CN1254484C - Solid-phase synthesis process of octreotide acetate - Google Patents
Solid-phase synthesis process of octreotide acetate Download PDFInfo
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- CN1254484C CN1254484C CN 200410010833 CN200410010833A CN1254484C CN 1254484 C CN1254484 C CN 1254484C CN 200410010833 CN200410010833 CN 200410010833 CN 200410010833 A CN200410010833 A CN 200410010833A CN 1254484 C CN1254484 C CN 1254484C
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- Prior art keywords
- sostatin
- octapeptide
- resin
- phase synthesis
- solid phase
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- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 14
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 title abstract description 8
- 108010016076 Octreotide Proteins 0.000 title abstract description 8
- 229960001494 octreotide acetate Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 229920005989 resin Polymers 0.000 claims abstract description 22
- 239000011347 resin Substances 0.000 claims abstract description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960000583 acetic acid Drugs 0.000 claims abstract description 10
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 9
- 229920002521 macromolecule Polymers 0.000 claims abstract description 5
- 125000000539 amino acid group Chemical group 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 5
- DYNFCHNNOHNJFG-UHFFFAOYSA-N 2-formylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C=O DYNFCHNNOHNJFG-UHFFFAOYSA-N 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- -1 carboxyl benzene acetal Chemical class 0.000 claims description 3
- 239000008176 lyophilized powder Substances 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 16
- 239000000047 product Substances 0.000 abstract description 12
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 5
- 229920001184 polypeptide Polymers 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 229960002700 octreotide Drugs 0.000 abstract 3
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000013329 compounding Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 239000007790 solid phase Substances 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- YOKDHMTZJSRRIQ-KZULUSFZSA-N 9h-fluoren-9-ylmethyl n-[(2r,3r)-1,3-dihydroxybutan-2-yl]carbamate Chemical compound C1=CC=C2C(COC(=O)N[C@H](CO)[C@H](O)C)C3=CC=CC=C3C2=C1 YOKDHMTZJSRRIQ-KZULUSFZSA-N 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000002699 waste material Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- ADOHASQZJSJZBT-AREMUKBSSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical group C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-AREMUKBSSA-N 0.000 description 2
- SJVFAHZPLIXNDH-JOCHJYFZSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical group C([C@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-JOCHJYFZSA-N 0.000 description 2
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 2
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 2
- OYULCCKKLJPNPU-DIFFPNOSSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-hydroxybutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](O)C)C(O)=O)C3=CC=CC=C3C2=C1 OYULCCKKLJPNPU-DIFFPNOSSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 206010033647 Pancreatitis acute Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 239000006035 Tryptophane Substances 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 201000003229 acute pancreatitis Diseases 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229960003742 phenol Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229920003002 synthetic resin Polymers 0.000 description 2
- 239000000057 synthetic resin Substances 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical group C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- GQYAUZAWKROOLF-IPIKRLCPSA-N (2s)-2-amino-4-methylsulfanylbutanoic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical compound CSCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 GQYAUZAWKROOLF-IPIKRLCPSA-N 0.000 description 1
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 1
- 206010051012 Gastric varices Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 1
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- 206010066901 Treatment failure Diseases 0.000 description 1
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- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 208000019425 cirrhosis of liver Diseases 0.000 description 1
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- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
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- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a solid-phase synthesis method of octreotide acetate, which belongs to the technical field of polypeptide synthesis. The solid-phase synthesis method of octreotide acetate comprises: firstly, an acetalation product and macro molecule resin are bonded; an ontained product after bonding is orderly bonded and deprotected with BOC-ASN-OH to obtain octapeptide resin; octapeptide is cut off from resin to prepare a water solution, and after naturally oxidized in air, the water solution is prepared into octreotide; after glacial acetic acid is added in the water solution of the octreotide, the water solution of the octreotide is frozen to be dry to prepare octreotide acetate. The present invention has the advantages of simple synthesis technology, easy operation, short technology time, small reaction compounding ratio, raw material saving, cost reduction, enhancement of yield and purity, few side reactions and by products and convenient purification, and is beneficial to mass production.
Description
Technical field
The present invention relates to the synthetic field of a peptide species, especially a kind of solid phase synthesis process of Sostatin LAR.
Background technology
The structure of Sostatin LAR is one to contain the polypeptide of 7 amino-acid residues and 1 Soviet Union ammonia alcohol.The main clinical application of Sostatin LAR (Octreotide Acetate) is in following treatment of diseases: the hemorrhage emergency treatment of esophagus-gastric varices due to the liver cirrhosis, share with special treatment (as endoscopic sclerosis agent treatment), peptide ulceration and answer the acromegalic of acute ulcer, acute pancreatitis, acute pancreatitis, prevention pancreas post-operative complication, underwent operative, radiotherapy or dopamine-receptor stimulant treatment failure, may command symptom, the concentration of tethelin and somatomedin C of reducing.Also be applicable to and can not or be reluctant the acromegalic that performs the operation, and radiotherapy patient of unenforced intermittent phase still.
In the synthetic patent documentation of nearest Sostatin LAR and analogue thereof, mainly adopt liquid-phase synthesis process.2002 disclosed Chinese invention patent on June 26, (CN1355173A) be exactly the liquid-phase synthesis process of Sostatin LAR; its fragment is divided into N-end tripeptides and N-end pentapeptide; the protection strategy is BOC (tertbutyloxycarbonyl)/BZL (benzyl) strategy, and it connects the peptide method and mainly adopts the HOBt-DCC method.
Comprehensive reference is both at home and abroad about the synthetic method characteristics of Sostatin, the exploration of our system the solid phase Sostatin synthetic method of relevant report and domestic literature about the Sostatin liquid-phase synthesis process, the method that draws in the technology exists some shortcomings, mainly show as: 1. the synthetic middle preparation time of liquid phase is long, each the step product needed be further purified, and in last commentaries on classics salt process consuming time and the waste organic solvent.2.Boc-HF deprotection system response condition is violent, and HF has the severe corrosive contaminate environment.
Summary of the invention
The technical problem to be solved in the present invention provides that a kind of synthesis technique is simple, reaction conditions is gentle, the reaction times is short, proportioning is little, cost is low, productive rate is high, equipment is simple, be convenient to operate, environmental pollution is little, be of value to the synthetic method of production in enormous quantities, and this method has overcome the deficiency in the existing preparation Sostatin LAR technology.
The solid phase synthesis process step of Sostatin LAR is as follows among the present invention:
With handle compound F 17-hydroxy-corticosterone moc-Thr-ol become with resin-bonded as shown in the formula:
With itself and protection amino acid deformity reaction successively in order, connect the back and generate band protection octapeptide resin
With the TFA solution reaction, deprotection obtains the straight chain octapeptide then
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol
The gained octapeptide is made behind the aqueous solution through atmospheric oxidation, obtained Sostatin.
The Sostatin aqueous solution is added an amount of Glacial acetic acid, obtain Sostatin LAR, the gained Sostatin LAR through lyophilize, is made Sostatin LAR dry powder.
The solid phase synthesis process summary of Sostatin LAR of the present invention is that process comprises: synthetic octapeptide; Octapeptide is made the aqueous solution in air, make Sostatin behind the natural oxidation; The Sostatin LAR lyophilized powder is made in freeze-drying behind the adding Glacial acetic acid in the Sostatin aqueous solution.The process of said synthetic octapeptide is: fluorenylmethyloxycarbonyl is revived amine alcohol with reaction generates fluorenylmethyloxycarbonyl Soviet Union amine alcohol to carboxyl benzene acetal to carboxyl benzaldehyde; it is bonded on the macromolecule resin carrier; obtain the octapeptide resin behind the bonding successively with the protection amino-acid residue in order then, octapeptide is cut from resin.
Said resin is the macromolecule resin carrier, can be amino AM resin (Rink Amide-AMResin) or amino mbha resin (Rink Amide-MBHA Resin).
The abbreviation of Shi Yonging in the present invention has following implication:
Phe: phenylalanine
Cys: halfcystine
Trp: tryptophane
Lys: Methionin
DCM: methylene dichloride
DMF:N, dinethylformamide
DCC: dicyclohexylcarbodiimide
HOBt:1-hydroxybenzene a pair of horses going side by side triazole
Boc: tertbutyloxycarbonyl
Fmoc: fluorenylmethyloxycarbonyl
Trt: trityl
TBu: the tertiary butyl
2-Cl-Z:2-benzyl chloride base
Acm: ethanamide methyl
HPO
3Bzl: metaphosphoric acid benzyl
Acetal: acetal
The NMP:N-methyl-2-pyrrolidone
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
TsOH: tosic acid
HBTU：O-(Benzotriazol-1-yl)-N，N，N，N-tetramethyl uroniumhexafluorophosphate
Lys: Methionin
Thr: Threonine
Fmoc-Thr-OH: fluorenylmethyloxycarbonyl Soviet Union amino acid
Fmoc-Thr-ol: fluorenylmethyloxycarbonyl Soviet Union amine alcohol
Fmoc-Thr-ol-Acetal: fluorenylmethyloxycarbonyl Soviet Union amine alcohol is to carboxyl benzene acetal
According to the present invention more particularly, the synthetic route among the Sostatin LAR preparation method of the present invention is as follows:
Preparation acetalation product: with Fmoc-Thr-ol, carboxyl benzaldehyde and tosic acid (mol ratio is 1: 1.0～2.0: 0.1～0.5) are dissolved in anhydrous chloroform, heating reflux reaction in oil bath, use the TLC monitoring reaction, after question response is complete the reaction solution concentrating under reduced pressure is removed solvent, obtain the handle compound.
Wherein Fmoc-Thr-ol can directly use, and also can make by synthetic.
The tosic acid that uses in the acetalation is a catalyzer.
Connect resin: aminoresin, acetalation product, DCC, HOBt (mol ratio is 1: 1.0～2.2: 1.0～2.2: 1.0～2.2) were dissolved among the NMP in solid phase reactor stirring reaction 60～90 minutes; washing then; take off protection, the abundant stirring reaction 6～10 hours of ventilating.
Adopt the DCC/HOBt method, speed of response is fast, productive rate is high, effective.
Progressively connect peptide in order; HOBt, HBTU are joined in the solid phase reactor successively with protection amino-acid residue (mol ratio is 1: 1.0～22: 1.0～2.2: 1.1～1.8) respectively, and different is: dipeptides protection amino-acid residue is Fmoc-Cys (Trt, Acm, OtBu, tBu); The used protection amino-acid residue of tripeptides is Fmoc-Thr (tBu, Trt, HPO
3Bzl)-OH; The used protection amino-acid residue of tetrapeptide is Fmoc-Lys (Boc, Ac, 2-Cl-Z)-0H; The used protection amino-acid residue of pentapeptide is Fmoc-D-Trp (Boc)-OH; The used protection amino-acid residue of six peptides is Fmoc-Phe-OH; The used protection amino-acid residue of seven peptides is Fmoc-Cys (Trt, Acm, OtBu, tBu)-OH; The used protection amino-acid residue of octapeptide is Fmoc-D-Phe-OH.
The protection amino acid here is the fluorenylmethyloxycarbonyl protection.
Cut peptide: in the solid phase reactor of finishing octapeptide synthetic resins is housed, add above-mentioned trifluoroacetic acid solution, fed the nitrogen room temperature reaction 2 hours, after the reaction solution Rotary Evaporators is concentrated, promptly can be made into octapeptide through behind the recrystallization.
The oxidation octapeptide: octapeptide is dissolved in the water, and concentration is made into 0.1～10mmoL/mL, regulates pH=7.0～7.5 with ammoniacal liquor, and magnetic stirrer stirring, room temperature reaction 24～72 hours can guarantee that sufficient reacting is complete.
Freeze-drying: add a certain amount of Glacial acetic acid in Sostatin solution, making the concentration of Glacial acetic acid in the Sostatin aqueous solution is 1～10%, passes through lyophilize then, makes the smelly bent peptide of acetic acid.
Compare with existing Sostatin LAR synthetic method, Sostatin LAR solid phase synthesis strategy has the following advantages among the present invention:
1) when acetalation product and resin-bonded, adopting DCC/HOBT is the catalyzing and condensing agent, and this method speed of reaction is fast, productive rate is high, side reaction is few.
2) in connecing the peptide process, adopt HOBt, HBTU to connect reactive polypeptide for the catalyzing and condensing agent, this method combination rate height, by product is few, the reaction times is short and reduce characteristics such as racemization, and this method reaches minimum protection strategy, can amplification quantity synthesize.
3) add in the solid phase synthesis of the present invention respectively to protect amino-acid residue mole proportioning be 1.0～1.8, economize in raw materials, and stable yield;
4) adopt the aqueous solution in the oxidising process, and concentration is 0.1～1mmol/ml, avoided like this liquid phase synthetic in volume excessive.
5) the commentaries on classics salt of Sostatin adopts in the method for dividing pure back directly to add Glacial acetic acid through HPLC, saves solvent like this and saves time.
Therefore we think that the new method for preparing Sostatin LAR of exploitation is necessary.
Embodiment
Below in conjunction with embodiment, the solid phase synthesis process of Sostatin LAR among the present invention is described further.
Embodiment 1:Fmoc-Thr-ol-Acetal's is synthetic
Fmoc-Thr-ol (3.28g) is added in the four-hole boiling flask, dissolve with anhydrous chloroform (200ml), adding is to carboxyl benzaldehyde 1.90g, and adding tosic acid 100mg, in 60 ℃ of heating in water bath back flow reaction, the TLC monitoring is after reacting completely then, concentrating under reduced pressure is removed solvent on Rotary Evaporators, obtains faint yellow dope.After the dope dilution, last silica gel column chromatography, use the developping solution methylene dichloride: ethyl acetate (3: 1), collect solution, get product 3.0g after the distillation.
Wherein Fmoc-Thr-ol can directly use, and also can make by following embodiment method:
Fmoc-Thr-OH (7.5g) joins among the 100ml THF and dissolves, and adds Vinyl chloroformate 3.1mL, NMM3.5mL then, and reacts 10min under 0 ℃, adds NaBH then
11.50g, in 0 ℃ of following stirring reaction 3h, add 1N HCl (230ml) behind the reaction 10min, extract secondary (each 150ml) with DCM then, merge organic phase, use anhydrous Na
2SO
4Drying, rotation are steamed and are desolventized, and recrystallization gets white powder 4.8g.
Synthesizing of embodiment 2 first peptides
1) acetalation product (3.4g), DCC (1.2g), HOBt (1.6g) are added NMP (30ml), induction stirring, room temperature reaction 1 hour down in ice bath.
2) resin (5.00g) is placed solid phase reactor, add methylene dichloride/dimethyl formamide=1/1 30ml solvent, and feed high pure nitrogen stirring 60 minutes.
3) reaction solution with the acetalation product joins in the solid phase reactor, aeration-agitation, room temperature reaction 16 hours.
Synthesizing of 3: the second peptides of embodiment
1) reaction soln is extruded by waste liquid outlet with gas, clean, in solid phase reactor, add methylene dichloride 30mL, diacetyl oxide 1.5mL pyridine 1.5mL then in the resin, stirred room temperature reaction 2 hours with methylene dichloride.
2) reaction soln is extruded by waste liquid outlet with gas, clean, add hexahydropyridine, each 15mL of dimethyl formamide then, room temperature reaction 1 hour with methylene dichloride.
3) reaction soln is extruded by waste liquid outlet with gas, clean with methylene dichloride, then Fmoc-Cys (Trt)-OH (4.34g), HOBt (1.10g), HBTU (3.10g) are joined in the solid phase reactor that the step reacting resin is housed, to wherein adding NMP (30ml), feed nitrogen simultaneously, ambient temperature overnight reaction 16 hours.
Synthesizing of 4: the three～octapeptides of embodiment:
Reactions steps is with embodiment 3, and different is:
The used protection amino-acid residue of tripeptides is Fmoc-Thr (tBu)-OH (2.94g).
The used protection amino-acid residue of tetrapeptide is Fmoc-Lys (Boc)-OH (3.47g).
The used protection amino-acid residue of pentapeptide is Fmoc-D-Trp (Boc)-OH (3.90g).
The used protection amino-acid residue of six peptides is Fmoc-Phe-OH (2.87g).
The used protection amino-acid residue of seven peptides is Fmoc-Cys (Trt)-OH (4.34g).
The used protection amino-acid residue of octapeptide is Fmoc-D-Phe-OH (2.87g).
Embodiment 5: the preparation of straight chain octapeptide
1) reaction soln extrudes by waste liquid outlet with gas, cleans with methylene dichloride, adds methylene dichloride 30mL, diacetyl oxide 1.5mL pyridine 1.5mL then in solid phase reactor in the resin, stirs room temperature reaction 2 hours.
2) reaction soln extrudes by waste liquid outlet with gas, cleans with methylene dichloride, adds hexahydropyridine, each 15mL of dimethyl formamide then, room temperature reaction 1 hour.
3) phenol (8.0g), thioanisole (6.0ml), dithioglycol (6.0ml), trifluoroacetic acid (70ml) join in the triangular flask, fully after the concussion, put into ice bath and preserve 1 hour.Then its adding is equipped with in the solid phase reactor of finishing octapeptide synthetic resins, feeds nitrogen, room temperature reaction 2 hours.Using gas extrudes reaction liquid.
4) after liquid concentrates with Rotary Evaporators, add ice ether (200ml), the adularescent precipitation produces, and filters collecting precipitation, and vacuum-drying is more than 10 hours.Collect dry back white precipitate (3.1 gram), be loaded in the Brown Glass Brown glass bottles and jars only to be enclosed within-20 ℃ of conditions and preserve.
Embodiment 6: the oxidation of Sostatin:
The embodiment 6 resulting reduced form Sostatins that contain impurity are dissolved in the water, make the final concentration of reduced form Sostatin reach 0.1～10mmol/ml, use 1M ammoniacal liquor to regulate pH=7.0～7.5, magnetic stirrer stirring, room temperature reaction 24～72 hours, whether complete with analysis mode HPLC monitoring oxidizing reaction.
Embodiment 7: the separation and purification of Sostatin
With the solution after the oxidation, use the 0.8um membrane filtration.
Mobile phase A: 0.1%TFA/ water
Mobile phase B: 0.1%TFA/65% acetonitrile/water
Flow velocity 20ml/min
The separation and purification gradient condition:
| Mobile phase A | Time opening min | Beginning concentration % | Concluding time min | Finish concentration % |
| Mobile phase A | 0.00 | 60 | 35 | 20 |
| Mobile phase A | 35 | 20 | 40 | 60 |
| Mobile phase A | 40 | 60 | 60 | 100 |
Collect principal product peak (retention time is about 18 minutes).
Embodiment 8: the preparation of Sostatin LAR
With the Sostatin product solution of collecting, use Rotary Evaporators to concentrate in 40 ℃.Remove acetonitrile, revolve and steam, obtain pure Sostatin solution to the absence of liquid outflow.After accurately measuring volume, add glacial acetic acid and make its concentration reach 1-10%, induction stirring 30 minutes is carried out freeze-drying.Obtain the acetate 1.13g of Sostatin, productive rate 33.3%.Total recovery: 23.44%.
Through identifying:
FAB-MS (M
++ H): 1019.8 (theoretical molecular is 1019.3)
Amino-acid sequence is analyzed: hold 7 amino-acid residues of C-end respectively to be from N-: Phe, Cys, Phe, Trp, Lys, Thr, Cys.
Amino acid composition is analyzed:
| Theoretical value | Actual value | |
| Phenylalanine Methionin Threonine tryptophane specific optical rotation: | 2(1.5～2.2) 1(0.4～1.1) 1(0.5～1.1) 1(0.4～1.1) -40°～50° | 1.59 0.98 0.69 0.61 -42.3° |
The method synthetic product is confirmed as Sostatin LAR by analysis thus.
Claims (4)
1. the solid phase synthesis process of a Sostatin LAR, process is: synthetic octapeptide; Octapeptide is made the aqueous solution in air, make Sostatin behind the natural oxidation; The Sostatin LAR lyophilized powder is made in freeze-drying behind the adding Glacial acetic acid in the Sostatin aqueous solution; It is characterized in that, the process of said synthetic octapeptide is: fluorenylmethyloxycarbonyl is revived amine alcohol with reaction generates fluorenylmethyloxycarbonyl Soviet Union amine alcohol to carboxyl benzene acetal to carboxyl benzaldehyde, it is bonded on the macromolecule resin carrier, obtain the octapeptide resin behind the bonding successively with the protection amino-acid residue in order then, octapeptide is cut from resin; Said macromolecule resin carrier is amino AM resin or amino mbha resin.
2. according to the solid phase synthesis process of the described Sostatin LAR of claim 1, it is characterized in that the catalyzer that uses in the acetalation is a tosic acid.
3. according to the solid phase synthesis process of claim 1 or 2 described Sostatin LARs, it is characterized in that making the octapeptide concentration of aqueous solution is 0.1～10mmoL/mL.
4. according to the solid phase synthesis process of claim 1 or 2 described Sostatin LARs, it is characterized in that make in the Sostatin LAR lyophilized powder process, the concentration of Glacial acetic acid in the Sostatin aqueous solution is 1～10%.
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| CN100335497C (en) * | 2005-03-21 | 2007-09-05 | 吉尔生化（上海）有限公司 | Process for solid phase synthesis of octreotide |
| WO2007114454A1 (en) * | 2006-03-29 | 2007-10-11 | Otsuka Chemical Co., Ltd. | Method for production of peptide thioester compound |
| CN101357936B (en) * | 2007-07-31 | 2013-07-03 | 崔颀 | Method for synthesizing triptorelin from solid phase polypeptide |
| CN101531699B (en) * | 2009-04-30 | 2012-02-15 | 昆明积大制药有限公司 | Polypeptide solid-state reaction method |
| WO2013132505A1 (en) | 2012-03-09 | 2013-09-12 | Natco Pharma Limited | Improved process for preparation of octreotide by solution phase peptide synthesis |
| CN102850438B (en) * | 2012-09-19 | 2014-11-05 | 上海昂博生物技术有限公司 | Solid phase preparation method of crude octrotide |
| CN103351426B (en) * | 2013-08-02 | 2018-11-02 | 上海苏豪逸明制药有限公司 | A kind of polypeptide synthesis method of octreotide acetate |
| CN103965291B (en) * | 2014-05-27 | 2016-09-21 | 上海第一生化药业有限公司 | Octreotide, the preparation method of octreotide acetate |
| CN106543269B (en) * | 2016-11-01 | 2020-06-02 | 苏州天马医药集团天吉生物制药有限公司 | Synthetic method for industrialized production of octreotide |
| CN111378009A (en) * | 2018-12-27 | 2020-07-07 | 江苏金斯瑞生物科技有限公司 | Preparation method of octreotide |
| CN112778400A (en) * | 2021-02-05 | 2021-05-11 | 合肥科生景肽生物科技有限公司 | Preparation method of octreotide |
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