[ CAS No. 122225-33-6 ] {[proInfo.proName]}

Name: 122225-33-6|(R)-2-Benzyl-4-(tert-butoxy)-4-oxobutanoic acid|97%
Brand: Ambeed
SKU: A325491
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2D 3D

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Quality Control of [ 122225-33-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 122225-33-6 ]

SDS Specification

Alternatived Products of [ 122225-33-6 ]

Product Details of [ 122225-33-6 ]

CAS No. :	122225-33-6	MDL No. :	MFCD12755810
Formula :	C₁₅H₂₀O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWMRLCPQQCHIBH-GFCCVEGCSA-N
M.W :	264.32	Pubchem ID :	13584974
Synonyms :

Calculated chemistry of [ 122225-33-6 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.47
Num. rotatable bonds :	7
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	72.96
TPSA :	63.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.22
Log Po/w (XLOGP3) :	2.52
Log Po/w (WLOGP) :	2.66
Log Po/w (MLOGP) :	2.64
Log Po/w (SILICOS-IT) :	2.79
Consensus Log Po/w :	2.57

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.84
Solubility :	0.384 mg/ml ; 0.00145 mol/l
Class :	Soluble
Log S (Ali) :	-3.5
Solubility :	0.0832 mg/ml ; 0.000315 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.53
Solubility :	0.0778 mg/ml ; 0.000294 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.65

Safety of [ 122225-33-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 122225-33-6 ]

* 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 [ 122225-33-6 ]
Downstream synthetic route of [ 122225-33-6 ]

[ 122225-33-6 ] Synthesis Path-Upstream 1~16

1
[ 1229380-18-0 ]
[ 122225-33-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With water; lithium hydroxide In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water	To a solution of (R)-4-tert-butyl 1-methyl 2-benzylsuccinate (308 mg, 1.11 mmol) in THF (3mL) was added a solution of lithium hydroxide (107 mg, 4.44 mmol) in water (3 mL). The mixture was stirred at RT overnight. TLC (cyclohexane/AcOEt=7/3) indicated reaction was complete. Reaction mixture was acidified to pH=l with 2M HCl and extracted with DCM (2x20 mL). Combined organic layers were passed through a phase separator and evaporated. Crude was purified by flash chromatography (cyclohexane/AcOEt= 9/l->7/3) (loading as solution in starting eluent) to yield title compound as a colorless oil. Y: 274mg (94percent), P>95percent, rt=4.17 mn (gradient A), (M+H)⁺ =209 (-/¹Bu).

Reference： [1] Patent: WO2010/66682, 2010, A1, . Location in patent: Page/Page column 207-208

2
[ 150544-79-9 ]
[ 122225-33-6 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 17, p. 6411 - 6417

3
[ 908290-87-9 ]
[ 908290-56-2 ]
[ 122225-33-6 ]

Reference： [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2753 - 2768

4
[ 287719-12-4 ]
[ 122225-33-6 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 9, p. 1461 - 1466

5
[ 116129-88-5 ]
[ 122225-33-6 ]

Reference： [1] Patent: US5164388, 1992, A,

6
[ 116129-79-4 ]
[ 122225-33-6 ]

Reference： [1] Patent: US5104869, 1992, A,

7
[ 5292-43-3 ]
[ 122225-33-6 ]

Reference： [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2753 - 2768
[2] Journal of Organic Chemistry, 1999, vol. 64, # 17, p. 6411 - 6417
[3] Synthetic Communications, 1992, vol. 22, # 6, p. 871 - 882

8
[ 253593-05-4 ]
[ 122225-33-6 ]

Reference： [1] Tetrahedron Asymmetry, 1999, vol. 10, # 17, p. 3285 - 3295

9
[ 136159-65-4 ]
[ 122225-33-6 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 17, p. 6411 - 6417

10
[ 908290-75-5 ]
[ 122225-33-6 ]

Reference： [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2753 - 2768

11
[ 645-45-4 ]
[ 122225-33-6 ]

Reference： [1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 14, p. 2753 - 2768

12
[ 61996-82-5 ]
[ 122225-33-6 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 9, p. 1461 - 1466

13
[ 287719-11-3 ]
[ 122225-33-6 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 9, p. 1461 - 1466

14
[ 49769-78-0 ]
[ 122225-33-6 ]

Reference： [1] Tetrahedron Asymmetry, 1999, vol. 10, # 17, p. 3285 - 3295

15
[ 100-52-7 ]
[ 122225-33-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 5169 - 5180

16
[ 1174275-13-8 ]
[ 122225-33-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 5169 - 5180

[ 122225-33-6 ] Synthesis Path-Downstream 1~51

1
[ 5557-81-3 ]
[ 122225-33-6 ]
[ 141215-90-9 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

2
1,1-dimethylethyl tetrahydro-8,8-dimethyl-γ-oxo-βR-(phenylmethyl)-7aβ-3H-3aR,3aα-6α-methano-2,1-benzisothiazole-1(4H)-butanoate [ No CAS ]
[ 122225-33-6 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

3
[ 119072-55-8 ]
[ 630-19-3 ]
[ 122225-33-6 ]
(R)-3-Benzyl-N-(1-tert-butylcarbamoyl-2,2-dimethyl-propyl)-succinamic acid tert-butyl ester [ No CAS ]

Reference： [1]Synlett,1998,p. 637 - 639

4
[ 150544-79-9 ]
[ 122225-33-6 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 6411 - 6417

5
[ 122225-33-6 ]
[ 100-51-6 ]
[ 245323-42-6 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 6411 - 6417

6
[ 253593-05-4 ]
[ 122225-33-6 ]

Reference： [1]Tetrahedron Asymmetry,1999,vol. 10,p. 3285 - 3295

7
[ 541-41-3 ]
[ 122225-33-6 ]
3-benzyl-4-ethoxycarbonyloxy-4-oxo-butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

8
[ 122225-33-6 ]
[ 21307-97-1 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

9
[ 287719-12-4 ]
[ 122225-33-6 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

10
[ 908290-87-9 ]
[ 908290-56-2 ]
[ 122225-33-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 2753 - 2768

11
[ 908290-75-5 ]
[ 122225-33-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 2753 - 2768

12
[ 5292-43-3 ]
[ 122225-33-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 2753 - 2768
[2]Journal of Organic Chemistry,1999,vol. 64,p. 6411 - 6417
[3]Synthetic Communications,1992,vol. 22,p. 871 - 882

13
[ 645-45-4 ]
[ 122225-33-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 2753 - 2768

14
[ 122225-33-6 ]
3-isocyanato-4-phenyl-butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

15
[ 122225-33-6 ]
3-azidocarbonyl-4-phenyl-butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

16
[ 122225-33-6 ]
3-tert-butoxycarbonylamino-4-phenyl-butyric acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

17
[ 61996-82-5 ]
[ 122225-33-6 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

18
[ 287719-11-3 ]
[ 122225-33-6 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 1 (2001),2000,p. 1461 - 1466

19
[ 49769-78-0 ]
[ 122225-33-6 ]

Reference： [1]Tetrahedron Asymmetry,1999,vol. 10,p. 3285 - 3295

20
[ 100-39-0 ]
t-BuOCOCH₂-X [ No CAS ]
[ 122225-33-6 ]

Reference： [1]Tetrahedron Asymmetry,1999,vol. 10,p. 3285 - 3295

21
2-benzyl-2-methoxycarbonyl-succinic acid 4-tert-butyl ester 1-methyl ester [ No CAS ]
[ 122225-33-6 ]

Reference： [1]Tetrahedron Asymmetry,1999,vol. 10,p. 3285 - 3295

22
[ 136159-65-4 ]
[ 122225-33-6 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 6411 - 6417

23
[ 122225-33-6 ]
[ 162998-91-6 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 6411 - 6417

24
[ 122225-33-6 ]
(R)-3-Benzyl-N-(1-tert-butylcarbamoyl-2,2-dimethyl-propyl)-succinamic acid [ No CAS ]

Reference： [1]Synlett,1998,p. 637 - 639

25
[ 122225-33-6 ]
[ 92175-57-0 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

26
[ 122225-33-6 ]
[ 141215-92-1 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

27
[ 122225-33-6 ]
[ 141215-91-0 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

28
bornane sultam [ No CAS ]
[ 122225-33-6 ]

Reference： [1]Synthetic Communications,1992,vol. 22,p. 871 - 882

Yield	Reaction Conditions	Operation in experiment
		B. In a similar manner, but replacing N-(4-methyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam with the appropriate compound of formula (Q), the following compounds of formula (Ka) were prepared: (2R)-3-phenyl-2-t-butoxycarbonylmethyl-propanoic acid, MS: 265 (M+H)+; (2R)-5-phenyl-2-t-butoxycarbonylmethyl-pentanoic acid, MS: 293 (M+H)+;
		B. In a similar manner, but replacing N-(4-methyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam with the appropriate compound of formula (Q), the following compounds of formula (Ka) were prepared: (2R)-3-phenyl-2-t-butoxycarbonylmethyl-propanoic acid, MS: 265 (M+H)+; (2R)-5-phenyl-2-t-butoxycarbonylmethyl-pentanoic acid, MS: 293 (M+H)+;

30
[ 122225-33-6 ]
[ 168681-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	With H2; In acetic acid;	C. (2R)-3-Phenyl-2-t-butoxycarbonylmethyl-propanoic acid (55 mg) was taken up in glacial acetic acid (20 mL) and PtO2 (25 mg) was added in acetic acid. Then the beaker was placed in a Parr bomb, it was evacuated and charged with 100 psi of H2. After stirring for 3 days, the mixture was suction filtered through a 1 cm bed of celite. The filtrate was then concentrated to a yellow oil, (2R)-3-cyclohexyl-2-t-butoxycarbonylmethyl-propanoic acid (56 mg), MS: 269 (M-H)-.
	With H2; In acetic acid;	14C. (2R)-3-Phenyl-2-t-butoxycarbonylmethyl-propanoic acid (55 mg) was taken up in glacial acetic acid (20 mL) and PtO2 (25 mg) was added in acetic acid. Then the beaker was placed in a Parr bomb, it was evacuated and charged with 100 psi of H2. After stirring for 3 days, the mixture was suction filtered through a 1 cm bed of celite. The filtrate was then concentrated to a yellow oil, (2R)-3-cyclohexyl-2-t-butoxycarbonylmethyl-propanoic acid (56 mg), MS: 269.5 (M-H)-.
	With H2; In acetic acid;	C. (2R)-3-Phenyl-2-t-butoxycarbonylmethyl-propanoic acid (55 mg) was taken up in glacial acetic acid (20 mL) and PtO2 (25 mg) was added in acetic acid. Then the beaker was placed in a Parr bomb, it was evacuated and charged with 100 psi of H2. After stirring for 3 days, the mixture was suction filtered through a 1 cm bed of celite. The filtrate was then concentrated to a yellow oil, (2R)-3-cyclohexyl-2-t-butoxycarbonylmethyl-propanoic acid (56 mg), MS: 269 (M-H)-.

Reference： [1]Patent: US6013792,2000,A
[2]Patent: US6037472,2000,A
[3]Patent: US5773428,1998,A

31
[ 116129-88-5 ]
[ 122225-33-6 ]

Yield	Reaction Conditions	Operation in experiment
1.03 g (98%)	palladium; In methanol;	EXAMPLE 99 (2R)-3-tert-Butyloxycarbonyl-2-phenylmethylpropionic Acid The diester from Example 98 (1.41 g) and 10% palladium on carbon (0.70 g) in methanol were stirred under a hydrogen atmosphere for 2 h. Filtration and solvent evaporation afforded 1.03 g (98%) of the desired product as an oil. 1 H NMR (CDCl3, TMS) delta 7.1-7.4 (m,5H), 2.95-3.15 (m,2H), 2.72 (dd,1H), 2.56 (dd,1H), 2.32 (dd,1H), 1.40 (s,9H).

Reference： [1]Patent: US5164388,1992,A

32
[ 122225-33-6 ]
tert-Butyl (3R)-4-Hydroxy-3-phenylmethylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.55 g (56%)	With BH3; In tetrahydrofuran;	EXAMPLE 100 tert-Butyl (3R)-4-Hydroxy-3-phenylmethylbutanoate To the resultant acid from Example 99 (1.03 g, 3.90 mmol) in tetrahydrofuran (4 ml, THF) at 0 C. was added BH3 in THF (5.8 ml, 5.8 mmol, 1.0 molar) over 2 min. After 2 h at 0 C. the mixture was brought to room temperature and stirred for 2 h. The reaction was poured into saturated NaHCO3 solution and extracted into ethyl acetate which was dried over Na2 SO4 and evaporated. Chromatography of the residue on silica gel with ethyl acetate/hexane mixtures afforded 0.55 g (56%) of the desired product as an oil. 1 H NMR (CDCl3, TMS) delta 7.15-7.35 (m,5H), 3.65 (m,1H), 3.52 (m,1H), 2.65 (m,2H), 2.30 (m,2H), 1.90 (m,1H), 1.46 (s,9H).

Reference： [1]Patent: US5164388,1992,A

33
[ 116129-79-4 ]
[ 122225-33-6 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide; dihydrogen peroxide; sodium hydrogencarbonate; sodium sulfite; In tetrahydrofuran; water;	REFERENCE EXAMPLE 21 (R)2-(Phenylmethyl)butanedioic acid, 4-(1,1-dimethylethyl)ester To a solution of 0.10 g of 1,1-dimethylethyl (S)4-(1-methylethyl)-gamma,2-dioxo-(R)beta-(phenylmethyl)-3-oxazolidinebutanoate in 9 ml of tetrahydrofuran and 3 ml of water, cooled to 0 C., was added 0.18 ml of 30% hydrogen peroxide, followed by addition of 23 mg of lithium hydroxide. The suspension was stirred at room temperature for 1.5 hours. To the solution was added, at 0 C., 2 ml of 1N sodium sulfite and the mixture stirred for 15 minutes at room temperature. Saturated sodium bicarbonate was added and the solvent removed under reduced pressure. The residue in 2 ml of water was extracted with two 5 ml portions of dichloromethane. The aqueous solution was acidified with 6N hydrochloric acid and extracted with 15 ml of ethyl acetate. The extract was dried (Na2 SO4) and the solvent removed to give 0.080 g of white solid; [alpha]D26 +8+-1 (c, 1.002, CHCl3).

Reference： [1]Patent: US5104869,1992,A

Yield	Reaction Conditions	Operation in experiment
		Example 54 (2R)-3-t-Butyloxycarbonyl-2-benzylpropionic Acid. The resultant compound from Example 46 and an equal weight of 10% palladium on carbon in methanol were stirred under a hydrogen atmosphere for 1 h. The mixture was filtered and evaporated to provide the desired product. 1H NMR (CDCl3, TMS) delta 7.25 (m,5H), 3.07 (m,2H), 2.73 (dd,1H), 2.56 (dd,1H), 2.33 (dd,1H), 1.40 (s,9H).
		Example 34 (2R)-3-t-Butyloxycarbonyl-2-benzylpropionic Acid. The resultant compound from Example 26 and an equal weight of 10% palladium on carbon in methanol were stirred under a hydrogen atmosphere for 1 h. The mixture was filtered and evaporated to provide the desired product. 1H NMR (CDCl3, TMS) delta 7.25 (m,5H), 3.07 (m,2H), 2.73 (dd,1H), 2.56 (dd,1H), 2.33 (dd,1H), 1.40 (s,9H).
		Example 50 (2R)-3-t-Butyloxycarbonyl-2-benzylpropionic Acid. The resultant compound from Example 42 and an equal weight of 10% palladium on carbon in methanol were stirred under a hydrogen atmosphere for 1 h. The mixture was filtered and evaporated to provide the desired product. 1H-NMR (CDCl3, TMS) delta 7.25 (m,5H), 3.07 (m,2H), 2.73 (dd,1H), 2.56 (dd,1H), 2.33 (dd,1H), 1.40 (s,9H).

35
[ 122225-33-6 ]
[ 74-88-4 ]
[ 1229380-16-8 ]

Yield	Reaction Conditions	Operation in experiment
87%		Example 68: compound n68: (3R)-3-benzyl-4-(4-(2-chlorophenyl)thiazol-2- ylamino)-2-methyl-4-oxobutanoic acid was synthesized as described in Scheme 7.

Reference： [1]Patent: WO2010/66682,2010,A1 .Location in patent: Page/Page column 193; 221

36
[ 21344-90-1 ]
[ 122225-33-6 ]
[ 1229380-22-6 ]

Yield	Reaction Conditions	Operation in experiment
67%		To a solution of (R)-2-benzyl-4-tert-butoxy-4-oxobutanoic acid Ib (1.21 mmol, 320 mg) in anhydrous DMF (5mL) was added HATU (1.33mmol, 505mg). After 5 min was added 4-(2-chlorophenyl)thiazol-2-amine 2a (1.33 mmol, 279 mg) and DIEA (1.815 mmol, 300 muL). Reaction mixture was stirred at RT for 4 days. TLC (cyclohexane/AcOEt=8/2) indicated reaction was complete. Reaction mixture (rm) was diluted with AcOEt (2OmL) and washed with sat. aq. NaHCO3 (1OmL) and water (3x10 mL). The organic phase was dried over MgSO4 and evaporated. Crude was purified by flash chromatography (cyclohexane/ AcOEt= 9/1) (loading onto silica) to yield title compound as a yellow gum. Y: 370 mg (67percent), P>95percent, rt=5.24 mn (gradient A), (M+H)+ =457.1. ACN was also used instead of DMF

Reference： [1]Patent: WO2010/66682,2010,A1 .Location in patent: Page/Page column 212

37
[ 1229380-18-0 ]
[ 122225-33-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a solution of (R)-4-tert-butyl 1-methyl 2-benzylsuccinate (308 mg, 1.11 mmol) in THF (3mL) was added a solution of lithium hydroxide (107 mg, 4.44 mmol) in water (3 mL). The mixture was stirred at RT overnight. TLC (cyclohexane/AcOEt=7/3) indicated reaction was complete. Reaction mixture was acidified to pH=l with 2M HCl and extracted with DCM (2x20 mL). Combined organic layers were passed through a phase separator and evaporated. Crude was purified by flash chromatography (cyclohexane/AcOEt= 9/l->7/3) (loading as solution in starting eluent) to yield title compound as a colorless oil. Y: 274mg (94%), P>95%, rt=4.17 mn (gradient A), (M+H)+ =209 (-/1Bu).

Reference： [1]Patent: WO2010/66682,2010,A1 .Location in patent: Page/Page column 207-208

38
[ 122225-33-6 ]
[ 1401625-08-8 ]

Reference： [1]Patent: WO2012/130299,2012,A1

39
[ 122225-33-6 ]
[ 1401625-09-9 ]

Reference： [1]Patent: WO2012/130299,2012,A1

40
[ 122225-33-6 ]
[ 1401625-12-4 ]

Reference： [1]Patent: WO2012/130299,2012,A1

41
[ 122225-33-6 ]
[ 1401624-38-1 ]

Reference： [1]Patent: WO2012/130299,2012,A1

42
methyl 1-amino-2-[4'-(4-methylplperailn-1-yI-sulfonyl)-biphenyl-4-yl]cyclopropanecarboxylate [ No CAS ]
[ 122225-33-6 ]
[ 1401625-06-6 ]
[ 1401625-07-7 ]

Yield	Reaction Conditions	Operation in experiment
	With DMT-MM; In dichloromethane; at 0℃; for 2h;	(lR<2R)-methyl-1 -((S)-2-(tert-butoxycartx>nylamino)-3-phenyl-propanamldo)-2-(4'-(4- methyl-piperazin-1 -yisuifonyi)biphenyI-4-yi)cyc.opropanecarboxylate (PZ10Q4-1), and (lS,2S)-methyl l-((S)-2-(tert-butoxycarbonylamlno)- 3-pheny.propanam.do}-2-(4'-(4- methylplperazln-1 -ylsulfonyl)blphenyl-4-yl)cyciopropanecarboxylate (PZ1005-1):A solution of PZ955-4 (See example 5; 2.5 g, 5.83 mmol) In d.chloromethane (30 mL) was mixed with a solution of Boc-Phe-OH (1.85 g, 7.0 mmol) and DMTM (1.94 g, 7.0 mmol) In dichloromethane (50 mL) at 0 C. The reaction was stirred for 2 h at 0 C, and quenched with a mixture of water/dichloromethane (100 mL 100 mL). The DCM phase was separated, and the aqueous phase was extracted with dichloromethane (100 mLx2), The organic phases were collected, dried over anhydrous Na2S04, and concentrated. The crude product was purified by HPFC (PE: EA = 1 : 3) to yield a mixture of stereomers (3.0 g), which was separated by chlral-HPLC to afford PZ1004-1 (1.4 g) (LC- S: 677.2 (M+l)) and PZ1005-1 (1.4 g) (LC-MS: 677.3 (M+l)).

Reference： [1]Patent: WO2012/130299,2012,A1 .Location in patent: Page/Page column 142

43
(E)-2-benzylidene-4-(tert-butoxy)-4-oxobutanoic acid [ No CAS ]
[ 122225-33-6 ]

Yield	Reaction Conditions	Operation in experiment
48%		The title compd was prepared following Scheme 1 (steps a-c). Step a: To a stirred solution of 4-(tert-butyl)-1-methyl-2-(dimethoxyphosphoryl) succinate (14, Scheme 1 ) (77g, 0.26mol) in THF (1 L), was added n-BuLi (1.6M in hexanes, 179mL, 0.29mol) dropwise (45min) at 5-15C (ice bath). The orange solution thus obtained was stirred at 5-15C for 90min. whereupon a THF solution (200mL) of benzaldehyde (27.5g, 0.26mol) added dropwise (30min) at 5-10C. The viscous solution was then allowed to warm gradually to rt and stirred overnight. Thereafter the reaction was quenched with ice/water (300mL), the volatiles removed in vacuo and the resultant residue taken up in saturated aq NaHCO3 (400mL) and then extracted with EtOAc (2400mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo to obtain a brown oil (85g) that was purified by silica gel flash chromatography using an increasing gradient from 1 to 10% EtOAc/petroleum ether to obtain 4-(tert-butyl) 1-methyl (E)-2-benzylidenesuccinate 15 (31g, 0.11mol, 42%) as an off-white solid. LCMS (Method B) m/z 277 (M+1). HPLC purity>98% (254nm). 1H NMR (CDCl3): delta 7.83 (s, 1H), 7.34 (m, 5H), 3.80 (s, 3H), 3.44 (s, 2H), 1.44 (s, 9H). Step b: To a stirred solution of 15 (29g, 0.11mol) in THF (600mL) was added Bu4NOH (1M in water, 210mL, 0.21mol) and stirred 75 min (reaction completion confirmed by LCMS). After removal of volatiles in vacuo, the reaction mixture was adjusted to pH 7 using pre-cooled 1M HCl (130mL) and the cloudy suspension extracted with EtOAc (400mL), washed with 0.5M HCl (3200mL), brine (50mL) and dried (Na2SO4) to obtain (E)-2-benzylidene-4-(tert-butoxy)-4-oxobutanoic acid, 16 (21.4g, 74%) as a pale yellow solid after removal of volatiles. LCMS (Method B) m/z 263 (M+1). HPLC purity>98% (254nm). 1H NMR (CDCl3): delta 7.95 (s, 1H), 7.37 (m, 5H), 3.46 (s, 2H), 1.45 (s, 9H). Step c: To a solution of 16 (36g, 0.137mol) in methanol (270mL) was added 27.36mL (0.137mol) of dicyclohexylamine whereupon the reaction vessel and mixture was thoroughly degassed using Ar. To this degassed solution was added RuCl2[(S)-BINAP] (350mg, 0.4mmol) under Ar and subsequently the reaction vessel was evacuated and back-filled with hydrogen three times; the hydrogen pressure was ultimately adjusted to 10 bars and reaction mixture heated (autoclave) at 55C and left stirring for 3days whereupon the mixture was allowed to reach rt, degassed and concentrated to dryness to obtain the crude product (%ee 82.8). This crude dicyclohexylamine salt was recrystallized three times from CH3CN/H2O (v/v, 50:1) and subsequently free-based by stirring the recrystallized salt in water, acidifying to pH 1 (6M aq. HCl) and EtOAc extraction to obtain 17 (17.3g, 48%). LCMS (Method B) m/z 265 (M+1). HPLC purity>98% (254nm). Chiral LC (Method C):>98 %ee (tR(R)=8.13min, tR(S)=8.97min). 1H NMR (CDCl3): delta 7.34 (m, 5H), 3.1 (m, 2H), 2.76 (dd, J=15.4, 10.6Hz, 1H), 2.52 (dd, J=16.8, 8.7Hz, 1H), 2.36 (dd, J=16.8, 4.2Hz, 1H), 1.41 (s, 9H).