Select Region or Location
Americas
  • Argentina
  • Brazil
  • Canada
  • Mexico
  • United States
  • Other Americas
Europe
  • Austria
  • Belgium
  • Bulgaria
  • Croatia/Hrvatska
  • Cyprus
  • Czech Republic
  • Denmark
  • Estonia
  • Finland
  • France
  • Germany
  • Greece
  • Hungary
  • Ireland
  • Italy
  • Latvia
  • Liechtenstein
  • Lithuania
  • Luxembourg
  • Malta
  • Netherlands
  • Norway
  • Poland
  • Portugal
  • Romania
  • Slovak Republic
  • Slovenia
  • Spain
  • Sweden
  • Switzerland
  • Turkey
  • United Kingdom
  • Other Europe
Asia Pacific
  • Australia
  • China
  • India
  • Indonesia
  • Japan
  • Korea, Republic of
  • Malaysia
  • New Zealand
  • Philippines
  • Singapore
  • Thailand
  • Vietnam
  • Other Asia Pacific
Africa And Middle East
  • Egypt
  • Israel
  • Other Africa And Middle East
USD
Home Cart Sign in  
Chemical Structure| 170908-81-3 Chemical Structure| 170908-81-3

Structure of DOTA-NHS-ester
CAS No.: 170908-81-3

Chemical Structure| 170908-81-3

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

,{[proInfo.pro_purity]}

4.5 *For Research Use Only! Not for Human Use. We Do Not Sell to Patients.

{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size Price VIP Price

DE Stock

US Stock

Asia Stock

Global Stock

In Stock
{[ item.pr_size ]}{[ size_append_text(item.pr_size, proInfo.prAm, 'list') ]} Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

  • {[ item.pr_size ]}
    {[ size_append_text(item.pr_size, proInfo.prAm, 'list') ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

  • 1-2 Day Shipping
  • High Quality
  • Technical Support
Product Citations

Alternative Products

Product Details of [ 170908-81-3 ]

CAS No. :170908-81-3
Formula : C20H31N5O10
M.W : 501.49
SMILES Code : O=C(ON1C(CCC1=O)=O)CN2CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC2
English Name :2,2',2''-(10-(2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid
MDL No. :MFCD23381190
InChI Key :XSVWFLQICKPQAA-UHFFFAOYSA-N
Pubchem ID :11488945

Safety of [ 170908-81-3 ]

Application In Synthesis of [ 170908-81-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 170908-81-3 ]

[ 170908-81-3 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 819869-77-7 ]
  • [ 170908-81-3 ]
YieldReaction ConditionsOperation in experiment
92% With trifluoroacetic acid In dichloromethane at 20℃; for 5h;
92% With trifluoroacetic acid In dichloromethane at 20℃; for 6h; Inert atmosphere; 8 Example 8- Synthesis of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid Example 8- Synthesis of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid Compound tri-tert-butyl 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate(400 mg, 0.6 mmol) was dissolved in 9 ml of CH2Cl2:TFA (1:2). This solution was stirred at room temperature for about 6 h. After removing the solvent, the residue was dissolved in 1 mL hot methanol. Diethyl ether (20 mL) was added and the final white solid product 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (276 mg, 92%) was obtained. Rf : 0.0 (CH2Cl2/MeOH, 1:1). 1H NMR (300MHz, CD3OD) δ 4.09 (br, 6H, H8, H13), 3.54 (br, 2H, H1'), 3.32-3.12 (m, 12H, H2, H3, H5), 3.12-2.98 (m, 4H, H6), 2.84 (s, H4'). 13C NMR (75MHz, CD3OD) δ 175.4 (C9, C14), 173.8 (C2'), 171.5 (C3'), 55.8-55.6 (C8, C13, C1'), 55.7-54.1 (C2, C3), 53.8-52.3 (C5, C6), 25.6 (C4'). MS (IC/NH3) : m/z 502 [M+H]+.
92% With trifluoroacetic acid In dichloromethane at 20℃; for 6h; 8 Synthesis of 2,2,,2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid Compound tri-tert-butyl 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (400 mg, 0.6 mmol) was dissolved in 9 ml of CH2Cl2:TFA (1:2). This solution was stirred at room temperature for about 6 h. After removing the solvent, the residue was dissolved in 1 ml hot methanol. Diethyl ether (20 ml) was added and the final white solid product 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (276 mg, 92%) was obtained. Rf : 0.0 (CH2Cl2/MeOH, 1:1). 1H NMR (300MHz, CD3OD) δ 4.09 (br, 6H, H8, H13), 3.54 (br, 2H, H1'), 3.32-3.12 (m, 12H, H2, H3, H5), 3.12-2.98 (m, 4H, H6), 2.84 (s, H4'). 13C NMR (75MHz, CD3OD) δ 175.4 (C9, C14), 173.8 (C2'), 171.5 (C3'), 55.8-55.6 (C8, C13, C1'), 55.7-54.1 (C2, C3), 53.8-52.3 (C5, C6), 25.6 (C4'). MS (IC/NH3) : m/z 502 [M+H]+.
90% With trifluoroacetic acid In dichloromethane at 20℃; for 12h; II II. Preparation of the Carboxylated Active Ester: DOTA mono-NHS II. Preparation of the Carboxylated Active Ester: DOTA mono-NHS [00068] The starting active ester was DOTA tris-tertiary butylester mono-NHS prepared as described above. About 13 gm of DOTA tris-tertiary butylester mono-NHS was dissolved or suspended in about 40 ml of dichloromethane in a round bottom flask. To this mixture was added 60 ml of trifluoroacetic acid (99% purity) and the reactive was allowed to proceed at room temperature with stirring for about 12 hours or longer. [00069] After this period, the dichloromethane and trifluoroacetic acid were both removed via rotary vacuum evaporation. The remaining material was then washed two times with 100 ml aliquots of anhydrous diethyl ether. After each wash, the diethylether was decanted leaving a white solid. After the final wash, the white solid was dried under a vacuum for about 5 hours. Based on the weight of the dried white solid, the isolated yields for this process are least about 50 mole percent, and more typically, between about 60 to 70 mole percent, and up to about 80 mole percent. Moreover, the isolated yield of the DOTA mono-NHS from the DOTA tris-tertiary butylester mono-NHS was at least about 90 percent and preferably greater than 95 mole percent and more preferably greater than about 99 mole percent.
80.14 % With trifluoroacetic acid In dichloromethane at 35℃;
With trifluoroacetic acid In dichloromethane at 25℃; 1.13 Step 13: Into a 50-mL round-bottom flask, was placed a mixture of tri-tert-butyl 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetate (5.0 g, 1 Eq, 7.5 mmol) and DCM (20 mL), to which was added TFA (10 mL). The reaction mixture was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure. The crude product was precipitated using diethyl ether to provide 2,2',2''-(10- (2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid (4.0 g, 6.8 mmol, 85 % purity, 91% yield) as a white solid. Calc’d for C20H31N5O10: 501.21, found [M+H]+: 502.4.
With trifluoroacetic acid In dichloromethane at 25℃; 1.13 Step 13: Into a 50-mL round-bottom flask, was placed a mixture of tri-tert-butyl 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetate (5.0 g, 1 Eq, 7.5 mmol) and DCM (20 mL), to which was added TFA (10 mL). The reaction mixture was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure. The crude product was precipitated using diethyl ether to provide 2,2',2''-(10- (2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid (4.0 g, 6.8 mmol, 85 % purity, 91% yield) as a white solid. Calc’d for C20H31N5O10: 501.21, found [M+H]+: 502.4.
8.8 g With trifluoroacetic acid In dichloromethane at 25℃; for 16h; To a mixture of compound G-3 (11.7 g, 1 eq, 17.5 mmol) and DCM (250 mL) in a 1 L flask was added TFA (500 mL). The reaction mixture was stirred at 25 °C for 16 hours and concentrated under reduced pressure. The crude product was triturated with 200 mL of ether, and the resulting mixture was stirred for 0.5 hour at room temperature. The mixture was filtered, and the filter cake was washed with ether (20 mL) and dried to afford G-4 (8.8 g, 16 mmol) as a white solid. [M + H]+=502.4.

  • 2
  • [ 2581199-35-9 ]
  • [ 170908-81-3 ]
  • [ 2581741-18-4 ]
YieldReaction ConditionsOperation in experiment
77.4% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide 8a Example 8a): Synthesis of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]- OH (3BP-3554) To the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (19.5 mg, 18 pmol, 3BP-4089 - described in Example 7a) in 300 m DMSO, 5 m DIPEA were added to adjust the pH value to approximately 7.5 - 8. Then 20.5 mg of DOTA-NHS (27 pmol, 1.5 eq compared to the peptide intermediate) in 200 pi DMSO were added. During the course of the LC/TOF- MS monitored reaction 5 pi DIPEA was added 3 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification (15 to 45% B in 30 min - Kinetex) to yield 20.44 mg of the pure title compound (77.4 % yield). HPLC: Rt = 5.9 min. LC/TOF-MS: exact mass 1469.640 (calculated 1469.639). C67H99N13O18S3 (MW = 1470.780).
20.44 mg With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide 2.2a Example 2a: Synthesis by two alternative cyclization methods in solution Both cyclization methods perform similarly and achieve comparable yields and similar purities. To the solution of the intermediate Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (in this example obtained by cyclization method B) in 300 pi DMSO, 5 pi DIPEA were added to adjust the pH value to approximately 7.5 - 8. Then 20.5 mg of DOTA-NHS (27 pmol, 1.5 eq compared to the peptide intermediate) in 20( were added. During the course of the LC/TOF-MS monitored reaction 5 pi DIPEA were added 3 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification * I .' so 45' 1 30 min - Kinetex) to yield 20.44 mg of the pure title compound (27.8% overall yield). HPLC: Rt = 5.9 min. LC/TOF-MS: exact mass 1469.640 (calculated 1469.639). C67H99N13O18S3 (MW = 1470.780).
77.4 % With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide 8a Example 8a): Synthesis of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]- OH (3BP-3554) To the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (19.5 mg, 18 pmol, 3BP-4089 - described in Example 7a) in 300 m DMSO, 5 m DIPEA were added to adjust the pH value to approximately 7.5 - 8. Then 20.5 mg of DOTA-NHS (27 pmol, 1.5 eq compared to the peptide intermediate) in 200 pi DMSO were added. During the course of the LC/TOF- MS monitored reaction 5 pi DIPEA was added 3 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification (15 to 45% B in 30 min - Kinetex) to yield 20.44 mg of the pure title compound (77.4 % yield). HPLC: Rt = 5.9 min. LC/TOF-MS: exact mass 1469.640 (calculated 1469.639). C67H99N13O18S3 (MW = 1470.780).
  • 3
  • [ 108-30-5 ]
  • [ 210830-03-8 ]
  • [ 2413365-27-0 ]
  • [ 2797110-66-6 ]
  • [ CAS Unavailable ]
  • [ 170908-81-3 ]
  • [ 2797110-53-1 ]
YieldReaction ConditionsOperation in experiment
16% Stage #1: (5S,10S,14S)-10,14-bis(tert-butoxycarbonyl)-5-hexyl-2,2-dimethyl-4,7,12-trioxo-3-oxa-6,11,13-triazaheptadecan-17-oic acid; C15H23N2O4Pol With 2,4,6-trimethyl-pyridine; 1-hydroxy-7-aza-benzotriazole; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 23.5h; Stage #2: With hydrazine In N,N-dimethyl-formamide for 0.333333h; Stage #3: succinic acid anhydride; Fmoc-D-Dap(Dde)-OH; Fmoc-D-Lys-OtBu*HCl; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimidyl ester); silicon-based fluoride acceptor-benzoic acid Further stages; L-Glu(L-2-Aoc-OtBu)-OtBu-(carbonyl)-L-Glu[D-Orn(Dde)-2-CT]-OtBu (S-24) According to GP2, fragment (35.5 mg, 56.4 µmol, 1.00 eq.) was coupled to resin-bound H-D-Orn(Dde) (18) (81.2 µmol 1.44 eq.), with TBTU (36.2 mg, 0.11 mmol, 2.00 eq.) and HOAt (15.0 mg, 0.11 mmol, 2.00 eq.) as coupling reagents and sym-collidine (67.7 µL, 0.51 mmol, 9.00 eq.) as base. After shaking for 23.5 h at room temperature, formation of product could be confirmed (GP7), as only one major peak with the expected m/z-ratio of 908.4 occurred. Chemical formula: C46H77N5O13; Molecular weight: 908.14 g/mol; Exact mass: 907.55 g/mol; tR-value: 12.7 min (40 - 95% B in 15 min, Method A) Capacity factor k: 7.5 ESI-MS: calculated monoisotopic mass (C46H77N5O13): 907.55; found: ESI (positive ion mode): m/z = 454.8 [M(S-24)+2H]2+, 908.4 [M(S-24)+H]+. Proinhibitor II (6) Further reactions on resin-bound compound were performed according to standard Fmoc-SPPS on 2-CT resin, applying the above-mentioned methods (GP2 - GP8). In brief, the Dde protective group was removed (GP4) and succinic anhydride (56.7 mg, 0.57 mmol, 7.00 eq.) was coupled (GP2) over a period of at least 2.5 h, only using DIPEA (96.4 µL, 0.57 mmol, 7.00 eq.) and no further coupling reagents. The peptide was elongated with Fmoc-D-Lys-OtBu*HCl (74.7 mg, 0.16 mmol, 2.00 eq.). Therefore, the resin-bound acid was preactivated for five minutes using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and DIPEA (82.7 µL, 0.49 mmol, 6.00 eq.). The amino acid was dissolved in DMF, added to the preactivated resin and shaken for at least 2.5 h. Fmoc-removal was conducted (GP3) and Fmoc-D-Dap(Dde)-OH (79.5 mg, 0.16 mmol, 2.00 eq.) was coupled for at least 2.5 h using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. Afterwards, Dde-removal was performed according to GP5. The SiFA-BA moiety (12.0 mg, 42.5 µmol, 0.53 eq.) was attached using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. After an incubation time of at least 2 h, the Fmoc protective group was removed (GP3) and the DOTA chelator moiety was added to the resin. Therefore, DOTA-NHS (67.8 mg, 89.6 µmol, 1.10eq.) and DIPEA (118 µL, 8.52 mmol, 7.00 eq.) were each dissolved in DMF. First, DIPEA in DMF was added to the resin for preactivation. After five minutes, DOTA-NHS in DMF was added and incubated with the resin-bound amine for 23.2 h. An adequate conversion (RP-HPLC/MS analysis after GP6) was achieved and the peptide was cleaved off the resin with TFA/TIPS/DCM (95/2.5/2.5, GP8) and purified afterwards by preparative RP-HPLC (40 - 70% C(A) in 20 min). Subsequent lyophilization afforded 20.0 mg (16.0% yield, chemical purity >99%) of pure product as a colorless powder. Chemical formula: C68H110FN13O24Si; Molecular weight: 1540.78 g/mol; Exact mass: 1539.75 g/mol; tR-value: 9.44 min (10 - 90% B in 15 min, Method A) Capacity factor k: 5.5 ESI-MS: calculated monoisotopic mass (C68H110FN13O24Si): 1539.75; found: ESI (positive ion mode): m/z = 770.5 [M(6)+2H]2+, 1539.9 [M(6)+H]+, 1924.9 [M5(6)+4H]4+.
16% Stage #1: (5S,10S,14S)-10,14-bis(tert-butoxycarbonyl)-5-hexyl-2,2-dimethyl-4,7,12-trioxo-3-oxa-6,11,13-triazaheptadecan-17-oic acid; C15H23N2O4Pol With 2,4,6-trimethyl-pyridine; 1-hydroxy-7-aza-benzotriazole; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 23.5h; Stage #2: With hydrazine In N,N-dimethyl-formamide for 0.333333h; Stage #3: succinic acid anhydride; Fmoc-D-Dap(Dde)-OH; Fmoc-D-Lys-OtBu*HCl; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimidyl ester); silicon-based fluoride acceptor-benzoic acid Further stages; L-Glu(L-2-Aoc-OtBu)-OtBu-(carbonyl)-L-Glu[D-Orn(Dde)-2-CT]-OtBu (S-24) According to GP2, fragment (35.5 mg, 56.4 µmol, 1.00 eq.) was coupled to resin-bound H-D-Orn(Dde) (18) (81.2 µmol 1.44 eq.), with TBTU (36.2 mg, 0.11 mmol, 2.00 eq.) and HOAt (15.0 mg, 0.11 mmol, 2.00 eq.) as coupling reagents and sym-collidine (67.7 µL, 0.51 mmol, 9.00 eq.) as base. After shaking for 23.5 h at room temperature, formation of product could be confirmed (GP7), as only one major peak with the expected m/z-ratio of 908.4 occurred. Chemical formula: C46H77N5O13; Molecular weight: 908.14 g/mol; Exact mass: 907.55 g/mol; tR-value: 12.7 min (40 - 95% B in 15 min, Method A) Capacity factor k: 7.5 ESI-MS: calculated monoisotopic mass (C46H77N5O13): 907.55; found: ESI (positive ion mode): m/z = 454.8 [M(S-24)+2H]2+, 908.4 [M(S-24)+H]+. Proinhibitor II (6) Further reactions on resin-bound compound were performed according to standard Fmoc-SPPS on 2-CT resin, applying the above-mentioned methods (GP2 - GP8). In brief, the Dde protective group was removed (GP4) and succinic anhydride (56.7 mg, 0.57 mmol, 7.00 eq.) was coupled (GP2) over a period of at least 2.5 h, only using DIPEA (96.4 µL, 0.57 mmol, 7.00 eq.) and no further coupling reagents. The peptide was elongated with Fmoc-D-Lys-OtBu*HCl (74.7 mg, 0.16 mmol, 2.00 eq.). Therefore, the resin-bound acid was preactivated for five minutes using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and DIPEA (82.7 µL, 0.49 mmol, 6.00 eq.). The amino acid was dissolved in DMF, added to the preactivated resin and shaken for at least 2.5 h. Fmoc-removal was conducted (GP3) and Fmoc-D-Dap(Dde)-OH (79.5 mg, 0.16 mmol, 2.00 eq.) was coupled for at least 2.5 h using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. Afterwards, Dde-removal was performed according to GP5. The SiFA-BA moiety (12.0 mg, 42.5 µmol, 0.53 eq.) was attached using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. After an incubation time of at least 2 h, the Fmoc protective group was removed (GP3) and the DOTA chelator moiety was added to the resin. Therefore, DOTA-NHS (67.8 mg, 89.6 µmol, 1.10eq.) and DIPEA (118 µL, 8.52 mmol, 7.00 eq.) were each dissolved in DMF. First, DIPEA in DMF was added to the resin for preactivation. After five minutes, DOTA-NHS in DMF was added and incubated with the resin-bound amine for 23.2 h. An adequate conversion (RP-HPLC/MS analysis after GP6) was achieved and the peptide was cleaved off the resin with TFA/TIPS/DCM (95/2.5/2.5, GP8) and purified afterwards by preparative RP-HPLC (40 - 70% C(A) in 20 min). Subsequent lyophilization afforded 20.0 mg (16.0% yield, chemical purity >99%) of pure product as a colorless powder. Chemical formula: C68H110FN13O24Si; Molecular weight: 1540.78 g/mol; Exact mass: 1539.75 g/mol; tR-value: 9.44 min (10 - 90% B in 15 min, Method A) Capacity factor k: 5.5 ESI-MS: calculated monoisotopic mass (C68H110FN13O24Si): 1539.75; found: ESI (positive ion mode): m/z = 770.5 [M(6)+2H]2+, 1539.9 [M(6)+H]+, 1924.9 [M5(6)+4H]4+.
16% Stage #1: (5S,10S,14S)-10,14-bis(tert-butoxycarbonyl)-5-hexyl-2,2-dimethyl-4,7,12-trioxo-3-oxa-6,11,13-triazaheptadecan-17-oic acid; C15H23N2O4Pol With 2,4,6-trimethyl-pyridine; 1-hydroxy-7-aza-benzotriazole; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 23.5h; Stage #2: With hydrazine In N,N-dimethyl-formamide for 0.333333h; Stage #3: succinic acid anhydride; Fmoc-D-Dap(Dde)-OH; Fmoc-D-Lys-OtBu*HCl; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimidyl ester); silicon-based fluoride acceptor-benzoic acid Further stages; L-Glu(L-2-Aoc-OtBu)-OtBu-(carbonyl)-L-Glu[D-Orn(Dde)-2-CT]-OtBu (S-24) According to GP2, fragment (35.5 mg, 56.4 µmol, 1.00 eq.) was coupled to resin-bound H-D-Orn(Dde) (18) (81.2 µmol 1.44 eq.), with TBTU (36.2 mg, 0.11 mmol, 2.00 eq.) and HOAt (15.0 mg, 0.11 mmol, 2.00 eq.) as coupling reagents and sym-collidine (67.7 µL, 0.51 mmol, 9.00 eq.) as base. After shaking for 23.5 h at room temperature, formation of product could be confirmed (GP7), as only one major peak with the expected m/z-ratio of 908.4 occurred. Chemical formula: C46H77N5O13; Molecular weight: 908.14 g/mol; Exact mass: 907.55 g/mol; tR-value: 12.7 min (40 - 95% B in 15 min, Method A) Capacity factor k: 7.5 ESI-MS: calculated monoisotopic mass (C46H77N5O13): 907.55; found: ESI (positive ion mode): m/z = 454.8 [M(S-24)+2H]2+, 908.4 [M(S-24)+H]+. Proinhibitor II (6) Further reactions on resin-bound compound were performed according to standard Fmoc-SPPS on 2-CT resin, applying the above-mentioned methods (GP2 - GP8). In brief, the Dde protective group was removed (GP4) and succinic anhydride (56.7 mg, 0.57 mmol, 7.00 eq.) was coupled (GP2) over a period of at least 2.5 h, only using DIPEA (96.4 µL, 0.57 mmol, 7.00 eq.) and no further coupling reagents. The peptide was elongated with Fmoc-D-Lys-OtBu*HCl (74.7 mg, 0.16 mmol, 2.00 eq.). Therefore, the resin-bound acid was preactivated for five minutes using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and DIPEA (82.7 µL, 0.49 mmol, 6.00 eq.). The amino acid was dissolved in DMF, added to the preactivated resin and shaken for at least 2.5 h. Fmoc-removal was conducted (GP3) and Fmoc-D-Dap(Dde)-OH (79.5 mg, 0.16 mmol, 2.00 eq.) was coupled for at least 2.5 h using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. Afterwards, Dde-removal was performed according to GP5. The SiFA-BA moiety (12.0 mg, 42.5 µmol, 0.53 eq.) was attached using TBTU (52.0 mg, 0.16 mmol, 2.00 eq.), HOAt (22.0 mg, 0.16 mmol, 2.00 eq.) and sym-collidine (75.2 µL, 0.57 mmol, 7.00 eq.) as coupling reagents. After an incubation time of at least 2 h, the Fmoc protective group was removed (GP3) and the DOTA chelator moiety was added to the resin. Therefore, DOTA-NHS (67.8 mg, 89.6 µmol, 1.10eq.) and DIPEA (118 µL, 8.52 mmol, 7.00 eq.) were each dissolved in DMF. First, DIPEA in DMF was added to the resin for preactivation. After five minutes, DOTA-NHS in DMF was added and incubated with the resin-bound amine for 23.2 h. An adequate conversion (RP-HPLC/MS analysis after GP6) was achieved and the peptide was cleaved off the resin with TFA/TIPS/DCM (95/2.5/2.5, GP8) and purified afterwards by preparative RP-HPLC (40 - 70% C(A) in 20 min). Subsequent lyophilization afforded 20.0 mg (16.0% yield, chemical purity >99%) of pure product as a colorless powder. Chemical formula: C68H110FN13O24Si; Molecular weight: 1540.78 g/mol; Exact mass: 1539.75 g/mol; tR-value: 9.44 min (10 - 90% B in 15 min, Method A) Capacity factor k: 5.5 ESI-MS: calculated monoisotopic mass (C68H110FN13O24Si): 1539.75; found: ESI (positive ion mode): m/z = 770.5 [M(6)+2H]2+, 1539.9 [M(6)+H]+, 1924.9 [M5(6)+4H]4+.
  • 4
  • [ 216961-61-4 ]
  • [ 170908-81-3 ]
  • [ 2866181-80-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dimethyl sulfoxide at 20℃; for 24h; 3 N-Boc-1,10-diaminodecane and DOTA-NHS were dissolved in DMSO at a ratio of 1:1 to 1:3, 1 to 3 equivalents of triethylamine was added, reacted at room temperature for 24 hours, and precipitated. obtaining the target intermediate E01;
  • 5
  • [ 60-23-1 ]
  • [ 170908-81-3 ]
  • [ 865470-67-3 ]
YieldReaction ConditionsOperation in experiment
71 % With triethylamine In N,N-dimethyl-formamide at 20℃; General procedure for the synthesis of the DOTA derivatives (7, 8, 9, 10 and 12) General procedure: To a solution of DOTA-NHS-ester (6; 100 mg, 0.13 mmol, 1 equiv.) and the corresponding amine (0.20 mmol, 1.5 equiv.) in DMF (1 mL), triethylamine (91 µL, 0.66 mmol, 5 equiv.) was added and the mixture was stirred at rt for 16 h. Then, the solvent was evaporated and the residue was purified by preparative HPLC.1,4,7,10-Tetraazacyclododecane-1,4,7-tris(acetic acid)-10-[3-oxo-3-(5-azadibenzocyclootyne)acetamide] (7, DOTA-DBCO). DBCO-amine (54 mg) was subjected to the general procedure above to give 49 mg of product 7, as a white solid (60%).
  • 6
  • [ 2310135-18-1 ]
  • [ 170908-81-3 ]
  • [ 3098665-00-7 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dimethyl sulfoxide 1.4 4) Synthesis of compound D-PMED Compound 4 (2 mg, 5 μmol) and DOTA-NHS (4 mg, 5 μmol) are dissolved in 200 μL of DMSO, and 15 μL of triethylamine is added for overnight reaction, and the crude product is separated by HPLC.
  • 7
  • [ 2883407-81-4 ]
  • [ 170908-81-3 ]
  • [ 2374782-04-2 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(methyl(3-(piperazin-1-yl)propyl)amino)quinoline-4-carboxamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimidyl ester) In N,N-dimethyl-formamide at 20℃; for 8h;
22 mg Stage #1: (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(methyl(3-(piperazin-1-yl)propyl)amino)quinoline-4-carboxamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(N-hydroxysuccinimidyl ester) In N,N-dimethyl-formamide at 20℃; for 8h; 20 (S)-2,2',2"-((10-(2-(4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)propyl)piperazin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid DIPEA (58 μL, 0.33 mmol) was added to a solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(methyl(3-(piperazin-1-yl)propyl)amino)quinoline-4-carboxamide (0.033 mmol) in anhydrous N,N-dimethylformamide (3 mL). After stirring at room temperature for 20 min, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS Ester) (17 mg, 0.033 mmol) was added and stirring at room temperature was continued for 8 h. The product was then separated by HPLC and lyophilized to obtain 22 mg of the title compound with a purity of 99% and a yield of 74%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
 

Historical Records

Categories