* 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.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 8, p. 1272 - 1280
3
[ 23680-31-1 ]
[ 4726-96-9 ]
Yield
Reaction Conditions
Operation in experiment
62.3%
With triethylsilane; trifluoroacetic acid In dichloromethane at 20℃; for 2 h;
The compound obtained in the previous step was dissolved in an appropriate amount of dry distilled DCM,TFA 1.0mL, triethylsilane 0.1mL, the reaction was stirred at room temperature for 2h,The reaction was complete by TLC.The solvent was distilled off under reduced pressure,Add saturated sodium bicarbonate solution to adjust the pH to 7 ~ 8,Then add DCM,Wash twice with saturated saline, concentrate the organic phase to give a yellow oily liquid.Silica gel column chromatography (chloroform: methanol = 15: 1) gave a yellow powdery solid in a yield of 62.3percent.
Reference：
[1] Patent: CN107082754, 2017, A, . Location in patent: Paragraph 0119; 0124
[2] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[3] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4149 - 4151
[4] ACS Chemical Neuroscience, 2017, vol. 8, # 8, p. 1681 - 1687
[5] Patent: WO2017/189866, 2017, A1, . Location in patent: Paragraph 0210
Reference：
[1] Journal of Medicinal Chemistry, 1979, vol. 22, p. 935 - 943
6
[ 3262-72-4 ]
[ 100-39-0 ]
[ 23680-31-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; mineral oil
Example 36 N-tert-Butoxycarbonyl-O-benzyl-L-serine 39: To a solution of Boc-L-serine (15 g, 73.09 mmol) in DMF (300 mL) at 0° C. was added NaH (6.43 g, 160.80 mmol, 60percent in mineral oil) and stirred for 1.5 h at 0° C. After the addition of benzyl bromide (13.75 g, 80.40 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in H2O. The crude product was partitioned between H2O and Et2O. The aqueous phase was acidified to pH<4 with 3 N HCl and extracted with EtOAc three times. The combined EtOAc solution was washed with H2O, dried with Na2SO4, filtered, and concentrated to give the N-tert-butoxycarbonyl-O-benzyl-L-serine (17.27 g, 80percent).
80%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; mineral oil
Example H36 N-tert-Butoxycarbonyl-O-benzyl-L-serine 39: To a solution of Boc-L-serine (15 g, 73.09 mmol) in DMF (300 mL) at 0° C. was added NaH (6.43 g, 160.80 mmol, 60percent in mineral oil) and stirred for 1.5 h at 0° C. After the addition of benzyl bromide (13.75 g, 80.40 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in H2O. The crude product was partitioned between H2O and Et2O. The aqueous phase was acidified to pH<4 with 3 N HCl and extracted with EtOAc three times. The combined EtOAc solution was washed with H2O, dried with Na2SO4, filtered, and concentrated to give the N-tert-butoxycarbonyl-O-benzyl-L-serine (17.27 g, 80percent).
75%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at -15℃; for 2 h; Stage #2: at -15 - 20℃;
To a stirring solution of 2S-Z (50 g, 245 mmol) in DMF (650 mL) was added NaH (60percent) (23 g, 563 mmol) at -15 °C and stirred for 2 h. Benzyl bromide (32.8 mL, 269 mmol) was slowly added. The reaction mixture temperature was warmed to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was poured into chilled water (200 mL) and extracted with diethylether (2x 250 mL). The aqueous layer was acidified with citric acid (pH~4) and extracted with EtOAc (2x500 mL). The combined organic layers were washed with water (3x250 mL). The organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford 2S-AA (54 g, 75percent) as brown syrup. H-NMR: (400 MHz, CDC13): δ 7.32-7.26 (m, 5H), 5.43 (d, J = 7.6 Hz, 1H), 4.70-4.46 (m, 1H), 4.45 (s, 2H), 4.13-3.91 (m, 1H), 3.73-3.70 (m, 1H), 1.44 (s, 9H).
75%
Stage #1: at -15℃; for 2 h; Stage #2: at 20 - 25℃; for 12 h;
To a stirring solution of Int A (50 g, 245 mmol) in DMF (650 mL) was added NaH (60percent) (23 g, 563 mmol) at -15 °C and stirred for 2 h. After adding benzyl bromide (32.8 mL, 269 mmol) slowly, the reaction mixture was warmed to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was poured into chilled water (200 mL) and extracted with diethylether (2x 250 mL). The aqueous layer was acidified with citric acid (pH~4) and extracted with EtOAc (2x500 mL). The combined organic layers were washed with water (3 x 250 mL). The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford Int B (54 g, 75percent) as a brown syrup. (0569) 1H NMR: (400 MHz, CDCl3): δ 7.32-7.26 (m, 5H), 5.43 (d, J = 7.6 Hz, 1H), 4.70-4.46 (m, 1H), 4.45 (s, 2H), 4.13-3.91 (m, 1H), 3.73-3.70 (m, 1H), 1.44 (s, 9H)
With sodium tetrahydroborate; triethanolamine In tetrahydrofuran; water; ethyl acetate
N-(tert-Butyloxycarbonyl)-O-Benzyl-L-Serinol (3) N-(tert-butyloxycarbonyl)-O- benzyl-L-serine 2 (6.0 g, 20.34 mmol) was dissolved in dry THF and cooled to -20° C. under argon atmosphere. To this cold stirred solution was added TEA (2.32 g, 23 mmol) and isobutyl chloroformate (3.13 g, 23 mmol). The stirring was continued for 30 min at -20° C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0° C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0° C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2 Cl2 -->EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 4.7 g (82percent) of the pure product as an oil. 1 H-NMR (CDCl3): δ1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2 Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
Reference：
[1] Patent: US5969135, 1999, A,
18
[ 23680-31-1 ]
[ 19525-87-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With thionyl chloride In dichloromethane at 0℃; for 14 h;
Example 44A; <n="114"/>To a solution of 300 mg (1.02 mmol) (S)-3-benzyloxy-2-tert-butoxycarbonylamino- propionic acid in 10 ml DCM is added 1.5 ml (20.5 mmol) thionylchloride at 00C. After stirring for 14 h the mixture is concentrated and evaporated several times after the additon of methanol to yield the hydrochlorde of the product as a solid. yield: 270 mg (100percent)LC-MS (Method 1s): RT = 0.92 minMS (ESI pos): m/z = 210 (M+H)+
(25)-3-(benzyloxy)-2-[(ter?-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N- Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to -20C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H20. The organic layers were combined, dried over Na2S04, and concentrated in vacuo. Purification by chromatography (silica, 4/1 : Hexane/EtOAc, Rf= 0.2) afforded tert-butyl N-[(lR)-2-(benzyloxy)-l- (hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92 %).
With borane-THF; In tetrahydrofuran; at 0 - 23℃;
To solution of (L)-N-Boc Ser(OBn)-OH 28 (1 g, 3.38 mmol) in anhydrous THF (6 mL) was added 1 M Borane-THF complex (7.5 mL, 7.5 mmol) at 0 C. After stirring at 0 C for 1 h, the reaction mixture was slowly warmed to 23 C and stirred for 3 h. The reaction mixture was cooled to 0 C, quenched by MeOH, concentrated, diluted with MeOH, and concentrated again. The concentrated oil was then subjected to flash column chromatography (EtOAc/ hexane) on silica gel to afford the alcohol 29 (0.87 g, 91%) as an oil.
(2S,4R)-1-{(2S,4R)-1-[2-(4,5-Dihydroxy-3-hydroxymethyl-tetrahydro-pyridazin-1-yl)-acetyl]-4-hydroxy-pyrrolidine-2-carbonyl}-4-hydroxy-pyrrolidine-2-carboxylic acid ((S)-1-carbamoyl-2-hydroxy-ethyl)-amide[ No CAS ]
Fmoc-Asp-Cys(Acm)-His-Leu-Gln-Ala-Val-Val-Leu-His-Leu-Ala-Arg-Arg-Ser-Val-Cys(Acm)-Val-His-Pro-Gln-Asn-Arg-Ser-Leu-Ala-Arg-Trp-Leu-Glu-Arg-Gln-Gly-S-CH2CH2CO-Leu-NH2[ No CAS ]
With thionyl chloride; In dichloromethane; at 0℃; for 14h;
Example 44A; <n="114"/>To a solution of 300 mg (1.02 mmol) (S)-3-benzyloxy-2-tert-butoxycarbonylamino- propionic acid in 10 ml DCM is added 1.5 ml (20.5 mmol) thionylchloride at 00C. After stirring for 14 h the mixture is concentrated and evaporated several times after the additon of methanol to yield the hydrochlorde of the product as a solid. yield: 270 mg (100%)LC-MS (Method 1s): RT = 0.92 minMS (ESI pos): m/z = 210 (M+H)+
General procedure: The peptides were synthesized manually accordingly to the standard Boc protocol [1] and [3]. In the Boc chemistry, after coupling the C-terminal amino acid to the resin, the successive alpha-amino group deprotection and neutralization steps were performed in 30% TFA/DCM (30 min) and 10% TEA/DCM (10 min). The amino acids were coupled with 3-fold excess, using DIC/HOBt in DMF and, if necessary, Boc-amino acid/(N-[(1H-benzotriazol-1-yl)-(dimethylaminomethylene)]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU)/HOBt (1:1:1), in the presence of excess of diisopropylethylamine (DIEA, 5 equiv.) using 20% DMSO/NMP as the solvent system. After a 3-h coupling period, the qualitative ninhydrin test was performed to estimate the completeness of the reaction. To check the purity of the synthesized peptide sequence attached to the resin, cleavage reactions with small aliquots of resin were carried out in anhydrous HF, at 0 C for 2 h.
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Cys-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 1 Synthesis of Glucagon Cys17(1-29) and Similar MonoCys Analogs (0283) 0.2mmole Boc Thr(OBzl) Pam resin (SynChem Inc) in a 60ml reaction vessel and the following sequence was entered and run on a modified Applied Biosystems 430A Peptide Synthesizer using FastBoc HBTU-activated single couplings. (0284) HSQGTFTSDYSKYLDSCRAQDFVQWLMNT (SEQ ID NO: 35) The following side chain protecting groups were used: Arg(Tos), Asp(OcHex), Asn(Xan), Cys(pMeBzl), Glu(OcHex), His(Boc), Lys(2Cl-Z), Ser(Bzl), Thr(Bzl), Trp(CHO), and Tyr(Br-Z). The completed peptidyl resin was treated with 20% piperidine/dimethylformamide to remove the Trp formyl protection then transferred to an HF reaction vessel and dried in vacuo. 1.0ml p-cresol and 0.5 ml dimehyl sulfide were added along with a magnetic stir bar. The vessel was attached to the HF apparatus (Pennisula Labs), cooled in a dry ice/methanol bath, evacuated, and aprox. 10ml liquid hydrogen fluoride was condensed in. The reaction was stirred in an ice bath for 1hr then the HF was removed in vacuo. The residue was suspended in ethyl ether; the solids were filtered, washed with ether, and the peptide extracted into 50 ml aqueous acetic acid. An analytical HPLC was run [0.46 x 5 cm Zorbax C8, 1 ml/min, 45C, 214nm, A buffer of 0.1%TFA, B buffer of 0.1%TFA/90%ACN, gradient=10%B to 80%B over 10min.] with a small sample of the cleavage extract. The remaining extract was loaded onto a 2.2 x 25cm Kromasil C18 preparative reverse phase column and an acetonitrile gradient was run using a Pharmacia FPLC system. 5min fractions were collected while monitoring the UV at 214nm (2.0A). A=0.1%TFA, B=0.1%TFA/50%acetonitrile. Gradient = 30%B to 100%B over 450min. (0285) The fractions containing the purest product (48-52) were combined frozen, and lyophilized to give 30.1mg. An HPLC analysis of the product demonstrated a purity of>90% and MALDI mass spectral analysis demonstrated the desired mass of 3429.7. Glucagon Cys21, Glucagon Cys24, and Glucagon Cys29 were similarly prepared.
EXAMPLE 2 Synthesis of Glucagon-Cex and Other C-Terminal Extended Analogs. (0286) 285mg (0.2mmole) methoxybenzhydrylamine resin (Midwest Biotech) was placed in a 60ml reaction vessel and the following sequence was entered and run on a modified Applied Biosystems 430A peptide synthesizer using FastBoc HBTU-activated single couplings. (0287) HSQGTFTSDYSKYLDSRRAQDFVQWLMNTGPSSGAPPPS (SEQ ID NO: 36) The following side chain protecting groups were used: Arg(Tos), Asp(OcHex), Asn(Xan), Cys(pMeBzl), Glu(OcHex), His(Boc), Lys(2Cl-Z), Ser(Bzl), Thr(Bzl), Trp(CHO), and Tyr(Br-Z). The completed peptidyl resin was treated with 20% piperidine/dimethylformamide to remove the Trp formyl protection then transferred to HF reaction vessel and dried in vacuo. 1.0ml p-cresol and 0.5 ml dimehyl sulfide were added along with a magnetic stir bar. The vessel was attached to the HF apparatus (Pennisula Labs), cooled in a dry ice/methanol bath, evacuated, and aprox. 10ml liquid hydrogen fluoride was condensed in. The reaction was stirred in an ice bath for 1hr then the HF was removed in vacuo. The residue was suspended in ethyl ether; the solids were filtered, washed with ether, and the peptide extracted into 50 ml aqueous acetic acid. An analytical HPLC was run [0.46 x 5 cm Zorbax C8, 1 ml/min, 45C, 214nm, A buffer of 0.1%TFA, B buffer of 0.1%TFA/90%ACN, gradient=10%B to 80%B over 10min.] on an aliquot of the cleavage extract. The extract was loaded onto a 2.2 x 25cm Kromasil C18 preparative reverse phase column and an acetonitrile gradient was run for elution using a Pharmacia FPLC system. 5min fractions were collected while monitoring the UV at 214nm (2.0A). A=0.1%TFA, B=0.1%TFA/50%acetonitrile. Gradient = 30%B to 100%B over 450min. Fractions 58-65 were combined, frozen and lyophilized to give 198.1mg. (0288) HPLC analysis of the product showed a purity of greater than 95%. MALDI mass spectral analysis showed the presence of the desired theoretical mass of 4316.7 with the product as a C-terminal amide. Oxyntomodulin and oxyntomodulin-KRNR were similarly prepared as the C-terminal carboxylic acids starting with the appropriately loaded PAM-resin.
HSQGTFTSDYSKYLDERRAQDFVQWLMNT-NH2, lactam 12-16[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 11 Synthesis of Glucagon Lactams (0299) 285 mg (0.2 mmole) methoxybenzhydrylamine resin (Midwest Biotech) was added to a 60 mL reaction vessels and the following sequence was assembled on a modified Applied Biosystems 430A peptide synthesizer using Boc DEPBT-activated single couplings. HSQGTFTSDYSKYLDERRAQDFVQWLMNT-NH2 (12-16 Lactam; SEQ ID NO: 12) (0300) The following side chain protecting groups were used: Arg(Tos), Asp(OcHx), Asn(Xan), Glu(OFm), His(BOM), Lys(Fmoc), Ser(Bzl), Thr(Bzl), Trp(CHO), Tyr(Br-Z). Lys(Cl-Z) was used at position 12 if lactams were constructed from 16-20, 20-24, or 24-28. The completed peptidyl resin was treated with 20% piperidine/dimethylformamide for one hour with rotation to remove the Trp formyl group as well as the Fmoc and OFm protection from Lys12 and Glu16. Upon confirmation of removal by a positive ninhydrin test, the resin was washed with dimethylformamide, followed by dichloromethane and than again with dimethylformamide. The resin was treated with 520 mg (1 mmole) Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) in dimethylformamide and diisopropylethylamine (DIEA). The reaction proceeded for 8-10 hours and the cyclization was confirmed by a negative ninhydrin reaction. The resin was washed with dimethylformamide, followed by dichloromethane and subsequently treated with trifluoroacetic acid for 10 minutes. The removal of the Boc group was confirmed by a positive ninhydrin reaction. The resin was washed with dimethylformamide and dichloromethane and dried before being transferred to a hydrofluoric acid (HF) reaction vessel. 500 muL p-cresol was added along with a magnetic stir bar. The vessel was attached to the HF apparatus (Peninsula Labs), cooled in a dry ice/methanol bath, evacuated, and approximately 10 mL of liquid hydrofluoric acid was condensed into the vessel. The reaction was stirred for 1 hour in an ice bath and the HF was subsequently removed in vacuo. The residue was suspended in ethyl ether; the solids were filtered, washed with ether, and the peptide was solubilized with 150 mL 20% acetonitrile/1% acetic acid. (0301) An analytical HPLC analysis of the crude solubilized peptide was conducted under the following conditions [4.6 X 30 mm Xterra C8, 1.50 mL/min, 220 nm, A buffer 0.1% TFA/10% ACN, B buffer 0.1% TFA/100% ACN, gradient 5-95%B over 15 minutes]. The extract was diluted twofold with water and loaded onto a 2.2 X 25 cm Vydac C4 preparative reverse phase column and eluted using an acetonitrile gradient on a Waters HPLC system (A buffer of 0.1% TFA/10% ACN, B buffer of 0.1% TFA/10% CAN and a gradient of 0-100% B over 120 minutes at a flow of 15.00 ml/min. HPLC analysis of the purified peptide demonstrated greater than 95% purity and electrospray ionization mass spectral analysis confirmed a mass of 3506 Da for the 12-16 lactam. Lactams from 16-20, 20-24, and 24-28 were prepared similarly.
The titled peptide was synthesized on a model 430A peptide synthesizer (Applied Rio systems, Foster City, Calif., U.S.A.) which was modified to do accelerated Hoc-chemistry solid phase peptide synthesis (Schnolzer, M. et al., mt. J Peptide Protein Res., (1992), 40:180). 4-Methylbenzhydry- lamine (MHHA) resin (Peninsula, Helmont, Calif., U.S.A.), with a substitution of0.91 mmol/g was used. Hoc amino acids (Midwest Hio-Tech, Fishers, Ind., U.S.A.; Novabiochem., San Diego, Calif., U.S.A.) were used with the following side chain protection: Hoc-Ala-OH, Hoc-Arg(Tos)-OH, Hoc-His (DNP)-OH, Hoc-Val-OH, Hoc-Ecu-OH, Hoc-Gly-OH, HocGln-OH, Hoc-Eys(2C1Z)?--OH, Hoc-Ser(Hzl)-OH, Hoc-PheOH, Hoc-Glu(OcHex)-OH and Hoc-Pro-OH. Fmoc-Glu (OtHu)-OH (Novabiochem, San Diego, Calif., U.S.A.) was used for the residue at the 3rd position in the sequence. The synthesis was carried out on a 0.25 mmol scale. The Hoc groups were removed by two treatments with 100percent TFA each lasting one minute. Hoc amino acids (2.5 mmol) were preactivated with HH11J (2.0 mmol) and DIEA (1.0 mE) in 4 mE of DMF and were coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 minutes. At the end of the assembly of the first 25 residues on theAHI 430A® peptide synthesizer and before the coupling of Fmoc-Glu (OtHu)-OH, the protected peptide-resin was transferred into a reaction vessel on a shaker for manual synthesis. After removing the Hoc protecting group with two, one-minute treatments with 100percent TFA and a washing with DMF, the resin was mixed with Fmoc-Glu(OtHu)-OH (2.5 mmol) which was preactivated with HHTU (2.0 mmol), HOHt (2.0 mmol) and DIEA (1.0 mE) in 4 mE of DMF. The mixture was shaken for 2 hours. This coupling step was repeated. After washing with DMF, the resin was treated with a TFA solution containing 5percent water and 5percent TIS for 2 hours to remove the tHu protecting group in the side chain of the Glu residue. The resin was neutralized with 10percent DIEA in DMF and washed with DMF and DCM. The resin was then treated twice with hexylamine (2.0 mmol), DIC (2.0 mmol), HOHt (2.0 mmol) in 5 ml of DCM for two hours per treatment. The resin was washed with DMF and treated with 25percent piperidine in DMF for 30 minutes to remove the Fmoc protecting group. Afier washing with DMF and DCM, the resin was transferred into the reaction vessel on the AHI 430A peptide synthesizer for the assembly of the rest two residues. At the end of the assembly of the whole peptide chain, the resin was treated with a solution of 20percent mercaptoethanol/10percent DIEA in DMF for 2x30 mm to remove the DNP group on the His side chain. The N-terminal Hoc group was then removed by two treatments of 100percent TFA for 2 minutes. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mE of HF containing 1 mE of anisole and dithiothreitol (50 mg) at 0° C. for 75 minutes. HF was removed by a flow of nitrogen. The residue was washed with ether (6x 10 mE) and extracted with 4N HOAc (6x10 mE). This crude product was purified on a reverse-phase preparative HPEC using a colunm (4x43 cm) of C18 DYNAMAX-100A°® (Varian, Walnut Creek, Calif., U.S.A.). The column was eluted with a linear gradient from 75percentAand25percent B to 55percentAand45percent B at flow rate of 10 mE/mm in an hour where A was 0.1percent TFA in water and B was 0.1percent TFA in acetonitrile. Fractions were collected and checked on an analytical HPEC. Those containing pure product were combined and lyophilized to dryness. 31.8 mg of a white solid was obtained. Purity was 89percent based on analytical HPEC analysis. Electro-spray ionization mass spectrometry (ESI MS) analysis gave the molecular weight at 3368.4 (in agreement with the calculated molecular weight of 3368.9).
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A mixture of L-valine p-TsOH salt 10a (100 mg, 0.30 mmol) and N-Boc valine (87.12 mg, 0.30 mmol) was taken in 2.5 mL of dry THF and cooled to 0 C under nitrogen atmosphere. After stirring, freshly distilled NMM (0.16 mL, 1.51 mmol) was added via syringe followed by HOBt (46.61 mg, 0.34mmol) and EDCI (65.18 mg, 0.34 mmol) in a single portion. The mixture was stirred overnight slowly warming to room temperature. After 12 hours, it was concentrated by a rotavapor and the residue was taken in EtOAc (20.0 mL), washed with saturated NaHCO3 solution followed by brine. The organic layer was dried over MgSO4, filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexane-EtOAc (8:2) to afford the title compound 11a
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