Iris
Substrates for Life Sciences From Grams to Multi-Ton Lots
B i o t e c h G m bH
New: Preloaded Resins for Synthesis of Peptide Amides Used for efficient and economic synthesis of bulk peptide APIs The Technology:
The Advantages:
Side chain attachment of amino acids and peptides on highly acid sensitive resins. ÎÎ NO amide linker is involved and therefore no linker typical side reactions and contamination thereof. ÎÎ Protected peptide acids & amides can be obtained in high yield and purity, because cleavage from the resins can be carried out in the presence of TFA sensitive protecting groups of the t-butyl type. ÎÎ Any intermediate can be cleaved as protected peptide fragment, enabling a very easy in process control through HPLC. ÎÎ This is especially useful during the optimization of any large scale synthesis!
This concept can be extended to any peptide acid&amide with side chain functions. References: ff K. Barlos et al. WO 2013/098802 A2. ff K. Barlos, D. Gatos et al., Int. J. Peptide and Protein Res. 1991; 38: 555-561. ff K. Barlos and D. Gatos, in Fmoc solid phase peptide synthesis, edit. W.C. Chan and P. D. White, Oxford University Press, 2000. ff Attachment of Histidine, Histamine and Urocanic acid to Resins of the Trityl-Type. Eleftheriou, S.; Gatos, D.; Panagopoulos, A.; Stathopoulos, S.; Barlos, K.; Tetrahedron Letters 1999; 40(14): 2825- 2828. ff G. Sabatino et al. Tetrahedron Letters 1999; 40: 809-812. ff E. Atherton et al. US 7,691,968 B2.
3763 / 0314
ff F. Albericio et al. WO 2008/040536 A1.
Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech
Easy Process Development of the synthesis of Bivalirudin (CBL!!!) Bivalirudine can be synthesized in bulk quantities in high purity and yield with fragment condensation techniques: a) As first step fragment (11-20) will be synthesized by standard SPPS Fmoc/tBu technology on the resin, starting with Tyr19–Leu20-OtBu immobilized through the side chain of Tyr19 to the highly acid sensitive 2-chlorotrity resin. b)
The N-terminal Boc and side chain protected fragment (1-10) will be synthesized also via standard solid phase technology on acid sensitive resin, for example on 2-chlorotrityl resins or 4-methoxybenzhydryl resin.
Sequence of Bivalirudin: D-Phe1-Pro2-Arg3-Pro4-Gly5-Gly6-Gly7-Gly8-Asn9-Gly10-Asp11-Phe12-Glu13-Glu14-Ile15-Pro16-Glu17-Glu18-Tyr19-Leu20 c)
In a last step the two fragments will be coupled with DIC/HOBt in NMP. When a ratio of 1:1 of both fragments is being applied a significant part has not been reacted to the complete sequence. This easily can be determined by taking out a sample of the reactor, applying cleavage with low concentration of TFA in DCM and injection into HPLC (pic #1). Adding additional 25% of fragment (1-10) and appropriate reaction time yields complete coupling (pic #2). Boc-(1-20)-OtBu Protected bivalirudin
Not reacted H-(11-20)-OtBu
RP8-HPLC-analysis of the product obtained after fragment condensation of 1.0 eq. of protected bivalirudin 1-10 with side chain attached bivalirudin 11-20 for 24 h at RT.
Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
RP8-HPLC-analysis of the product obtained after the addition of excess 0.25 eq. of protected bivalirudin 1-10 and additional 24 h coupling. Column 150X4mm, 5 Îź, 100 A, Detection at 214 nm, flow rate 1 ml/min, 50%B to 100%B in 30 min (A = 0,1% TFA in water, B = 0,1% TFA in AcN).
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech
Already available: Article No.
RAA2610
Fmoc-L-Asp(2CT resin)-NH2
Fmoc-L-Aspartate alpha-amide-beta-(2-chlorotrityl resin) ester (100-200 mesh, ca. 0.5 mmol/g) O
€ 125,00
RAA2610.0025 5 g
€ 500,00
(S)
O
NH2 O
RAA2620
RAA2610.0005 5 g
Cl
O HN
Quantity Price
O
Fmoc-L-Cys(Mmt resin)-NH2
Fmoc-L-Cysteine alpha-amide-S-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g)
RAA2620.0005 5 g
€ 200,00
RAA2620.0025 25 g
€ 800,00
RAA2700.0005 5 g
€ 250,00
RAA2700.0025 25 g
€ 1000,00
RAA2630.0005 5 g
€ 125,00
RAA2630.0025 25 g
€ 500,00
RAA2640.0005 5 g
€ 200,00
RAA2640.0025 25 g
€ 800,00
RAA2650.0005 5 g
€ 200,00
RAA2650.0025 25 g
€ 800,00
RAA2660.0025 25 g
€ 800,00
RAA2660.0005 5 g
€ 200,00
OMe
S HN
(R)
O
NH2 O
RAA2700
O
H-L-Glu(2CT resin)-OtBu
L-Glutamate alpha-t-butyl ester-gamma-(2-chlorotrityl resin) ester (100-200 mesh, ca. 0.5 mmol/g) O
Cl
O
H2N
(S)
O O
RAA2630
Fmoc-L-Glu(2CT resin)-NH2
Fmoc-L-Glutamate alpha-amide-gamma-(2-chlorotrityl resin) ester (100-200 mesh, ca. 0.5 mmol/g) O
Cl
O
HN
(S)
O
NH2 O
RAA2640
O
Fmoc-L-His(Mmt resin)-NH2
Fmoc-L-Histidine alpha-amide-Nim-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g)
OMe
N N HN
(S)
O
O O
RAA2650
O
Fmoc-L-Lys(Mmt resin)-NH2
Fmoc-L-Lysine alpha-amide-N-epsilon-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g)
OMe
NH
HN
(S)
O
NH2 O
RAA2660
O
Fmoc-L-Lys(Mmt resin)-O-Trt
Fmoc-L-Lysine alpha-trityl ester-N-epsilon-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g)
OMe
NH
HN
(S)
O
O O
Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
O
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech Article No.
RAA2670
Fmoc-L-Ser(2CT resin)-NH2
Fmoc-L-Serine alpha-amide-O-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g) O HN
€ 125,00
RAA2670.0025 25 g
€ 500,00
RAA2680.0025 25 g
€ 500,00
RAA2680.0005 5 g
€ 125,00
RAA2690.0005 5 g
€ 125,00
RAA2690.0025 25 g
€ 500,00
Cl
NH2 O
Fmoc-L-Thr(MeO-BH resin)-NH2
RAA2670.0005 5 g
(S)
O
RAA2680
Quantity Price
O
MeO
Fmoc-L-Threonine alpha-amide-O-(4-methoxytrityl resin) (100-200 mesh, ca. 0.5 mmol/g)
O (R)
HN
(S)
O
NH2 O
RAA2690
O
Fmoc-L-Tyr(2CT resin)-NH2
Fmoc-L-Tyrosine alpha-amide-O-(2-chlorotrityl resin) (100-200 mesh, ca. 0.5 mmol/g) O
Cl
HN
(S)
O
NH2 O
O
Article No.
CAA1002 Fmoc-L-Asp(Wang-Resin)-OAll N-alpha-(9-Fluorenylmethyloxycarbonyl)-L-Asp(Wang-Resin)-OAll (100-200 mesh, 0.15-0.5 mmol/g)
O
H N
O
O
(S)
O
O
O
Quantity Price
CAA1002.0001 1 g
€ 225,00
CAA1002.0005 5 g
€ 600,00
CAA1002.0025 25 g
€ 2200,00
O
CAA1000 Fmoc-L-Asn(Rink-Resin)-OAll
please inquire!
O
9-Fluorenylmethyloxycarbonyl-L-Asn(AM-Rink-Resin)-OAll (100-200 mesh, 0.15-0.5 mmol/g)
O
NH
O
O
O
(S)
HN O
N H O
MeO
Me OMe
CAA1004 Fmoc-L-Glu(Wang-Resin)-OAll Fmoc-L-Glu(Wang-Resin)-OAll (100-200 mesh, 0.15-0.5 mmol/g)
H N
O
O O
(S)
CAA1004.0001 1 g
€ 325,00
CAA1004.0005 5 g
€ 600,00
O
O
O O
CAA1008 Fmoc-L-Lys(Trt-Resin)-OAll Fmoc-L-Lys(Trityl-Resin)-OAll (100-200 mesh, 0.15-0.5 mmol/g)
H N
O
please inquire!
O (S)
O
O
HN
More products of this type in preparation. Any product of this type can be supplied on custom synthesis basis. Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech
Examples for commercial applications: Fmoc-Tyr(MeO-BH Resin)-Leu-OtBu
Fmoc-Threoninol(MeO-BH Resin)-OTrt
OMe
OMe
O
H N
(S)
HN O
(R)
O (S)
O
HN
O
O
O
O
(R)
O
O
Bivalirudin
Octreotid
D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH
H-D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-ol
Fmoc-Tyr(CT Resin)-Pro-OtBu
Fmoc-Ser(CT Resin)-NH2
O
Cl
O O HN
(S)
O
HN
N O
O O
(S)
O
(R)
NH2 O
O
Cl
O
Cosyntropin, or ACTH 1-24, or tetracosactide hexaacetate
Exenatide
Brand names: Cortrosyn, Cosyntropin, Synacthen Indication: Diagnosis of adrenocortical insufficiency
Indication: Glycemic control in patients with type 2 diabetes mellitus
Brand name: Byetta
H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-LysVal-Tyr-Pro-OH
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-ArgLeu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
Fmoc-Tyr(CT Resin)-NH2
Fmoc-Orn(CT resin)-NH2
HN
O HN
(S)
O
HN
NH2 O
Cl
Cl (S)
O
O
NH2 O
O
Pramlintide
Sermorelin or GRF 1-29
Brand name: Symlin
Indication: Growth hormone deficiency, diagnosis evaluation of pituitary
Indication: Type 1 and type 2 diabetes
H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-LysLeu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2
H-Lys-cyclo[Cys-Asn-Thr-Ala-Thr-Cys]-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-SerSer-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH2, acetate
More products of this type in preparation. Any product of this type can be supplied on custom synthesis basis. Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech
Ornithine as Arginine Analogue R
R
H N
O
H N
O
N H
O
N H
O
NH
MeO
NH HN
O
N
N
N
R/H
N
O NH
O
R/H
O
Article No.
RL-1052 Pyrazol(Boc)2
O N
N
N,N‘-Bis-(t-butyloxycarbonyl)-1-guanylpyrazole, N,N‘-Di-Boc-1H-pyrazole1-carboxamidine
N
O NH
O
Quantity Price
RL-1052.0005 5 g
€ 95,00
RL-1052.0025 25 g
€ 280,00
RL-1052.0100 100 g
€ 850,00
RL-1162.0005
5g
€ 125,00
RL-1162.0025
25 g
€ 400,00
RL-1162.0100
100 g
€ 1200,00
O
RL-1162 Pyrazol(Z)2
O
N,N-Bisbenzyloxycarbonyl-1-guanylpyrazole, N,N‘-Di-Cbz-1H-pyrazole-1-carboxamidine
N
N N
O NH
O O
The synthesis of peptides with contain one or several Arginines often develops difficulties during synthesis as the standard guanidine protecting group Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) requires long cleavage time. The difficulties are even larger the more arginines are present in the sequence. An elegant way to circumvent these difficulties is using Ornithine at the place of Arginine and transfer the amino group into a guanidine group by appropriate guanylating reagents. A series of differently protected ornithines is available from standard Boc protection to highly acid sensitive group, like Mtt and several Fmoc/tBu strategy orthogonal groups like Alloc, Dde, ivDde and Cbz. Article No.
FAA1730 Fmoc-L-Orn(2-Cl-Z)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-(2-chlorobenzyloxycarbonyl)-L-ornithine
O
H N
O
O N H
H N
(S)
OH O N H
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Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
FAA1730.0025 25 g
€ 800,00
FAA1417.0005 5 g
€ 85,00
FAA1417.0025 25 g
€ 280,00
FAA1417.0100 100 g
€ 850,00
Cl
O
O
Internet: www.iris-biotech.de Email: info@iris-biotech.de
€ 200,00
O
FAA1417 Fmoc-L-Orn(Aloc)-OH O
FAA1730.0005 5 g OH
(S)
O
N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-allyloxycarbonyl-L-ornithine
Quantity Price
O
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany
Iris
Biotech Article No.
FAA1155 Fmoc-L-Orn(Boc)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-t-butyloxycarbonyl-Lornithine
O
H N
O
OH
(S)
O
O N H
O
H N
O
OH
(S)
FAA1155.0025 25 g
€ 120,00
FAA1155.0100 100 g
€ 340,00
FAA1155.0500 500 g
€ 1200,00
FAA1502.0001 1 g
€ 85,00
FAA1502.0005 5 g
€ 300,00
FAA1502.0025 25 g
€ 1200,00
FAA1623.0025 25 g
€ 230,00
FAA1623.0100 100 g
€ 600,00
FAA1503.0001 1 g
€ 120,00
FAA1503.0005 5 g
€ 480,00
FAA1503.0025 25 g
€ 1900,00
FAA1165.0005 5 g
€ 150,00
FAA1165.0025 25 g
€ 600,00
FAA1165.0100 100 g
€ 1850,00
FAA6880.0001 1 g
€ 160,00
FAA6880.0005 5 g
€ 600,00
FAA6880.0025 25 g
€ 2400,00
FAA1779.0001 1 g
€ 150,00
FAA1779.0005 5 g
€ 500,00
FAA1779.0025 25 g
€ 2000,00
FAA1731.0005 5 g
€ 90,00
FAA1731.0025 25 g
€ 250,00
FAA1731.0100 100 g
€ 750,00
O
FAA1502 Fmoc-L-Orn(Dde)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl]-L-ornithine
Quantity Price
O
O
N H O
FAA1623 Fmoc-L-Orn(Fmoc)-OH N-alpha-N-delta-Bis(9-fluorenylmethyloxycarbonyl)-L-ornithine
O
H N
O
OH
(S)
O
NH O
FAA1503 Fmoc-L-Orn(ivDde)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl]-L-ornithine
O
H N
O
O
OH
(S)
O O NH
O
FAA1165
Fmoc-L-Orn(Mtt)-OH (solv.)
N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-methyltrityl-L-ornithine (solvate with 5-8 % MTBE)
O
H N
O
Me OH
(S)
O
N H
FAA6880 Fmoc-L-Orn(N3)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-δ-azido-L-ornithine, N-alpha-(9Fluorenylmethyloxycarbonyl)-delta-azido-L-norvaline, (S)-2-(9-Fluorenylmethyloxycarbonylamino)-5-azidopentanoic acid
O
H N
O
OH
(S)
O
N
N+
N-
FAA1779 Fmoc-L-Orn(Palm)-OH
O
H N
O
N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-palmitoyl-L-ornithine
(S)
OH
O
NH O
FAA1731 Fmoc-L-Orn(Z)-OH N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-delta-benzyloxycarbonyl-Lornithine
H N
O
O (S)
OH
O
O N H
Internet: www.iris-biotech.de Email: info@iris-biotech.de
Tel.: +49-9231-9619-73 Fax: +49-9231-9619-99
Belgium Office: Tel.: +32 56 31 52 00 Fax: +32 56 31 15 00
O
Iris Biotech GmbH Waldershofer Str. 49-51 D-95615 Marktredwitz, Germany