[ CAS No. 31139-36-3 ] {[proInfo.proName]}

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2D 3D

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Quality Control of [ 31139-36-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 31139-36-3 ]

Product Details of [ 31139-36-3 ]

CAS No. :	31139-36-3	MDL No. :	MFCD00043124
Formula :	C₁₆H₁₄O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FHRRJZZGSJXPRQ-UHFFFAOYSA-N
M.W :	286.28	Pubchem ID :	3649378
Synonyms :

Calculated chemistry of [ 31139-36-3 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.12
Num. rotatable bonds :	8
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	74.75
TPSA :	61.83 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.43 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.73
Log Po/w (XLOGP3) :	3.69
Log Po/w (WLOGP) :	3.37
Log Po/w (MLOGP) :	2.64
Log Po/w (SILICOS-IT) :	2.63
Consensus Log Po/w :	3.01

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.83
Solubility :	0.0419 mg/ml ; 0.000146 mol/l
Class :	Soluble
Log S (Ali) :	-4.68
Solubility :	0.006 mg/ml ; 0.000021 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.84
Solubility :	0.00416 mg/ml ; 0.0000145 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.15

Safety of [ 31139-36-3 ]

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 [ 31139-36-3 ]

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

Upstream synthesis route of [ 31139-36-3 ]
Downstream synthetic route of [ 31139-36-3 ]

[ 31139-36-3 ] Synthesis Path-Upstream 1~11

1
[ 31139-36-3 ]
[ 73-22-3 ]
[ 7432-21-5 ]

Reference： [1] Synthesis, 1986, # 11, p. 958 - 960

2
[ 59-67-6 ]
[ 31139-36-3 ]
[ 94-44-0 ]

Reference： [1] Advanced Synthesis and Catalysis, 2003, vol. 345, # 8, p. 943 - 947

3
[ 31139-36-3 ]
[ 65564-05-8 ]

Reference： [1] Tetrahedron Letters, 2001, vol. 42, # 2, p. 183 - 185

4
[ 4726-96-9 ]
[ 31139-36-3 ]
[ 20806-43-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium carbonate In 1,4-dioxane; water	To a stirred solution of O-benzyl-L-serine (25.0 g, 128 mmole) in water (200 ml) and dioxane (100 ml) was added sodium carbonate (7.46 g, 70 mmole) at room temperature. A solution of dibenzyldicarbonate (36.1 g, 126 mmole) in dioxane (100 ml) was added dropwise and the mixture stirred for 18 hours. Dioxane was evaporated under vacuum and the aqueous residue extracted with diethyl ether. Evaporation of the dried (Na₂ SO₄) extracts under vacuum gave a white solid which was washed with hexane to yield crude N-benzyloxycarbonyl-O-benzyl-L-serine (39.57 g, 95percent).
95%	With sodium carbonate In 1,4-dioxane; water	To a stirred solution of O-benzyl-L-serine (25.0 g, 128 mmole) in water (200 ml) and dioxane (100 ml) was added sodium carbonate (7.46 g, 70 mmole) at room temperature. A solution of dibenzyldicarbonate (36.1 g, 126 mmole) in dioxane (100 ml) was added dropwise and the mixture stirred for 18 hours. Dioxane was evaporated under vacuum and the aqueous residue extracted with diethyl ether. Evaporation of the dried (Na₂SO₄) extracts under vacuum gave a white solid which was washed with hexane to yield crude N-benzyloxycarbonyl-O-benzyl-L-serine (39.57 g, 95percent).

Reference： [1] Liebigs Annalen der Chemie, 1994, # 6, p. 641 - 644
[2] Patent: US5030654, 1991, A,
[3] Patent: EP274234, 1991, B1,

5
[ 31139-36-3 ]
[ 63219-70-5 ]

Reference： [1] Liebigs Annales, 1996, # 2, p. 235 - 238

6
[ 35418-16-7 ]
[ 31139-36-3 ]
[ 81470-51-1 ]

Reference： [1] Organic Preparations and Procedures International, 2001, vol. 33, # 4, p. 405 - 409

7
[ 31139-36-3 ]
[ 116183-82-5 ]
[ 122536-73-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6779 - 6784

8
[ 40499-83-0 ]
[ 31139-36-3 ]
[ 95656-88-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydroxide In tetrahydrofuran; water at 20℃; for 3 h;	To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO₃(2.x.20mL) and saturated NaCl (2.x.20 mL). The solution was dried over Na₂SO₄, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47percent) was isolated by prep. HPLC YMC ODSA 30.x.100 mm, 20-100percent MeOH/H₂O (0. 1percent TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H₂O 0.1percent TFA).

Reference： [1] Patent: US2007/161685, 2007, A1, . Location in patent: Page/Page column 126

9
[ 31139-36-3 ]
[ 7144-05-0 ]
[ 157023-34-2 ]

Reference： [1] Patent: US6329380, 2001, B1,

10
[ 6457-49-4 ]
[ 31139-36-3 ]
[ 122860-33-7 ]

Reference： [1] Patent: US4968704, 1990, A,

11
[ 31139-36-3 ]
[ 869468-32-6 ]

Reference： [1] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8790 - 8800

[ 31139-36-3 ] Synthesis Path-Downstream 1~30

1
[ 4726-96-9 ]
[ 31139-36-3 ]
[ 20806-43-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium carbonate; In 1,4-dioxane; water;	To a stirred solution of O-benzyl-L-serine (25.0 g, 128 mmole) in water (200 ml) and dioxane (100 ml) was added sodium carbonate (7.46 g, 70 mmole) at room temperature. A solution of dibenzyldicarbonate (36.1 g, 126 mmole) in dioxane (100 ml) was added dropwise and the mixture stirred for 18 hours. Dioxane was evaporated under vacuum and the aqueous residue extracted with diethyl ether. Evaporation of the dried (Na2 SO4) extracts under vacuum gave a white solid which was washed with hexane to yield crude N-benzyloxycarbonyl-O-benzyl-L-serine (39.57 g, 95%).
95%	With sodium carbonate; In 1,4-dioxane; water;	To a stirred solution of O-benzyl-L-serine (25.0 g, 128 mmole) in water (200 ml) and dioxane (100 ml) was added sodium carbonate (7.46 g, 70 mmole) at room temperature. A solution of dibenzyldicarbonate (36.1 g, 126 mmole) in dioxane (100 ml) was added dropwise and the mixture stirred for 18 hours. Dioxane was evaporated under vacuum and the aqueous residue extracted with diethyl ether. Evaporation of the dried (Na2SO4) extracts under vacuum gave a white solid which was washed with hexane to yield crude N-benzyloxycarbonyl-O-benzyl-L-serine (39.57 g, 95%).

Reference： [1]Liebigs Annalen der Chemie,1994,p. 641 - 644
[2]Patent: US5030654,1991,A
[3]Patent: EP274234,1991,B1

2
[ 10433-52-0 ]
[ 31139-36-3 ]
[ 20806-42-2 ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 11321 - 11328

3
[ 6945-92-2 ]
[ 31139-36-3 ]
[ 4503-58-6 ]
[ 4467-44-1 ]
[ 100260-20-6 ]

Reference： [1]Tetrahedron Letters,1991,vol. 32,p. 2765 - 2768

4
[ 31139-36-3 ]
[ 83392-10-3 ]
[ 113283-99-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1905 - 1912
[2]Journal of the Chemical Society. Chemical communications,1987,p. 1250 - 1251

5
[ 31139-36-3 ]
[ 113283-93-5 ]
[ 113283-95-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1905 - 1912
[2]Journal of the Chemical Society. Chemical communications,1987,p. 1250 - 1251

6
[ 13734-34-4 ]
[ 31139-36-3 ]
[ 66617-58-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap In tetrahydrofuran for 0.333333h;

Reference： [1]Takeda; Akiyama; Nakamura; Takizawa; Mizuno; Takayanagi; Harigaya [Synthesis, 1994, # 10, p. 1063 - 1066]

7
[ 31139-36-3 ]
[ 99726-03-1 ]
[ 186759-45-5 ]

Yield	Reaction Conditions	Operation in experiment
8.7 g	With sodium hydrogencarbonate In methanol; water; ethyl acetate biphasic;

Reference： [1]Sabat, Mark; Johnson, Carl R. [Organic Letters, 2000, vol. 2, # 8, p. 1089 - 1091]

8
[ 31139-36-3 ]
[ 156-87-6 ]
[ 34637-22-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In methanol for 1h; Heating;

Reference： [1]DeMong, Duane E.; Williams, Robert M. [Tetrahedron Letters, 2001, vol. 42, # 2, p. 183 - 185]

9
[ 31139-36-3 ]
[ 4931-66-2 ]
[ 75857-94-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap In acetonitrile at 20℃; for 3h;

Reference： [1]Jain, Rahul [Organic Preparations and Procedures International, 2001, vol. 33, # 4, p. 405 - 409]

10
[ 31139-36-3 ]
[ 148546-99-0 ]
[ 378759-37-6 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3946 - 3955

11
[ 6304-89-8 ]
[ 31139-36-3 ]
3-acetoxybenzoic acid benzyl ester [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2003,vol. 345,p. 943 - 947

12
[ 14527-26-5 ]
[ 31139-36-3 ]
[ 25508-20-7 ]

Reference： [1]Synthesis,2004,p. 37 - 42

13
[ 31139-36-3 ]
[ 23356-96-9 ]
[ 6216-63-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 3153 - 3164

14
[ 31139-36-3 ]
[ 869468-32-6 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 8790 - 8800

15
[ 31139-36-3 ]
[ 63219-70-5 ]

Reference： [1]Liebigs Annales,1996,p. 235 - 238

16
[ 31139-36-3 ]
[ 99793-10-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 94 percent / 0.27N NaOH / dioxane / 0.5 h / Ambient temperature 2: 1.) Cs₂CO₃ / 1.) THF/H₂O, r.t.; 2.) DMF, r.t. 3: 95 percent / TFA / CH₂Cl₂ / 0.5 h

Reference： [1]Xaus, N.; Clapes, P.; Bardaji, E.; Torres, J. L.; Jorba, X.; et al. [Tetrahedron, 1989, vol. 45, # 23, p. 7421 - 7426]

17
[ 3544-25-0 ]
[ 31139-36-3 ]
[ 861250-54-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	In 1,4-dioxane at 20℃; for 1h;	62.2 Stage 62.2 [4-(Cyano-methyl)-phenyl]-carbamic acid benzyl ester (4-Amino-phenyl)-acetonitrile (2 g, 15.1 mmol) and dibenzyl dicarbonate (4.33 g, 15.1 mmol) dissolved in dioxane (16 mL) are stirred for 1 hour at RT. After evaporating the solvent, the product is isolated by flash chromatography (silica gel, 4.5×25 cm, CH2Cl2/MeOH=99:1): white solid (3.82 g, 14.4 mmol; 95%); ES-MS: M-H=265.0; Rf(CH2Cl2/MeOH=95:5)=0.49; HPLC: AtRet=6.32 minutes. 1H-NMR (400 MHz, DMSO-d6): 9.82 (s, 1H, NH), 7.51-7.35 (m, 7H, aryl), 7.26 (d, 8.5 Hz, 2H, aryl), 5.15 (s, 2H, CH2), 3.95 (s, 2H, CH2).
95%	In 1,4-dioxane at 20℃; for 1h;	69.62.2 Stage 62.2 [4-(Cyano-methyl)-phenyl]-carbamic acid benzyl ester Stage 62.2 [4-(Cyano-methyl)-phenyl]-carbamic acid benzyl ester (4-Amino-phenyl)-acetonitrile (2 g, 15.1 mmol) and dibenzyl dicarbonate (4.33 g, 15.1 mmol) dissolved in dioxane (16 mL) are stirred for 1 hour at RT. After evaporating the solvent, the product is isolated by flash chromatography (silica gel, 4.5*25 cm, CH2Cl2/MeOH=99:1): white solid (3.82 g, 14.4 mmol; 95%); ES-MS: M-H=265.0; Rf (CH2Cl2/MeOH=95:5)=0.49; HPLC: AtRet=6.32 minutes. 1H-NMR (400 MHz, DMSO-d6): 9.82 (s, 1H, NH), 7.51-7.35 (m, 7H, aryl), 7.26 (d, 8.5 Hz, 2H, aryl), 5.15 (s, 2H, CH2), 3.95 (s, 2H, CH2).
95%	In 1,4-dioxane at 20℃; for 1h;	62.62.2 (4-Amino-phenyl)-acetonitrile (2 g, 15.1 mmol) and dibenzyl dicarbonate (4.33 g, 15.1 mmol) dissolved in dioxane (16 mL) are stirred for 1 hour at RT. After evaporating the solvent, the product is isolated by flash chromatography (silica gel, 4.5 x 25 cm, CH2CI2/MeOH = 99: 1): white solid (3.82 g, 14.4 mmol ; 95%); ES-MS: M-H = 265.0 ; Rf (CH2Cl2/MeOH = 95: 5) = 0.49 ; HPLC: AtRet = 6.32 minutes. 'H-NMR (400 MHz, DMSO-d6) : 9.82 (s, 1 H, NH), 7.51-7. 35 (m, 7H, aryl), 7.26 (d, 8.5 Hz, 2H, aryl), 5.15 (s, 2H, CH2), 3.95 (s, 2H, CH2).

68%

In water at 20℃; for 0.333333h;

19.2 19.2 Preparation of benzyl (4-(cyanomethyl)phenyl)carbamate General procedure: A 5 mL microwave vial was charged with the amine (1.0 equiv.) and a HPMC-solution (40-60 cps, 2 wt% in Millipore water, 1.5 mL). After the addition of dibenzyl dicarbonate (1.0 equiv.) the reaction mixture was stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. Ethyl acetate (1 mL) was added followed by a saturated solution of sodium sulfate in water (2 mL). The organic phase was dried over sodium sulfate and the product was obtained after column chromatography on silica gel.; Following the general procedure using 4-aminophenylacetonitrile (66.0 mg, 0.50 mmol, 1.0 equiv) and dibenzyl dicarbonate (143.0 mg, 0.50 mmol, 1.0 equiv) the reaction was stirred for 20 min at room temperature. After column chromatography on silica gel (0-1 % dichloromethane - methanol) the product was obtained as a white solid (91 mg, 0.34 mmol, 68 %).ESI-MS: m/z (%): 267.1 (80, [M+H]+).1H NMR (600MHz, CDC13): δ [ppm]: 7.51 - 6.84 (m, 10H), 5.18 (s, 2H), 3.66 (s, 2H).

Reference： [1]Current Patent Assignee: DISTRIBUTION PRODUIT ALIMENTAIRE; NOVARTIS AG; BOLD (inventors); Novartis (w/o Sandoz); FLOERSHEIMER; FURET; YODOGAWA STEEL WORKS LTD; IMBACH; NIBR (in: Novartis); MARTINY BARON - US2005/222171, 2005, A1 Location in patent: Page/Page column 41
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2009/69315, 2009, A1 Location in patent: Page/Page column 48
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/70431, 2005, A1 Location in patent: Page/Page column 88-89
[4]Current Patent Assignee: ABBVIE INC - WO2017/129796, 2017, A1 Location in patent: Page/Page column 256; 257

18
[ 356572-08-2 ]
[ 31139-36-3 ]
[ 356572-20-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; sodium sulfate In water; N,N-dimethyl-formamide	9 Synthesis of 1-(benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (13) EXAMPLE 9 Synthesis of 1-(benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (13) To a solution of 1-amino-3,5-dimethyl-7-hydroxyadamantane hydrochloride (570 mg) in DMF (5 mL) and water (0.3 mL) was added dibenzyl dicarbonate (1.41 g) and sodium carbonate (1.3 g). The reaction mixture was stirred overnight. The product was extracted with t-butyl methyl ether (500 mL) and washed with water (400 mL2). The organic phase was dried using sodium sulfate and the solvent was removed in vacuo. The product was purified by flash column chromatography eluding with ethyl acetate and hexane (1/3, v/v) to afford 701 mg of white solid. 1H NMR (DMSO-d6, ppm): 7.35-7.28 (m, 5 H, C6H5), 6.96 (brs, 1 H, NH), 4.94 (s, 2 H, OCH2), 4.41 (1 H, OH), 1.62 (s, 2 H), 1.43 (s, 4 H), 1.24-1.14 (dd, 4 H, J=11.5,22.0 Hz), 0.97 (s, 2 H), 0.83 (s, 6 H, 2CH3).
	With sodium carbonate In water; N,N-dimethyl-formamide	9 Synthesis of 1-(benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (13) EXAMPLE 9 Synthesis of 1-(benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (13) To a solution of 1-amino-3,5-dimethyl-7-hydroxyadamantane hydrochloride (570 mg) in DMF (5 ml) and water (0.3 mL) was added dibenzyl dicarbonate (1.41 g) and sodium carbonate (1.3 g). The reaction mixture was stirred overnight. The product was (brs, 1H, OH), 1.59 (s, 2H), 1.40 (s, 4H), 1.35 (s, 9H, 3CH3), 1.22-1.13 (dd, 4H, J 11.1, 20.6 Hz), 0.99 (s, 2H), 0.82 (s, 6H, 2CH3).

Reference： [1]Current Patent Assignee: PANORAMA RESEARCH INC - US6444702, 2002, B1
[2]Current Patent Assignee: SUPERNUS PHARMACEUTICALS INC - US2004/122090, 2004, A1

19
[ 31139-36-3 ]
[ 21339-55-9 ]
CBZ-1-methyl-DL-tryptophan [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In 1,4-dioxane; water;	Step 1: CBZ-1-methyl-DL-tryptophan 1-Methyl-DL-tryptophan was suspended in H2 O/dioxan (20 mL) and NaHCO3 (0.072 g, 8 mmol) added. A solution of dibenzyldicarbonate (1.37 g, 4.8 mmol) was added and the reaction was stirred at room temperature overnight. The solution was diluted with water then washed with ether. The aqueous was then acidified to pH 1 with concentrated HCl and extracted with ethylacetate. The combined organic extracts were washed with water, dried over MgSO4, and the solvent removed in vacuo. The brown oil obtained was purified by reverse phase chromatography (0.800 g, 65percent); mp 58°-60° C.; [alpha D20 =0 (c=0.25, MeOH); IR (film): 1716 (urethane CO), 1507 cm-1 (amide II); NMR (DMSO-d6): delta 2.99 (1H, dxd, J=14.7, 9.5 Hz, one of betaCH2); 3.16 (1H, dxd, J=14.7 and 4.5 Hz, one of betaCH2); 3.71 (3H, s, NCH3); 4.32 (1H, m, alphaCH); 4.97 (2H, s, CH2 Ph); 7.01-7.65 (11H, m, aromatic protons, urethane NH); 12.65 (1H, s, br, CO2 H);

Reference： [1]Patent: US5594022,1997,A

20
[ 6457-49-4 ]
[ 31139-36-3 ]
[ 122860-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; water;	(i) 1-(Benzyloxycarbonyl)-4-piperidinemethanol Dibenzyldicarbonate (28.6 g) was added portionwise to a stirred solution of 4-piperidinemethanol (11.3 g) in 1,4-dioxane (50 ml) and water (50 ml). The solution was stirred for 1 hour and then evaporated. Water was added to the residue and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated to give an oil which was chromatographed on silica gel, eluding with ether. Earlier fractions contained impurity and the pure product was eluted in the later fractions. The product fractions were combined and evaporated to give a viscous oil, (18.45 g), which was used without further purification.

Reference： [1]Patent: US4968704,1990,A

21
[ 4125-93-3 ]
[ 31139-36-3 ]
[ 47307-26-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃;	(S)~2-Amino-succinic acid 1-tert-butyl ester (0.9g, 4.75mmol) and sodium hydroxide (0.28g, 7.13mmol, 1.5eq) were dissolved in 25% water in dioxane (50ml). The solution was stirred at 50C and dibenzyldicarbonate (2g, 4.13mmol, 1.5eq) in dioxane (10ml) was added slowly. The mixture was stirred at O0C for 1 h and then at r. t. overnight. Water (10ml) was added and the mixture was extracted with EtOAc (2 x 20ml). The organic phase was back extracted with a sat. aq. Solution of sodium bicarbonate (2 x 10ml). The combined aq. Layers were acidified to pH 1 with 1M HCI, and extracted with EtOAc (3 x 10ml). The combined organic fractions were dried over MgSO4 and concentrated under reduced pressure. The product was purified by column chromatography (35% EtOAc in heptane) to afford the title compound as a colorless oil (0.76g, 50%). m/z 346 [M+23] +, 1H NMR (300 MHz, CDCI3), delta: 7.39-7.32 (5H, m), 5.72 (1H, d, J = 8.1Hz), 5.13 (2H, s), 4.58-4.50 (1H, m), 3.10-2.99 (1 H, m), 2.94-2.83 91 H, m), 1.45 (9H, s).
50%	With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃;	(S)-2-Amino-succinic acid 1-tert-butyl ester (0.9 g, 4.75 mmol) and sodium hydroxide (0,28 g, 7.13 mmol, 1.5 eq) were dissolved in 25% water in dioxane (50 ml). The solution was stirred at 50C and dibenzyldicarbonate (2 g, 4.13 mmol, 1.5 eq) in dioxane (10 ml) was added slowly. The mixture was stirred at O0C for 1 hour and then at room temperature overnight. Water (10 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic phase was back extracted with a saturated aqueous solution of sodium bicarbonate (2 x 10 ml). The combined aqueous layers were acidified to pH 1 with 1M HCI, and extracted with ethyl acetate (3 x 10 ml). The combined organic fractions were dried over magnesium sulphate and concentrated under reduced pressure. The product was purified by column chromatography (35% ethyl acetate in heptane) to provide 0.76 g (50% yield) of title compound as a colourless oil.LC/MS: m/z 346 [M+23] +, 1H NMR (300 MHz, CDCI3), delta 7.39-7.32 (5H, m), 5.72 (1 H, d, J=8.1 Hz), 5.13 (2H, s), 4.58-4.50 (1H, m), 3.10-2.99 (1 H, m), 2.94-2.83 (1 H, m), 1.45 (9H, s).

Reference： [1]Patent: WO2006/117567,2006,A2 .Location in patent: Page/Page column 45
[2]Patent: WO2006/117552,2006,A1 .Location in patent: Page/Page column 101-103

22
[ 1776-53-0 ]
[ 31139-36-3 ]
[ 220851-34-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium carbonate; In 1,4-dioxane; water;	(a) Preparation of cis-4-benzyloxycarbonylaminocyclohexane carboxylic acid Sodium carbonate (4.03 g, 38 mmole) was added in small portions to a stirred solution of cis-4-aminocyclohexane carboxylic acid (10.0 g, 69 mmole) in a mixture of dioxane (80 ml) and water (40 ml). After 15 minutes a solution of dibenzyl dicarbonate (19.47 g, 68 mmole) in dioxane (40 ml) was added dropwise followed by water (40 ml). The mixture was stirred for 18 hours at room temperature, the solvent evaporated under vacuum and the residue partitioned between diethyl ether and water. The organic phase was washed with dilute hydrochloric acid and water, dried over sodium sulphate and evaporated under vacuum to give cis-4-benzyloxycarbonylaminocyclohexane carboxylic acid as an oil (14.5 g, 75%). Found: C,64.88; H,6.98; N,5.13. C15 H19 NO4 requires C,64.97; H,6.91; N,5.05%.

Reference： [1]Patent: US5030654,1991,A

23
[ 1776-53-0 ]
[ 31139-36-3 ]
3-{1-[(cis-4-{5-Indanyloxycarbonyl}cyclohexyl)carbamoyl]cyclopentyl}-2-(2-methoxyethoxy)propanoic acid [ No CAS ]
[ 220851-34-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium carbonate; In 1,4-dioxane; water;	(a) Preparation of cis-4-benzyloxycarbonylaminocyclohexane carboxylic acid Sodium carbonate (4.03 g, 38 mmole) was added in small portions to a stirred solution of cis-4-aminocyclohexane carboxylic acid (10.0 g, 69 mmole) in a mixture of dioxane (80 ml) and water (40 ml). After 15 minutes a solution of dibenzyl dicarbonate (19.47 g, 68 mmole) in dioxane (40 ml) was added dropwise followed by water (40 ml). The mixture was stirred for 18 hours at room temperature, the solvent evaporated under vacuum and the residue partitioned between diethyl ether and water. The organic phase was washed with dilute hydrochloric acid and water, dried over sodium sulphate and evaporated under vacuum to give cis-4-benzyloxycarbonylaminocyclohexane carboxylic acid as an oil (14.5 g, 75%). Found: C,64.88; H,6.98; N,5.13. C15H19NO4 requires C,64.97; H,6.91; N,5.05%.

Reference： [1]Patent: EP274234,1991,B1

24
[ 31139-36-3 ]
[ 7144-05-0 ]
[ 157023-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzaldehyde; In toluene;	Step A 1-Benzyloxycarbonyl-4-(aminomethyl)piperidine To a solution of 4-(aminomethyl)piperidine (200 mg, 1.75 mmol) in toluene (2.3 mL) was added benzaldehyde (178 muL, 1.75 mmol) and the reaction mixture was refluxed for 3 h with azeotropic removal of water. The reaction mixture was cooled and dibenzyl dicarbonate (471 muL, 1.92 mmol) was added dropwise. After stirring overnight, toluene was removed under reduced pressure and the residue was stirred in 1NKHSO4 (2 mL) for 5 h. The residue was washed with Et2O (discarded) then made strongly basic (>pH 12) with SN NaOH. The aqueous layer was extracted with CH2Cl2 (4 times), and the combined extracts were washed with brine. After drying (Na2SO4) and removal of the solvent under reduced pressure, 340 mg of the title compound was obtained. Partial 1H NMR (500 MHz, CDCl3): delta 7.38-7.27 (m, 5H); 5.1 (s, 2H); 4.19 (br s, 2H); 2.76 (br s, 2H); 2.57 (d, J=6.5 Hz 2H); 1.69 (brm, 2H); 1.44 (m, 1H); 1.09 (brm, 2H).

Reference： [1]Patent: US6329380,2001,B1

25
[ 40499-83-0 ]
[ 31139-36-3 ]
[ 95656-88-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 3h;	To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2×20mL) and saturated NaCl (2×20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47%) was isolated by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0. 1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1% TFA).

Reference： [1]Patent: US2007/161685,2007,A1 .Location in patent: Page/Page column 126

26
[ 31139-36-3 ]
[ 184954-75-4 ]
C₁₉H₂₈N₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2425 - 2430

27
[ 1492-24-6 ]
[ 31139-36-3 ]
[ 42918-86-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4585 - 4592

28
[ 31139-36-3 ]
[ 112159-16-7 ]
[ 132245-78-4 ]

Yield	Reaction Conditions	Operation in experiment
82.3%	With triethylamine In methanol at 30℃;	2 Example 2 The Preparation of 1-benzyl-5-methyl-2-((tert-butyloxycarbonyl)amino)pentanedioate To a 100 ml one-necked flask was added 5-methyl-2-((tert-butyloxycarbonyl)amino)-pentanedioate (7.8 g, 24.6 mmol), di-benzyl dicarbonate (6.86 g, 27 mmol), triethylamine (0.75 g, 7.4 mmol) and 30 ml methanol. After the mixture was stirred at 30° C. for one night, the solvent was evaporated and the residue was purified by column chromatography to afford 7.1 g 1-benzyl-5-methyl-2-((tert-butyloxycarbonyl)amino)pentanedioate as white solid with a yield of 82.3%.

Reference： [1]Current Patent Assignee: ZHEJIANG JIUZHOU PHARMACEUTICAL CO., LTD. - US2016/145208, 2016, A1 Location in patent: Paragraph 0071; 0072

29
[ 356572-08-2 ]
[ 31139-36-3 ]
[ 356572-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate; sodium sulfate / water; N,N-dimethyl-formamide 2: N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: PANORAMA RESEARCH INC - US6444702, 2002, B1

30
[ 31139-36-3 ]
[ 4298-08-2 ]
[ 62182-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In tetrahydrofuran; water at 20℃; for 8h;	A solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (73, 4.90 g, 37.4 mmol), 4 mol/L sodium hydroxide solution (10.5 mL, 37.4 mmol) and di-tert-butyl dicarbonate (13.01 g, 56.1 mol) in a mixed solution of tetrahydrofuran (40 mL) and water (20 mL) was stirred for 8 h at room temperature. After almost half of the solvent was removed under reduced pressure, the pH value of the aqueous layer was adjusted to 2.0 by using 10% potassium hydrogen sulfate solution. The mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated. The residue was washed with a mixed solution of hexane and diethyl ethyl (3/1) to give a colorless solid (7.85 g). To an ice-cooled solution of this solid in tetrahydrofuran (120 mL) was added borane-tetrahydrofuran complex (102 mL, 97.0 mmol). The mixture was stirred for 18 h at room temperature under argon atmosphere. 4 mol/L sodium hydroxide solution (80 mL) was added, and the mixture was stirred for 30 min at room temperature. After the pH value of the solution was adjusted using 2 mol/L hydrochloric acid, the mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated to give the corresponding diol as colorless oil (7.50 g). To an ice-cooled solution of the diol and triethylamine (24.1 mL, 173 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (13.5 mL, 173 mmol). The mixture was stirred for 18 h at room temperature. After water was added, the mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over sodium sulfate then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate; 80:20 to 60:40) to give 74 as colorless oil (11.0 g, 79% over 3 steps).

Reference： [1]Sakai, Hiroki; Inoue, Hidekazu; Murata, Kenji; Toba, Tetsuya; Takemoto, Naohiro; Matsumoto, Takahiro; Kawabata, Takeo [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 9]

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P378
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P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
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H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 31139-36-3 ] {[proInfo.proName]}

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[ 31139-36-3 ] Synthesis Path-Upstream 1~11

[ 31139-36-3 ] Synthesis Path-Downstream 1~30

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