protected by C-terminal methyl esterification, peptide grafting is activated by a phosgene method, catalytic hydrogenation is carried out to remove protective groups, cyclization is carried out for several steps to form cyclic (D-phenylalanine-D-group) dipeptide, the traditional liquid alkali is replaced by the solid alkali, the commonly used phosphorus oxychloride is replaced by phosgene, the pollution and the consumption are reduced, and the efficiency is improved.
Description
Technical field
The present invention relates to the preparation method of a kind of ring (D-phenylpropyl alcohol-D-group) dipeptides.
Background technology
Optical active cyanalcohol has a wide range of applications in the synthesis of optically active agricultural chemicals, but also synthesis of optically active medicine simultaneously can be used for synthetic β-adrenergic blocking agent as it.Two of cyanalcohol functional groups Be Controlled and be transformed into alpha hydroxy acid at an easy rate in addition, alpha-hydroxy esters, a series of optically active isomers such as alpha-alcohol ketone and beta-hydroxy amine, they all be important agricultural chemicals and medicine intermediate [woods Guoqiang work. chirality is synthetic---asymmetric reaction and application thereof. Beijing: Science Press, first version, 2000:1～34].Therefore, the cyanalcohol isomer of preparation enantiomer-pure in theory still all has great importance in practice.Chiral catalyst commonly used mainly contains following several [Zhu Ying, Yang Lirong, Zhu Ziqiang. the optical active cyanalcohol progress. organic chemistry, 1999,19 (5): 468-474]: enzyme, chiral metal complex compound, chirality ring dipeptides, chirality glycolylurea and optical activity alkaloid.When wherein making catalyzer, be that productive rate or efficient are all better with chirality ring dipeptides.
The synthetic method of chirality ring (phenylpropyl alcohol-group) dipeptides mainly contains mixed anhydride method and active ester method according to the literature.The child makes a leapleap forward, and [child makes a leapleap forward; Ding Mengxian; with the asymmetric synthesis of the catalytic fragrant cyanalcohol of Cyclo (L-Phe-L-His), applied chemistry, 1990; 7 (1): 464-470] etc. with the L-phenylalanine; the L-Histidine is a raw material, and (through N end carbobenzoxy-(Cbz), the esterification of C end is protected with active ester method; connecing peptide with the isobutyl chlorocarbonate activation gets) through synthetic Cyclo (L-Phe-L-His) of three steps, overall yield is 65%.[Stoutamire DonaldW such as Stoutamire Donald W; Tieman Charles H; Dong Walter Cyclo (D-phenylal anyl-D-histidine) EP0451927] with the D-phenylalanine; the D-Histidine is a raw material, through N end carbobenzoxy-(Cbz), and C end esterification protection; connect peptide with nitro phenyl ester method and get Cyclo (D-Phe-D-His), productive rate is 60%.English Patent [GB2143823] report is with the R-phenylalanine, and the R-Histidine is a raw material, and through N end carbobenzoxy-(Cbz), C end esterification protection connects peptide with DCC and gets Cyclo (R-Phe-R-His), and productive rate is 62%.In this several method, method one isobutyl chlorocarbonate is difficult for preparation, costs an arm and a leg, and wants-25 ℃ low temperature; Method two need use phosphorus oxychloride, and the waste environmental pollution is very big; The DCC that uses in method three is relatively more expensive, and uses acetonitrile to make solvent, and three kinds of methods all use the liquid base three waste discharge to be difficult to control.Several method in sum all has cost higher, and the shortcoming that environmental pollution is bigger is unfavorable for industrialization.
Summary of the invention
The objective of the invention is to avoid weak point in the above-mentioned prior art and the N end carbobenzoxy-(Cbz) protection under the solid alkali condition of a kind of phenylalanine is provided; Histidine C end esterification protection; the phosgenation activation connects peptide, and catalytic hydrogenation deprotection base becomes synthetic ring of several steps of ring (D-phenylpropyl alcohol-D-group) dipeptides.
Product of the present invention is ring (D-phenylpropyl alcohol-D-group) dipeptides, and molecular formula is:
Ring (D-phenylpropyl alcohol-D-group) dipeptides can be used as the catalyzer of synthesis of chiral cyanalcohol.
Preparation method of the present invention is as follows:
The technology according to the present invention; the preparation of compound ring (D-phenylpropyl alcohol-D-group) dipeptides needs to finish by the reaction of five steps; the first step: esterification (protection carboxyl) takes place with alcohol in the D-Histidine under the catalysis of sulfur oxychloride (or hydrogenchloride); alcohol commonly used is methyl alcohol, ethanol, benzylalcohol, obtains D-Histidine ester.Second step: the D-phenylalanine is at organic solvent (methyl alcohol; ethanol; ether) in; solid alkali (sodium hydroxide; sodium bicarbonate; yellow soda ash) under the catalysis; amino with the chloroformic acid benzyl ester protection; obtain N-carbobenzoxy-D-phenylalanine-(Z-D-Phe); the 3rd step: with phosgene and p-NP the Z-D-Phe activation is obtained N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester again, the 4th step: intermediate N carbobenzoxy-D-phenylalanine-p-nitrophenyl ester and D-Histidine ester carry out condensation reaction and obtain N-carbobenzoxy-D-phenylalanine-D-Histidine methyl esters (Z-D-Phe-D-His-OMe).The 5th step: Z-D-Phe-D-His-OMe promptly gets products C yclo (D-Phe-D-His) white solid ((R)-3-benzyl-(R)-6-(4-imidazoles methyl)-2,5-piperazinedione) [DDCPH] with its deprotection base, cyclisation in methyl alcohol.mp＝243-245℃，
(C＝0.2CH
3OH)。
Its synthetic route is as follows:
The new process of production of ring of the present invention (D-phenylpropyl alcohol-D-group) dipeptides has the following advantages:
1, replaces liquid base, replaces phosphorus oxychloride with solid alkali among the present invention, reduce and pollute and consumption, improved efficient with phosgene.
2, productive rate of present method and rotary light yield are all higher, and overall yield can reach 65% (with D-Histidine note), product
(C=0.2CH
3OH).
3, become route simple, raw material is easy to get, and cost is low, is suitable for suitability for industrialized production.
Can more be expressly understood this invention with reference to following Example.These examples are for reaction process is described, but are not limited thereto.
Embodiment
Embodiment 1
Preparation Histidine methyl ester hydrochloride
Amino acid 20mmol, methyl alcohol 50ml drops into thermometer is housed, and in the there-necked flask of agitator, frozen water is as cold as 0 ℃, and at the sulfur oxychloride 5ml (0.04mol) that 0-5 ℃ of dropping heavily steamed, amino acid dissolves gradually.Approximately 30-45min dropwises, and removes ice bath, and normal temperature continues reaction 10h, and reaction finishes the back decompression and sloughs methyl alcohol and sulfur oxychloride, adds fresh methyl alcohol, and methyl alcohol is sloughed in decompression again, repeatedly for several times fully to remove sulfur oxychloride.Product uses an amount of anhydrous diethyl ether washing, weighs, and calculated yield, reaction result sees Table 1.
Table 1 SOCl
2Catalytic reaction condition is to the influence of productive rate
N-carbobenzoxy-D-phenylalanine-(Z-D-Phe) synthetic
In 100ml methyl alcohol D-Phe 15g, NaHCO
310g adds chloroformic acid benzyl ester 17g in batches, and stirring reaction 1h is transferred to pH=4 with the HCl of 6mol/L, filter, washing, vacuum-drying gets white solid, and it is dissolved in anhydrous diethyl ether, the HCl of 2mol/L washes, washing, anhydrous sodium sulfate drying, remove desolvate colorless oil.
Synthesizing of N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester
There-necked flask at 300mL adds Z-D-Phe 27g successively, 200ml pyridine, 13g p-NP, frozen water is as cold as below 10 ℃, feeds the 15g phosgene again, 5 ℃ of reaction 2h, be warmed up to then 30 ℃ the reaction 1h, with reaction solution pour in the 400mL cold water, stir, filter solid.Through washing, hexanaphthene washes, after the vacuum-drying with the white crystal of dehydrated alcohol recrystallization.mp＝122-124℃.
Synthesizing of N-carbobenzoxy-D-phenylalanine-D-Histidine methyl esters (Z-D-Phe-D-His-OMe)
Add D-HisOMe2HCl 5g successively at there-necked flask, 100ml chloroform, triethylamine 5g; 8g N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester; stirring reaction 3h, reactant is washed with 30ml * 2, and 30% ammoniacal liquor 30ml * 2 are washed; combining water layer is used the 30ml chloroform extraction again; merge organic layer, organic layer is removed most of solvent with an amount of anhydrous sodium sulfate drying, decompression; get white solid through silica gel column chromatography, mp=114-116 ℃.
Synthetic Cyclo (D-Phe-D-His)
Get Z-D-Phe-D-His-OMe 2.5g in the 100ml anhydrous methanol, add 0.5g Pd/C, normal temperature and pressure hydrogenation 10h changes reflux heating reflux reaction 72h again into, the elimination catalyzer, most of methyl alcohol is removed in decompression, adds anhydrous diethyl ether 300ml ,-5 ℃ of refrigeration 3h, filter, washing, vacuum-drying get white solid Cyclo (D-Phe-D-His) ((R)-3-benzyl-(R)-6-(4-imidazoles methyl)-2,5-piperazinedione) [DDCPH].mp＝243-245℃，
(C＝0.2 CH
3OH)。
Table 2 takes off the selection of benzyl and cyclisation conditions
| Sequence number | Reactant (g) | Methyl alcohol (ml) | Take off the benzyl time | Take off the benzyl temperature | The cyclisation time | Productive rate |
| 1 | 2.5 | 50 | 7h | 15℃ | 24h | 70％ |
| 2 | 2.5 | 80 | 7h | 35℃ | 48h | Do not have |
| 3 | 2.5 | 80 | 10h | 15℃ | 70h | 90％ |
| 4 | 2.5 | 80 | 12h | 15℃ | 70h | 85％ |
| 5 | 2.5 | 80 | 12h | 15℃ | 72h | 88％ |
Embodiment 2
Preparation Histidine methyl ester hydrochloride
Amino acid 0.02mol after methyl alcohol 100ml, frozen water are cooled to 0 ℃, under agitation feeds HCl gas, about ventilatory response 1h, removes ice bath, and normal temperature continues to react 6h again, and after reaction finished, decompression removed solvent repeatedly.Product uses an amount of anhydrous diethyl ether washing, drying, and yield is 92%.
Table 3 HCl catalytic reaction condition is to the influence of productive rate
N-carbobenzoxy-D-phenylalanine-(Z-D-Phe) synthetic
In 100ml ethanol D-Phe 15g, NaOH 2g, add chloroformic acid benzyl ester 17g, stirring reaction 30min in batches, add NaOH 2g, restir reaction 40min is transferred to pH=4 with the HCl of 6mol/L, filter, washing, vacuum-drying gets white solid, it is dissolved in anhydrous diethyl ether, the HCl of 2mol/L washes, washing, anhydrous sodium sulfate drying, remove desolvate colorless oil, yield is 90%.
Synthesizing of N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester
There-necked flask at 300ml adds Z-D-Phe 27g successively, 200ml pyridine, 13g p-NP, frozen water is as cold as below 10 ℃, feeds the 20g phosgene again, 5 ℃ of reaction 2h, be warmed up to then 30 ℃ the reaction 1h, with reaction solution pour in the 800ml cold water, stir, filter solid.Wash, use dehydrated alcohol recrystallization final vacuum exsiccant white crystal through washing, hexanaphthene, yield is 95%.
Synthesizing of N-carbobenzoxy-D-phenylalanine-D-Histidine methyl esters (Z-D-Phe-D-His-OMe)
Add D-HisOMe2HCl 5g successively at there-necked flask, 100ml methylene dichloride, triethylamine 5g; 8g N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester; stirring reaction 3h, reactant is washed with 30ml * 2, and 30% ammoniacal liquor 30ml * 2 are washed; combining water layer is used the 30ml chloroform extraction again; merge organic layer, organic layer is removed most of solvent with an amount of anhydrous sodium sulfate drying, decompression; get white solid through silica gel column chromatography, yield is 89%.
Synthetic Cyclo (D-Phe-D-His)
Get Z-D-Phe-D-His-OMe 2.5g in the 100ml anhydrous methanol, add 1g Pd/C, normal temperature and pressure hydrogenation 10h changes reflux heating reflux reaction 72h again into, the elimination catalyzer, most of methyl alcohol is removed in decompression, adds anhydrous diethyl ether 300ml ,-5 ℃ of refrigeration 3h, filter, washing, vacuum-drying get white solid Cyclo (D-Phe-D-His) ((R)-3-benzyl-(R)-6-(4-imidazoles methyl)-2,5-piperazinedione).mp＝243-245℃，
(C＝0.2CH
3OH)。Yield is 82%, and total recovery is 62.4%.
The reaction conditions of embodiment 3～embodiment 8 and the results are shown in Table 4.
Table 4: reaction conditions is to the influence of product yield
| Sequence number | Solvent | Solid alkali (the amount g of adding) | The amount (g) of logical phosgene | Total recovery (%) |
| 3 | Methyl alcohol | NaCO 3(13) | 15 | 60 |
| 4 | Ethanol | NaHCO 3(10) | 20 | 62 |
| 5 | Benzylalcohol | NaOH(4) | 15 | 50 |
| 6 | Methyl alcohol | NaHCO 3(10) | 20 | 65 |
| 7 | Ethanol | NaCO 3(13) | 15 | 57 |
| 8 | Benzylalcohol | NaOH(4) | 20 | 55 |
Claims (2)
1, the preparation method of a kind of ring (D-Phe-D-His) dipeptides comprises the steps:
The first step: esterification takes place with alcohol in the D-Histidine under the catalysis of sulfur oxychloride or hydrogenchloride, obtain D-Histidine ester;
Second step: the D-phenylalanine obtains N-carbobenzoxy-D-phenylalanine with the chloroformic acid benzyl ester reaction in organic solvent and under the catalyzed by solid base;
The 3rd step: with phosgene and p-NP N-carbobenzoxy-D-phenylalanine activation is obtained N-carbobenzoxy-D-phenylalanine-p-nitrophenyl ester again;
The 4th step: intermediate N carbobenzoxy-D-phenylalanine-p-nitrophenyl ester and D-Histidine ester carry out condensation reaction and obtain N-carbobenzoxy-D-phenylalanine-D-Histidine methyl esters; With
The 5th step: N-carbobenzoxy-D-phenylalanine-D-Histidine methyl esters with its in methyl alcohol with Pd/C shortening deprotection base, cyclisation promptly gets product white solid (R)-3-benzyl-(R)-6-(4-imidazoles methyl)-2,5-piperazinedione again.
2, the preparation method of ring according to claim 1 (D-Phe-D-His) dipeptides, the organic solvent described in second one step preparation method is methyl alcohol, ethanol or ether; And solid alkali is sodium hydroxide, sodium bicarbonate or yellow soda ash.
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