[ CAS No. 204316-32-5 ] {[proInfo.proName]}

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2D 3D

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Quality Control of [ 204316-32-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 204316-32-5 ]

SDS Specification

Alternatived Products of [ 204316-32-5 ]

Product Details of [ 204316-32-5 ]

CAS No. :	204316-32-5	MDL No. :	MFCD00798634
Formula :	C₂₃H₂₄N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YIVBOSPUFNDYMF-FQEVSTJZSA-N
M.W :	424.45	Pubchem ID :	2756102
Synonyms :

Calculated chemistry of [ 204316-32-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	31
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.26
Num. rotatable bonds :	13
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	113.21
TPSA :	113.96 ?2

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.73
Log Po/w (XLOGP3) :	3.41
Log Po/w (WLOGP) :	3.28
Log Po/w (MLOGP) :	2.1
Log Po/w (SILICOS-IT) :	2.88
Consensus Log Po/w :	2.88

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.05
Solubility :	0.038 mg/ml ; 0.0000895 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.48
Solubility :	0.0014 mg/ml ; 0.00000329 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.83
Solubility :	0.000635 mg/ml ; 0.0000015 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.18

Safety of [ 204316-32-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 204316-32-5 ]

* 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.

Upstream synthesis route of [ 204316-32-5 ]
Downstream synthetic route of [ 204316-32-5 ]

[ 204316-32-5 ] Synthesis Path-Upstream 1~3

1
[ 918428-73-6 ]
[ 204316-32-5 ]

Reference： [1] Synthetic Communications, 2006, vol. 36, # 19, p. 2901 - 2912

2
[ 918428-66-7 ]
[ 204316-32-5 ]

Reference： [1] Synthetic Communications, 2006, vol. 36, # 19, p. 2901 - 2912

3
[ 159530-17-3 ]
[ 204316-32-5 ]

Reference： [1] Synthetic Communications, 2006, vol. 36, # 19, p. 2901 - 2912

[ 204316-32-5 ] Synthesis Path-Downstream 1~21

1
[ 35661-60-0 ]
DHP-Resin Fmoc-L-Thr-OAllyl [ No CAS ]
[ 86123-10-6 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₇₉H₁₁₄N₁₁O₂₁Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1068 - 1077

2
N-α-(9-fluorenylmethoxycaebonyl)-N-γ-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl]-L-2,4-diaminobutyric acid [ No CAS ]
[ 35661-60-0 ]
DHP-Resin Fmoc-L-Thr-OAllyl [ No CAS ]
[ 86123-10-6 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₈₇H₁₂₄N₁₁O₂₁Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1068 - 1077

3
N-α-(9-fluorenylmethoxycaebonyl)-N-γ-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl]-L-2,4-diaminobutyric acid [ No CAS ]
[ 35661-60-0 ]
DHP-Resin Fmoc-L-Thr-OAllyl [ No CAS ]
[ 86123-10-6 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₈₇H₁₂₄N₁₁O₂₁Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1068 - 1077

4
N-α-(9-fluorenylmethoxycaebonyl)-N-γ-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl]-L-2,4-diaminobutyric acid [ No CAS ]
[ 35661-60-0 ]
DHP-Resin Fmoc-L-Thr-OAllyl [ No CAS ]
[ 86123-10-6 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₈₇H₁₂₄N₁₁O₂₁Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1068 - 1077

5
[ 334-48-5 ]
[ 35661-60-0 ]
C₂₃H₂₇NO₅ [ No CAS ]
[ 35661-60-0 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₅₈H₁₀₈N₁₆O₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The linear peptide was assembled by SPPS using Fmoc/tBu protocol. 2-CTC resin of loading 1.6 mmol/g (0.8 g, 0.5 mmol) was pre-activated using 10percent SOCl2 in dry DCM(v/v) overnight. The resin was washed thoroughly using dry DCM and was placed in a 10 mL polypropylene syringe fitted with a polyethylene disc. To this was added Fmoc-Thr(tBu)-OH (198.73 mg, 1 equiv.) and DIEA (25 equiv.) and allowed to react for 1h. After coupling, the resin was washed with DCM/DMF/DCM (4x each) followed by MeOH (0.1 mL) in excess DCM to cap all the unwanted reactive points on the resin, followed by washing with DCM (2x). The Fmoc groups were removed using 20percent piperidine in DMF (v/v) twice (1 min and 10 min), washed with DCM/DMF. Couplings were achieved with Fmoc-amino acid: HBTU/COMU: DIEA (3 : 3 : 6 equiv.) using DMF (2 mL) as the solvent followed by thorough washings with DCM and DMF (10 mL, 4x each). After each coupling, the reaction was confirmed by the ninhydrin test and if positive, coupling was repeated. After the coupling of all the amino acids, decanoic acid (10 equiv., 43.07 mg) was attached to the peptide on-resin using DIC : HOBt (10 equiv. each; 38.7 muL/ 33.8 mg) in DMF (1 mL) and reacting overnight. A small quantity of the peptidyl-resin (5 mg) was cleaved using TFA (0.1 mL) to ensure the formation of the desired product. The product obtained after work-up was verified by MALDI-TOF-MS (Fig. S1). MALDI-TOF-MS: 1307.652 [M+Na]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1885 - 1888

6
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 334-48-5 ]
[ 35661-60-0 ]
C₂₃H₂₇NO₅ [ No CAS ]
[ 35661-60-0 ]
[ 125238-99-5 ]
[ 204316-32-5 ]
C₉₁H₁₆₃N₁₆O₂₆Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The linear peptide was assembled by SPPS using Fmoc/tBu protocol. 2-CTC resin of loading 1.6 mmol/g (0.8 g, 0.5 mmol) was pre-activated using 10percent SOCl2 in dry DCM(v/v) overnight. The resin was washed thoroughly using dry DCM and was placed in a 10 mL polypropylene syringe fitted with a polyethylene disc. To this was added Fmoc-Thr(tBu)-OH (198.73 mg, 1 equiv.) and DIEA (25 equiv.) and allowed to react for 1h. After coupling, the resin was washed with DCM/DMF/DCM (4x each) followed by MeOH (0.1 mL) in excess DCM to cap all the unwanted reactive points on the resin, followed by washing with DCM (2x). The Fmoc groups were removed using 20percent piperidine in DMF (v/v) twice (1 min and 10 min), washed with DCM/DMF. Couplings were achieved with Fmoc-amino acid: HBTU/COMU: DIEA (3 : 3 : 6 equiv.) using DMF (2 mL) as the solvent followed by thorough washings with DCM and DMF (10 mL, 4x each). After each coupling, the reaction was confirmed by the ninhydrin test and if positive, coupling was repeated. After the coupling of all the amino acids, decanoic acid (10 equiv., 43.07 mg) was attached to the peptide on-resin using DIC : HOBt (10 equiv. each; 38.7 muL/ 33.8 mg) in DMF (1 mL) and reacting overnight. A small quantity of the peptidyl-resin (5 mg) was cleaved using TFA (0.1 mL) to ensure the formation of the desired product. The product obtained after work-up was verified by MALDI-TOF-MS (Fig. S1). MALDI-TOF-MS: 1307.652 [M+Na]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1885 - 1888

7
[ 455-40-3 ]
[ 71989-31-6 ]
[ 103478-62-2 ]
[ 138775-22-1 ]
1-[(1,1-dimethylethoxy)carbonyl]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-tryptophan [ No CAS ]
[ 107-92-6 ]
[ 204316-32-5 ]
(2S)-1-[(2S)-2-[[(2S)-2-[butanoyl(methyl)amino]-3-(1H-indol-3-yl)propanoyl]methylamino]-4-methylpentanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methyl-pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). After that, Fmoc-N- methyl-L-leucine (Fmoc-NMeLeu-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). After that, Na- Fmoc-N(in)-Boc-N-methyl-L-tryptophan (Fmoc-NMe-L-Trp(Boc)-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). Butiric acid is coupled to the tryptophan moiety by adding to the resin 3 eq of the acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPli3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 14. The compound is purified using reverse-phase chromatography.

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 66-68

8
[ 6303-58-8 ]
[ 455-40-3 ]
[ 138775-22-1 ]
(2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid [ No CAS ]
[ 204316-32-5 ]
(2S)-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-4,4-difluoro-N-methyl-1-(4-phenoxybutanoyl)pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- 4,4-difluoro-L-Proline moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5 ', 1 x 10' and 1 x 15 ') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). 4-phenoxybutiric acid is coupled to the proline moiety by adding to the resin 3 eq of the acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 10. The compound is purified using reverse-phase chromatography.

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 57-59

9
[ 99-66-1 ]
[ 455-40-3 ]
[ 71989-31-6 ]
[ 138775-22-1 ]
[ 204316-32-5 ]
(2S)-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methyl-1-(2-propylpentanoyl)pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of the additive oxymaO pure and dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). After that, <strong>[138775-22-1]Fmoc-N-methyl-L-isoleucine</strong> (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5 ', 1 x 10' and 1 x 15'). After that, Fmoc-L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure aredissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5 :20:70) (1 x 5'). 2-propyl pentanoic acid is coupled to the proline moiety by adding to the resin 3 eq of the acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example8. The compound is purified using reverse-phase chromatography

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 53-55

10
[ 6303-58-8 ]
[ 455-40-3 ]
[ 71989-31-6 ]
[ 138775-22-1 ]
[ 204316-32-5 ]
(2S)-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methyl-1-(4-phenoxybutanoyl)pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-L-NMelle-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). 4-phenoxybutiric acid is coupled to the proline moiety by adding to the resin 3 eq of the acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 9. The compound is purified using reverse-phase chromatography

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 55-57

11
[ 455-40-3 ]
[ 71989-31-6 ]
[ 108-24-7 ]
[ 77128-73-5 ]
[ 138775-22-1 ]
[ 204316-32-5 ]
(2S)-1-[(2S)-2-[acetyl(methyl)amino]-3-phenylpropanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methyl-pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20percent piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure aredissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20percent piperidine in DMF (1 x 5 ', 1 x 10' and 1 x 15'). After that, <strong>[138775-22-1]Fmoc-N-methyl-L-isoleucine</strong> (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20percent piperidine in DMF (1 x 5 ', 1 x 10' and 1 x 15'). After that, Fmoc-L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20percent piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). After that, Fmoc-N-methyl-L-phenylalanine (Fmoc-NMe-L-Phe-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20percent piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the acetylation of the N-part terminal part of the peptide, 20 eq of acetic anhydride and 20 eq of DIE A are added to the resin. The mixture is allowed to react for 30 minutes and the extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5- difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 11. The compound is purified using reverse-phase chromatography

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 59-61

12
[ 455-40-3 ]
[ 35661-39-3 ]
[ 6214-20-6 ]
[ 71989-31-6 ]
[ 108-24-7 ]
[ 138775-22-1 ]
[ 204316-32-5 ]
(2S)-1-[(2S)-2-[acetyl(methyl)amino]propanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methyl-pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure aredissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). After that, Fmoc-N-L- alanine (Fmoc-L-Ala-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). The N-methylation of the amino group is achieved by treating the resin with 3 eq of 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5- ene and 4 eq of para-nitrobencensulfonate in DMF for 30 minutes (3 treatments). Between treatments the resin is washed thoroughly with DMF and DCM. After the N- methylation of the Ala amino group, the ortho-nitro benzene sulfonyl protecting group is removed by treating the resin with 10 eq of beta-mercaptoethanol and 5 eq of DBU (1 x 10' and 1 x 40'). The removal of the ortho-nitro benzene sulfonyl group is assessed using the chloranil test. For the acetylation of the N-part terminal part of the peptide, 20 eq of acetic anhydride and 20 eq of DIEA are added to the resin. The mixture is allowed to react for 30 minutes and the extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 12. The compound is purified using reverse-phase chromatography.

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 61-63

13
[ 455-40-3 ]
[ 6214-20-6 ]
[ 35737-10-1 ]
[ 71989-31-6 ]
[ 108-24-7 ]
[ 138775-22-1 ]
[ 204316-32-5 ]
(2S)-1-[3-[acetyl(methyl)amino]propanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methylpyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- L-Proline (Fmoc-L-Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). After that, Fmoc-beta- alanine (Fmoc-P-Ala-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). The N-methylation of the amino group is achieved by treating the resin with 3 eq of 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5- ene and 4 eq of para-nitrobencensulfonate in DMF for 30 minutes (3 treatments). Between treatments the resin is washed thoroughly with DMF and DCM. After the N- methylation of the beta -Ala amino group, the ortho-nitro benzene sulfonyl protecting group is removed by treating the resin with 10 eq of beta-mercaptoethanol and 5 eq of DBU (1 x 10' and 1 x 40'). The removal of the ortho-nitro benzene sulfonyl group is assessed using the chloranil test. For the acetylation of the N-part terminal part of the peptide, 20 eq of acetic anhydride and 20 eq of DIE A are added to the resin. The mixture is allowed to react for 30 minutes and the extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 13. The compound is purified using reverse-phase chromatography.

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 63-66

14
[ 65-85-0 ]
[ 138775-22-1 ]
[ 142-62-1 ]
[ 203866-20-0 ]
[ 204316-32-5 ]
(2S,4R)-N-[(1S)-1-[[(1S)-3-benzamido-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-4-fluoro-N-methyl-1-hexanoyl-pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.5 eq of commercially available Fmoc-NH-OH and DIEA (10 eq) are added to the 2-chlorotrityl resin in 2 mL DCM. The mixture is intermittently stirred manually during 24h. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-NY-alloc-L-2,4-diaminobutyric acid (Fmoc-L-Dab(alloc)-OH), 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- N-methyl-L-iso leucine (Fmoc-NMe-L-Ile-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15 '). After that, Fmoc- trans-4-Fluoro-L-Proline (Fmoc-L-(F)Pro-OH) moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). Hexanoic acid is coupled to the proline moiety by adding to the resin 3 eq of the acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting the mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the benzoic acid on the side chain of the diaminoethyl moiety, 3 eq of said acid, 3 eq of the coupling agent DIC and 3 eq of oxyma pure are dissolved in a small amount of DMF and premixed for 2 minutes. The resulting mixture is added to the resin and the reaction is allowed to proceed for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The peptide is cleaved from the resin by adding a solution of DCM/TFA (95:5), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with DCM. This cleavage procedure is repeated twice. All the filtrates are pooled and the solvent is evaporated under vacuum, yielding example 16. The compound is purified using reverse-phase chromatography.

Reference： [1]Patent: WO2017/85034,2017,A1 .Location in patent: Page/Page column 70-72

15
[ 200344-33-8 ]
[ 334-49-6 ]
[ 2592-18-9 ]
[ 71989-33-8 ]
[ 132388-59-1 ]
[ 198543-08-7 ]
[ 204316-32-5 ]
C₃₅H₆₃N₁₁O₁₂ [ No CAS ]