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Chemical Structure| 26607-51-2 Chemical Structure| 26607-51-2

Structure of Z-D-Ala-OH
CAS No.: 26607-51-2

Chemical Structure| 26607-51-2

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Product Details of [ 26607-51-2 ]

CAS No. :26607-51-2
Formula : C11H13NO4
M.W : 223.23
SMILES Code : C[C@@H](NC(OCC1=CC=CC=C1)=O)C(O)=O
English Name :Z-D-Ala-OH
MDL No. :MFCD00063126
InChI Key :TYRGLVWXHJRKMT-MRVPVSSYSA-N
Pubchem ID :70832

Safety of [ 26607-51-2 ]

Computational Chemistry of [ 26607-51-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.27
Num. rotatable bonds 6
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 56.88
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

75.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.88
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.43
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.23
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.15
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.78
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.29

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.01
Solubility 2.2 mg/ml ; 0.00985 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.62
Solubility 0.531 mg/ml ; 0.00238 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.36
Solubility 0.974 mg/ml ; 0.00437 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.65 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.51

Application In Synthesis of [ 26607-51-2 ]

* 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 [ 26607-51-2 ]

[ 26607-51-2 ] Synthesis Path-Downstream   1~26

  • 1
  • [ 26607-51-2 ]
  • [ 4089-07-0 ]
  • [ 150571-00-9 ]
  • 2
  • [ 67-56-1 ]
  • [ 26607-51-2 ]
  • [ 67799-99-9 ]
YieldReaction ConditionsOperation in experiment
46.9% With thionyl chloride at 90℃; for 16h; 2.1 1. Preparation of ((benzyloxy)carbonyl)-D-alanine methyl ester ((Benzyloxy)carbonyl)-D-alanine (6.0g, 26.9mmol), methanol (50ml), add thionyl chloride (6.4g, 53.8mmol), heat to 90, 16h, spin dry, The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 3.0 g of compound, yield: 46.9%
With thionyl chloride
  • 3
  • [ 26607-51-2 ]
  • [ 63060-94-6 ]
  • Z-D-Ala-D-Phe-OEt [ No CAS ]
  • 5
  • [ 26607-51-2 ]
  • [ 77-78-1 ]
  • [ 67799-99-9 ]
YieldReaction ConditionsOperation in experiment
95% With potassium hydrogencarbonate In N,N-dimethyl-formamide for 4h; Ambient temperature;
  • 7
  • [ 26607-51-2 ]
  • [ 16741-80-3 ]
  • (R)-2-((R)-2-Benzyloxycarbonylamino-propionylamino)-3-benzylsulfanyl-propionic acid [ No CAS ]
  • 8
  • [ 26607-51-2 ]
  • [ 7622-23-3 ]
  • [ 174538-88-6 ]
  • 9
  • [ 6066-82-6 ]
  • [ 26607-51-2 ]
  • [ 27167-53-9 ]
YieldReaction ConditionsOperation in experiment
85% With dicyclohexyl-carbodiimide In acetonitrile at 0 - 20℃; for 12.5h; 5; 17 EXAMPLE 17 Preparation of Z-D-Ala-OSu (22) Z-D-Ala-OSu (22). EXAMPLE 17 Preparation of Z-D-Ala-OSu (22) Z-D-Ala-OSu (22). 51.8 g of Z-(D)Ala-OH and 30.3 g of SucOH (1 .05 eq) 21 were dissolved in 560 ml acetonitrile and the solution cooled to 0 °C. 54.6 g of DCC (1.1 eq) dissolved in 80 ml acetonitrile and slowly added. Thirty min after the addition the solution was brought to room temperature. After overnight aging the conversion was >99% by HPLC. The DCU by-product was removed by filtration and washed the cake with acetonitrile (2x 250 ml). The filtrate and washings were combined and concentrated under vacuum to afford a solution weighing 573g. To this solution was added 1920 ml iPrOH and the mixture was cooled at 4 °C overnight. The obtained crystals were filtered-off and washed with IPA (2x 165 mL). After overnight drying 65g of 22 was isolated (HPLC purity: 100% RS (chromatogram below), yield: 85%).
57% With dicyclohexyl-carbodiimide In acetonitrile at -20℃;
With dicyclohexyl-carbodiimide In 1,4-dioxane for 12h; Ambient temperature;
  • 10
  • [ 1125-88-8 ]
  • [ 26607-51-2 ]
  • [ 143564-89-0 ]
  • [ 135923-87-4 ]
YieldReaction ConditionsOperation in experiment
72% With boron trifluoride diethyl etherate In diethyl ether at -15℃; for 96h;
With boron trifluoride diethyl etherate In diethyl ether at -20℃; for 24h;
  • 11
  • [ 26607-51-2 ]
  • [ 151378-81-3 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: N-benzyloxycarbonyl-D-alanine With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h; 4.3.19 4.3. Typical procedure for the primary amidation of Cbz-l-Phe-OH 3a with NH4Cl General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N at 0°C. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86% yield) of Cbz-L-Phe-NH2 4a.
With ammonia; triethylamine; isobutyl chloroformate 1.) THF, -15 deg C, 10 min, 2.) -15 deg C to room temp., 1 h; Yield given. Multistep reaction;
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / 0.17 h / -15 °C 2: gaseous NH3 / tetrahydrofuran / 1.5 h / -15 - 20 °C
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.5 h / 0 °C 2: ammonium chloride / tetrahydrofuran; water / 0.5 h / 0 °C
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 2: ammonia / methanol / 50 °C / Sealed tube

  • 12
  • [ 26607-51-2 ]
  • [ 100-52-7 ]
  • [ 143564-89-0 ]
YieldReaction ConditionsOperation in experiment
With boron trifluoride diethyl etherate at -15℃;
  • 13
  • [ 1125-88-8 ]
  • [ 26607-51-2 ]
  • [ 143564-89-0 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0 - 20℃; for 4h;
72.3% With boron trifluoride diethyl etherate In diethyl ether at -15℃;
65% With boron trifluoride diethyl etherate In diethyl ether at -20℃; for 96h; 1 Dimethyl benzaldehyde acetal (10.0 mL, 67.2 mmol) was added to a cooled solution of CBZ-D-alanine (15.0 g, 67.2 mmol) in Et20 (180 mL), followed by BF3. Et20 (50.6 mL, 403.2 mmol) over 15 min. The reaction mixture was stirred at-20 °C for 4 days and quenched by addition of ice cold saturated NaHC03 (350.0 mL). The organic layer was diluted with Et20 (500 mL), separated, washed with NaHC03 (5% aqueous solution), brine, dried over MgS04, filtered and concentrated. The crude was recrystallized using Et20/hexane to yield 347A (13.6 g, 65%).
63% With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃; for 4h; Inert atmosphere;
57% Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran for 0.166667h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 4h; 184.1 Step 1: Synthesis of benzyl (2R,4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol, 1 equiv) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol, 1.1 equiv) in THF (35 mL) at 0 °C was added SOCl2 (2.93 g, 24.64 mmol, 1.1 equiv). The resulting mixture was stirred for 10 min, then ZnCl2 (3.36 g, 24.64 mmol, 1.1 equiv) was added. The reaction mixture was stirred at 0 °C for 4 h then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→10% EtOAc/petroleum ether) to afford benzyl (2R,4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate (20 g, 64.24 mmol, 57% yield) as yellow oil.1H NMR (400MHz, CDCl3) δ ppm 7.52 - 7.14 (m, 10H), 6.66 (s, 1H), 5.26 - 5.09 (m, 2H), 4.50 (q, J = 6.9 Hz, 1H), 1.59 (d, J = 7.0 Hz, 3H).
57.4% Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 4h; Step 1:
Synthesis of benzyl (2R,4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate Five batches were completed in parallel. To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.71 mL, 24.64 mmol) in THF (35 mL) was added SOCl2 (1.79 mL, 24.64 mmol) in one portion at 0° C. After the mixture was stirred for 10 min, ZnCl2 (1.15 mL, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0° C. for 4 h. The give batches were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1→10% EtOAc/pet. ether) to afford product (20 g, 57.4% yield).
46% With thionyl chloride; zinc(II) chloride In tetrahydrofuran at -15 - 0℃; for 4h; Inert atmosphere; 1.1 Example 1 (1): 200 g of Cbz-D-alanine was dissolved in 1 L of tetrahydrofuran, and 157 g of benzaldehyde dimethyl acetal was added, and a nitrogen substitution system was introduced.The ice salt bath was cooled to -15 ° C, and 106.7 g of thionyl chloride was added dropwise.The control temperature is lower than 0 ° C, and the mixture is stirred until the temperature reaches -15 ° C.122g anhydrous zinc chloride was added in batches, and the temperature was controlled below 0 °C.After stirring for 4 hours, the reaction was quenched by adding 1 L of water.Then extracted with 600 mL of ethyl acetate.The organic phase is washed sequentially with water and a saturated sodium bicarbonate solution until neutral.Dry over anhydrous sodium sulfate, concentrate and recrystallize from 300 mL of isopropyl ether and 200 mL of petroleum ether.Filtration and drying gave 129 g of Intermediate 1, and the hydrogen spectrum is shown in Figure 2.White solid,The yield was 46%.
With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃;
With boron trifluoride diethyl etherate In diethyl ether at -78 - 20℃; Inert atmosphere; 13 4.1.13 (2R,4S)-Benzyl-4-allyl-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate 15 General procedure: Properly dried Z-(S)-alanine (22.3g, 100mmol) and benzaldehyde dimethyl acetal (14.4mL, 95.9mmol) in diethyl ether (500mL) were cooled to -78°C followed by the dropwise addition of BF3·Et2O (60.2mL, 489mmol) under a nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred until completion of the reaction as monitored by TLC. The reaction mixture was treated with saturated aqueous NaHCO3 at 0°C, initially in small portions until strong bubbling ceased, and then the mixture was extracted with Et2O (3×150mL). The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the predominant cis-isomer was obtained from the crude mixture by silica gel column chromatography using ethyl acetate in hexane (1:4) as the eluent. The compound was further crystallised from diethyl ether/hexane to yield compound 1 (18.66g, 60% yield) as white crystalline solid
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; Step 1: Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 mL ) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCl2 (-3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHCO3, then extracted with EtOAc (3 x 50 mL ). The organic layer was washed with a sat. aq. NaHCC>3 (30 mL ) and brine (30 mL ), dried over Na2S O4, and concentrated. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for CisHisNCU: 311.14; found: 312.1.
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; Step 1. Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 mL) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCL (3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHCO3, then extracted with EtOAc (3 x 50 mL). The organic layer was washed with a sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried over Na2SCO4, and concentrated. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for CisHisNCU: 311.14; found: 312.1.
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; Step 1: Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 mL ) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCl2 (-3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHCO3, then extracted with EtOAc (3 x 50 mL ). The organic layer was washed with a sat. aq. NaHCC>3 (30 mL ) and brine (30 mL ), dried over Na2S O4, and concentrated. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for CisHisNCU: 311.14; found: 312.1.
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; Step 1. Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 mL) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCL (3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHCO3, then extracted with EtOAc (3 x 50 mL). The organic layer was washed with a sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried over Na2SCO4, and concentrated. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for CisHisNCU: 311.14; found: 312.1.
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; 14.1 Step 1: Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 ml_) was added SOC (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCL (3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHC03, then extracted with EtOAc (3 x 50 ml_). The organic layer was washed with a sat. aq. NaHCCb (30 mL) and brine (30 ml_), dried over Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography (020% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for C18H18NO4: 311.14; found: 312.1.
46 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; 14.1 Step 1: Synthesis of benzyl (2 R, 4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-D-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.75 g, 24.64 mmol) in THF (35 ml_) was added SOC (2.93 g, 24.64 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCL (3.36 g, 24.64 mmol) was added to the solution. Then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH 5 with sat. aq. NaHC03, then extracted with EtOAc (3 x 50 ml_). The organic layer was washed with a sat. aq. NaHCCb (30 mL) and brine (30 ml_), dried over Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography (020% EtOAc/pet. ether) to afford the product (3.19 g, 46% yield) as an oil. LCMS (ESI) m/z [M + H] calcd for C18H18NO4: 311.14; found: 312.1.
59.2 % Stage #1: benzaldehyde dimethyl acetal; N-benzyloxycarbonyl-D-alanine With thionyl chloride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; Inert atmosphere;
With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃; for 4h;

References: [1]Long, Ya-Qiu; Huang, Shao-Xu; Zawahir, Zahrah; Xu, Zhong-Liang; Li, Huiyuan; Sanchez, Tino W.; Zhi, Ying; De Houwer, Stephanie; Christ, Frauke; Debyser, Zeger; Neamati, Nouri [Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5601 - 5612].
[2]Location in patent: experimental part Long, Ya-Qiu; Xue, Ting; Song, Yan-Li; Liu, Zu-Long; Huang, Shao-Xu; Yu, Qiang [Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6371 - 6380].
[3]Current Patent Assignee: MERCK SHARP DOHME - WO2005/87731, 2005, A1 Location in patent: Page/Page column 159-160.
[4]Location in patent: experimental part Meyer, Falco-Magnus; Collins, James C.; Borin, Brendan; Bradow, James; Liras, Spiros; Limberakis, Chris; Mathiowetz, Alan M.; Philippe, Laurence; Price, David; Song, Kun; James, Keith [Journal of Organic Chemistry, 2012, vol. 77, # 7, p. 3099 - 3114].
[5]Current Patent Assignee: REVOLUTION MEDICINES - WO2021/108683, 2021, A1 Location in patent: Page/Page column 299.
[6]Current Patent Assignee: REVOLUTION MEDICINES - US2021/130326, 2021, A1 Location in patent: Paragraph 1673-1674.
[7]Current Patent Assignee: KANGHUA SHANGHAI NEW DRUG R D - CN109206331, 2019, A Location in patent: Paragraph 0021; 0022; 0026.
[8]Coe, Diane M; Perciaccante, Rossana; Procopiou, Panayiotis A [Organic and biomolecular chemistry, 2003, vol. 1, # 7, p. 1106 - 1111].
[9]Tiwari, Vinay Shankar; Murugula, Raghavendra; Yadav, Shyam Raj; Haq, Wahajul [Tetrahedron Asymmetry, 2016, vol. 27, # 17-18, p. 865 - 871].
[10]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235866, 2022, A1 Location in patent: Page/Page column 53-54.
[11]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235870, 2022, A1 Location in patent: Page/Page column 208.
[12]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235866, 2022, A1 Location in patent: Page/Page column 53-54.
[13]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235870, 2022, A1 Location in patent: Page/Page column 208.
[14]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/251292, 2022, A1 Location in patent: Page/Page column 765.
[15]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/251292, 2022, A1 Location in patent: Page/Page column 765.
[16]Passley, Kyle D.; Ruble, J. Craig; Kerr, Mark S.; Organ, Michael G. [Journal of Organic Chemistry, 2024, vol. 89, # 5, p. 3211 - 3213].
[17]Current Patent Assignee: ARROMAX PHARMATECH SUZHOU - CN119899179, 2025, A Location in patent: Paragraph 0324-0327.
  • 14
  • [ 26607-51-2 ]
  • [ 61425-27-2 ]
YieldReaction ConditionsOperation in experiment
72% With sodium tetrahydroborate; 2-(6-nitro-1-oxy-benzotriazol-3-yl)-1,1,3,3-Me4-uronium*PF6; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h;
Multi-step reaction with 2 steps 1: 95 percent / KHCO3 / dimethylformamide / 4 h / Ambient temperature 2: 95 percent / LiBH4 / tetrahydrofuran; ethanol
Multi-step reaction with 2 steps 1: SOCl2 2: NaBH4, CaCl2 / tetrahydrofuran
Stage #1: N-benzyloxycarbonyl-D-alanine With N-ethyl-N,N-diisopropylamine; isobutyl chloroformate Stage #2: With sodium tetrahydroborate; water

  • 15
  • [ 68166-83-6 ]
  • [ 26607-51-2 ]
  • [ 817185-93-6 ]
YieldReaction ConditionsOperation in experiment
88% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at -20℃; for 3h;
  • 16
  • [ 26607-51-2 ]
  • [ 74-88-4 ]
  • [ 67799-99-9 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: N-benzyloxycarbonyl-D-alanine With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide 3.2.1. General Method A: Synthesis of Protected Amino Acid Methyl Ester: General procedure: To a solution of N-protected-amino acid (26.4 mmol) in dry DMF (70 mL) caesium carbonate (4.72 g, 14.5 mmol) was added and the mixture was stirred for 30 min at room temperature. After dropwise addition of methyl iodide (1.73 mL, 27.8 mmol), the reaction was stirred overnight. Ethyl acetate (50 mL) was then added to the mixture and it was washed with water (3 50 mL), then the combined aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was washed with 10% K2CO3 solution (2 30 mL), then with brine (30 mL), dried over MgSO4,and subsequently filtered. The solvent was removed under reduced pressure to give the product as a white solid.
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 5h;
  • 17
  • [ 26607-51-2 ]
  • [ 473797-71-6 ]
  • [ 1193377-28-4 ]
YieldReaction ConditionsOperation in experiment
49% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane Inert atmosphere;
  • 18
  • [ 26607-51-2 ]
  • [ 22203-98-1 ]
  • [ 1121627-38-0 ]
YieldReaction ConditionsOperation in experiment
31% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at -10℃; for 4h;
With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at -15℃;
  • 19
  • [ 26607-51-2 ]
  • [ 1682648-28-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: thionyl chloride / tetrahydrofuran / 0.33 h / 20 °C 1.2: 2 h / 20 °C 2.1: triethylamine / water; acetonitrile / 50 °C / Microwave irradiation
Multi-step reaction with 2 steps 1.1: thionyl chloride / 0.33 h / 20 °C 1.2: 20 °C 2.1: triethylamine / acetonitrile; water / 20 °C
  • 20
  • [ 26607-51-2 ]
  • [ 1292210-87-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
52% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 24h; A solution of 1 (50g), Z-D-Ala-OH (46.84g), HOBT (28.64 g), EDCxHCl (40.63g) and DMAP (2.59g) in DCM (500ml) was stirred for 24h.The organic phase was washed with satd. NaHCO3 The organic layer was dried with NaSO4 and concentrated under reduced pressure. The crude product was purified by chromatography (Toluol → Toluol/EE 4-1) to give 11 (48.7g, 0.11 mol, 52 %) as colorless oil 1HNMR in CDCl3: 7.35-7.15(m, 10H), 5.25 (d,j=6.7, 1H), 5.10 (m, 2H), 4.41-4.02 (m, 6H), 2.60, (m, 4H), 2.38 (m, 4H), 1.85 (m, 4H). 2.62, (m, 2H), 2.38 (m, 2H), 1.88 (m, 2H), 1.42 (d, j=7.2, 3H). M+Na=467.
  • 21
  • [ 616224-38-5 ]
  • [ 26607-51-2 ]
  • [ 1890230-90-6 ]
YieldReaction ConditionsOperation in experiment
79% With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 15h; Representative example for 4-9: Preparation of methyl4-[[(2R)-2-(benzyloxycarbonylamino)-3-methyl-butanoyl]amino]-3-(methylamino)benzoate (7) General procedure: Toa solution of Z-D-Val-OH (0.98 g,3.88 mmol) in DMF (6 ml), methyl 4-amino-3-(methylamino)benzoate [1] (0.7 g,3.88 mmol) in DMF (2ml) was added at 0 oC. Subsequently, HOAt (0.79 g,5.82 mmol) and WSCI*HCl (1.12 g,5.82 mmol) were added to the former solution at 0 oC and stirred for15 h. The reaction mixture was quenched with saturated NH4Cl (10 ml)and extracted with EtOAc (100 ml). The combined extracts were washed with waterand brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.4 g of 7.
  • 22
  • [ 26607-51-2 ]
  • [ 2174940-65-7 ]
  • [ 2174942-02-8 ]
YieldReaction ConditionsOperation in experiment
306 mg With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 12h; 105 EXAMPLE 105 109761 N-((R)- 1 -((R)-3 -(1 -(1 -((R)- 1 -(2,4-dichlorophenyl)ethyl)-3 -(trifluoromethyl)- 1 Hpyrazolo[3 ,4-b]pyrazin-6-yl)azetidin-3 -yl)piperidin- 1 -yl)propan-2-yl)acetamide. Precursor VI (270 mg, 1.13 mmol) was condensed with (2R)-2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) in DIVIF (3 mL) using 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (642 mg, 1.69 mmol) and N,NDiisopropylethylamine (0.587 mL, 3.38 mmol) for 12 hours and then poured into ethyl acetate (50 mL), washed with brine (5OmL), dried over sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography using silica gel and a gradient of ethyl acetate (10 to 100%) in hexanes to afford tert-butyl 3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propanoyl] -3 -piperidyl ] azetidine- 1 -carboxylate (306 mg, 0.687 mmol). tert-butyl 3 -[(3R)- 1- [(2R)-2-(b enzyloxycarbonylamino)propanoyl] -3 -piperidyl] azetidine- 1- carboxylate (306 mg, 0.687 mmol) was dissolved in tetrahydrofuran (6 mL) and treated with boranetetrahydrofuran complex (2.06 mL, 2.06 mmol, 1M in tetrahydrofuran) and stirred for 12 hours, quenched with methanol and concentrated under reduced pressure, the residue was purified by flashchromatography using silica gel and a gradient of methanol (0 to 20%) in DCM to afford tert-butyl3- [(3R)- 1- [(2R)-2-(benzyloxycarbonylamino)propyl] -3 -piperidyl] azetidine- 1 -carboxylate (296 mg,0.687 mmol). tert-butyl 3- [(3R)- 1 -[(2R)-2-(benzyloxycarbonylamino)propyl] -3 -piperidyl] azetidine1-carboxylate (296 mg, 0.687 mmol) was dissolved in methanol (5mL) and palladium on carbon 10wt.% (89.4 mg) was added, the mixture was then placed under a hydrogen atmosphere (balloon) andstirred for 15 minutes, filtered through celite, concentrated under reduced pressure, diluted withDCM (5 mL), treated with triethylamine (0.29 mL, 2.07 mmol) and acetyl chloride (0.15 mL, 2.07mmol), stirred for 30 minutes, quenched with 1M sodium carbonate, extracted with ethyl acetate (2x 5 mL), dried over sodium sulfate, concentrated in vacuo to afford tert-butyl 3-[(3R)-1-[(2R)-2-acetamidopropyl] -3 -piperidyl] azetidine- 1 -carboxylate (220 mg, 0.648 mmol). tert-butyl 3 -[(3R)- 1-[(2R)-2-acetamidopropyl] -3 -piperidyl] azetidine- 1 -carboxylate was then condensed with Precursor Vusing general procedures C and D to afford the title compound. ‘H NIVIR (400 MHz, Methanol-d4 HC1 Salt) 7.93 (s, 1H), 7.49 (d, J= 2.1 Hz, 1H), 7.35 (d, J= 8.5 Hz, 1H), 7.31 (dd, J 8.5, 2.0 Hz, 1H), 6.44 (q, J= 7.2 Hz, 1H), 4.39 - 4.24 (m, 3H), 4.08 - 3.93 (m, 2H), 3.58 - 3.47 (m, 1H), 3.44 -3.34 (m, 1H), 3.17 -2.94 (m, 2H), 2.86 -2.49 (m, 2H), 2.19 -2.00 (m, 1H), 2.00 (s, 3H), 1.98 -1.94 (m, 3H), 1.91 (d, J= 7.1 Hz, 3H), 1.83 - 1.68 (m, 1H), 1.24 (d, J= 6.8 Hz, 3H), 1.20- 1.17 (m,
  • 23
  • [ 23778-52-1 ]
  • [ 26607-51-2 ]
  • [ 2029237-51-0 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; S1.a a, cbz-L-alanine,Pentaethylene glycol monomethyl ether,EDCI,DMAP massage ratio 1:1:1.1:0.2,Add in a two-neck bottle,Using dichloromethane as a solvent, reacting at room temperature overnight;TLC showed that the reaction was complete and washed 3 times with water.Washed with saturated sodium bicarbonate solution 3 times,Wash the saturated sodium chloride solution 3 times,Collect organic phase,Dry with anhydrous sodium sulfate for 3 h,Anhydrous sodium sulfate was removed by suction filtration.Rotating to remove the solvent,Purified by silica gel column (eluent is petroleum ether and ethyl acetate,Wherein the volume ratio of petroleum ether to ethyl acetate is 1:1),The product was collected, the solvent was removed, and dried in vacuo to give product I, and its structural formula is:
  • 24
  • [ 236406-55-6 ]
  • [ 26607-51-2 ]
  • [ 2269513-67-7 ]
YieldReaction ConditionsOperation in experiment
99% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; Inert atmosphere; 16.1 Step 1 : benzyl N-[(1R)-2-(2,7-diazaspiro[3.5]nonan-7-yl)-1-methyl-2-oxoethyl]carbamate (18B) [0239] No.18 Tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (6A) (0.45g, 2mmol), No.2 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (780 mg, 4.1mmol), No.2 1-hydroxybenzotriazole (340 mg, 2.5 mmol), No.30 (2R)-2-(benzyloxycarbonylamino)propanoic acid (446 mg, 2.0 mmol) and No.2 dichloromethane (30 mL) were added in a 50 mL reaction flask, and the system was allowed to react at room temperature for 5 h. Then the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v:v)=50:1) to obtain No.30 benzyl N-[(1R)-2-(2,7-diazaspiro[3.5]nonan-7-yl)-1-methyl-2-oxoethyl]carbamate (18B) as white solid (860 mg, yield 99%). MS m/Z= 454.2 [M+Na]+.
  • 25
  • [ 26607-51-2 ]
  • [ 1375066-73-1 ]
  • [ 3062119-46-1 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: N-benzyloxycarbonyl-D-alanine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -10 - 10℃; for 0.333333h; Inert atmosphere; Stage #2: 3-methyl-1,2,4-thiadiazole-5-carbohydrazide In tetrahydrofuran for 0.166667h; Inert atmosphere; 4 Example 4 Add compound E2 (5g, 1.0eq.), N-methylmorpholine (2.7g, 1.2eq.), and 50mL of tetrahydrofuran to a 100mL three-necked flask and cool to 0°C under nitrogen protection. Control the temperature in the reaction flask between -10 and 10°C, and add isobutyl chloroformate (3.2g, 1.05eq.) dropwise. After the addition is complete, keep warm and stir for 20 minutes, and add compound F (3.5g, 1.0eq.) in batches. After the addition is complete, keep warm and stir for 10 minutes. Add 10% citric acid aqueous solution. Concentrate under reduced pressure to remove tetrahydrofuran, add dichloromethane to extract twice, and concentrate the obtained organic phase to obtain a crude product. The crude product is chromatographed on a silica gel column to obtain 6.7g of compound G2, with a yield of 82%, and a light yellow oil. The chiral purity is 99.9%.
  • 26
  • [ 67799-99-9 ]
  • [ 26607-51-2 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In ethanol at 5℃; for 10h; 4 Synthesis of N-Cbz-alanine (Formula 2) 10 g of N-Cbz-alanine methyl ester was dissolved in 100 ml of ethanol. 1.7 g of sodium hydroxide was added in portions at 5°C with stirring. The reaction was carried out for 10 hours. After the reaction was complete, the ethanol was concentrated, 100 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated, and a white solid of 9.8 g was obtained. This solid was then slurried with ethyl acetate and petroleum ether at a ratio of 1:10 (V/V), filtered, and a white solid of 8.3 g was obtained. The yield was 90%, and the HPLC purity was 99%.
 

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