[ CAS No. 295349-62-1 ] {[proInfo.proName]}

Name: 295349-62-1|tert-Butyl 2-chloroisonicotinate|97%
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SKU: A407962
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Quality Control of [ 295349-62-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 295349-62-1 ]

Product Details of [ 295349-62-1 ]

CAS No. :	295349-62-1	MDL No. :	MFCD03411667
Formula :	C₁₀H₁₂ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FPUSSPQEUANTGI-UHFFFAOYSA-N
M.W :	213.66	Pubchem ID :	2762480
Synonyms :

Calculated chemistry of [ 295349-62-1 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.4
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	54.99
TPSA :	39.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.89 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.56
Log Po/w (XLOGP3) :	2.42
Log Po/w (WLOGP) :	2.69
Log Po/w (MLOGP) :	1.84
Log Po/w (SILICOS-IT) :	2.54
Consensus Log Po/w :	2.41

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.81
Solubility :	0.332 mg/ml ; 0.00155 mol/l
Class :	Soluble
Log S (Ali) :	-2.89
Solubility :	0.278 mg/ml ; 0.0013 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.55
Solubility :	0.0606 mg/ml ; 0.000284 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 295349-62-1 ]

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 [ 295349-62-1 ]

* 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 [ 295349-62-1 ]
Downstream synthetic route of [ 295349-62-1 ]

[ 295349-62-1 ] Synthesis Path-Upstream 1~5

1
[ 6313-54-8 ]
[ 36805-97-7 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	for 2 h; Heating / reflux	A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]⁺ ¹H-NMR (300 MHz, CDCl₃): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%	at 90℃; for 20 h;	a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.

Reference： [1] Patent: US2008/132477, 2008, A1, . Location in patent: Page/Page column 28
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 110 - 130
[3] Patent: WO2014/141171, 2014, A1, . Location in patent: Page/Page column 17; 18

2
[ 6313-54-8 ]
[ 24424-99-5 ]
[ 295349-62-1 ]

Reference： [1] Patent: WO2008/11499, 2008, A1, . Location in patent: Page/Page column 37
[2] Organic Process Research and Development, 2009, vol. 13, # 6, p. 1145 - 1155

3
[ 65287-34-5 ]
[ 295349-62-1 ]

Reference： [1] Patent: US6548514, 2003, B1,

4
[ 65287-34-5 ]
[ 865-47-4 ]
[ 295349-62-1 ]

Reference： [1] Patent: WO2007/75896, 2007, A2, . Location in patent: Page/Page column 132

5
[ 6313-54-8 ]
[ 67098-46-8 ]
[ 295349-62-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4233 - 4249

[ 295349-62-1 ] Synthesis Path-Downstream 1~52

1
[ 6313-54-8 ]
[ 24424-99-5 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In 1-methyl-pyrrolidin-2-one; at 25℃; for 17.0h;	Example 5 to~/-butyl 2-chloroisonicotinate; A 1-L jacketed 3-neck round bottom flask equipped with overhead stirrer, N2-InIeI vented to the atmosphere and thermocouple was charged with 2-chloroisonicotinic acid (78,0 g, 495 mrnol), di-foer/-butyl dicarbonate (230.1 g, 1054 mmol), and l-methyl-2-pyitauolidinone (179 3 g) A solution of 4-dimethyJamino pyridine (1 1.61 g, 95 mrnol) dissolved in l -methyl-2- pyriolidinone (60 0 g) was charged to the mixture and the temperature was adjusted to 25 +/-10°C The reaction was quenched after stirring for about 17 hours by the addition of an ice-cold solution of sodium chloride (30 0 g) and monobasic potassium phosphate (30 2 g) in water (320~7 g). Methyl tert-buty. ethei (278 g) was added, and the mixture was stirred and allowed to settle. The layers were separated The organic phase was washed three times with water1 (-230-240 g each) then diluted with toluene (239 g) and distilled under vacuum to a red oil (150 8 g,KP 29 9 ppm H2O), 1H NMR (400 MHz, CDCl3) delta ppm 1.60 (s, 9 H) 7 69 - 7 72 (m, 1 H) 7.79 -7.81 (m, 1 H) 8 49 (dd, 7=5.08, 0..69 Hz, 1 H)

Reference： [1]Patent: WO2008/11499,2008,A1 .Location in patent: Page/Page column 37
[2]Organic Process Research and Development,2009,vol. 13,p. 1145 - 1155

2
[ 295349-62-1 ]
[ 1195748-58-3 ]
tert-butyl 2-(4-carbamoyl-4-methylpiperidin-1-yl)isonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; toluene; at 100℃; for 36.0h;	Example 11 terf-butyl 2-[4-(ammocarbonv.)-4-methv1piperidin- 1 -yllisonicotinate; A 500-mL, 3-neck flask was charged with the product obtained from Example 10 (344 g,109 4 rarnol), K2CO3 (325 mesh, 35 3 g, 255.1 nimol) and a dimethyl sulfoxide/toluene solution of Example 5 (27 8 g of a 56 1 wtpercent solution, 72 9 mmol) The mixtures were stirred at 100° C for about 36 hours. The mixture was cooled to room temperature and water (220 g) was added, slowly at first The addition of water caused the product to precipitate out of solution After stipiing for about 1 hour, the mixture was filtered and the solid was washed with water and dried under vacuum to give the title compound, 1H NMR (400 MHz, CDCl3) delta ppm 1.28 (s, 3 H) 1 53 - 1.63 (m, 2 H) 1 58 (s, 9 H) 2 03 - 2 1 1 (m, 2 H) 3 42 - 3 51 (m, 2 H) 3 78 - 3 86 (m, 2 H) 5 41 -5 69 (m, 2 H) 7,03 (dd, J=5 08, 1 24 Hz, 1 H) 7 18 (s, 1 H) 8 22 (dd, J=5 15, 0 75 Hz, 1 H).

Reference： [1]Organic Process Research and Development,2009,vol. 13,p. 1145 - 1155
[2]Patent: WO2008/11499,2008,A1 .Location in patent: Page/Page column 41

3
[ 295349-62-1 ]
[ 104-78-9 ]
tert-butyl 2-(3-(N,N-diethylamino)prop-1-ylamino)-isonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper; potassium carbonate;18-crown-6 ether; for 4.0h;Heating / reflux;	1.02 g (4.77 mmol) of <strong>[295349-62-1]tert-butyl 2-chloroisonicotinate</strong>, 5 ml of 3-diethylamino-1-propylamine, 0.66 g (4.77 mmol) of potassium carbonate, a spatula tip of Cu powder and a spatula tip of 18-crown-6 were refluxed for 4 hours. Flash chromatography of the reaction mixture (toluene/tetrahydro-furan/methanol, 4/1/1+2.5percent triethylamine) resulted in 0.69 g of pale brown oil.

Reference： [1]Patent: US6696437,2004,B1 .Location in patent: Page column 21

4
[ 288-32-4 ]
[ 295349-62-1 ]
potassium 1,1-dimethylethyl malonate [ No CAS ]
[ 335255-87-3 ]
[ 335255-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With formic acid; thionyl chloride; MgCl2; NaH; triethylamine; In N,N-dimethyl-formamide; toluene; acetonitrile;	Example M5 3-(2-Imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester Prepared from 2-imidazol-1-yl-isonicotinoyl chloride hydrochloride [prepared by reaction of <strong>[295349-62-1]tert.-butyl 2-chloroisonicotinoate</strong> with imidazole and NaH in DMF at 80° C., treatment with formic acid at 50° C. and reaction with thionylchloride in toluene at 100° C.] and tert.-butyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure M (method a). Obtained as a brown solid (10.8 g). MS (EI) 287 (M+); mp 80° C. (dec.).
	With formic acid; thionyl chloride; MgCl2; NaH; triethylamine; In N,N-dimethyl-formamide; toluene; acetonitrile;	Example H5 3-(2-Imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic Acid tert.-Butyl Ester Prepared from 2-imidazol-1-yl-isonicotinoyl chloride hydrochloride [prepared by reaction of <strong>[295349-62-1]tert.-butyl 2-chloroisonicotinoate</strong> with imidazole and NaH in DMF at 80° C., treatment with formic acid at 50° C. and reaction with thionylchloride in toluene at 100° C.] and tert.-butyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a brown solid (10.8 g). MS (EI) 287 (M+); mp 80° C. (dec.).

Reference： [1]Patent: US6407094,2002,B1
[2]Patent: US6509328,2003,B1

5
[ 65287-34-5 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran;	2-Chloropyridine-4-carbonyl chloride (11.2 g) was added to a stirred mixture of potassium tert-butoxide (7.15 g) and THF (50 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. There was thus obtained tert-butyl 2-chloropyridine-4-carboxylate (10.5 g); NMR Spectrum: (CDCl3) 1.6 (s, 9H), 7.72 (d, 1H), 7.82 (s, 1H), 8.51 (d, 1H).

Reference： [1]Patent: US6548514,2003,B1

6
[ 110-91-8 ]
[ 295349-62-1 ]
[ 295349-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 80℃; for 60.0h;	Step 2. A solution of <strong>[295349-62-1]tert-butyl 2-chloroisonicotinate</strong> (427 mg, 2 mmol) and morpholine (5.2 ml, 60 mmol) in DMSO (1 ml) was heated at 800C for 60 hr. Morpholine was evaporated and the residue was dissolved in EtOAc/ aqueous NaHCO3. The aqueous <n="134"/>phase was extracted with EtOAc. The combined organic phase was washed with water, and dried over Na2SO-J. After evaporation the crude product was subjected to silica gel column chromatography (40 g silica gel column) using DCM/EtOAc as eluents. t-Butyl 2- morpholinoisonicotinate was isolated as a thick brown oil (525 mg, purity >95percent). 1H NMR (DMSO-d6) delta (ppm) 8.24 (d, I H), 7.18 (s, I H), 7.00 (d, IH), 3.74 (t, 4H), 3.52 (t, 4H), 1.54 (s, 9H).

Reference： [1]Patent: WO2007/75896,2007,A2 .Location in patent: Page/Page column 132-133

7
[ 65287-34-5 ]
[ 865-47-4 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 4 - 20℃;	Intermediate K: Heterocvclylisonicotinate derivatives. Step 1. To a solution of 2-chloroisonicotinic acid (2.36 g, 15 mmol) in DCM (40 ml) and THF (10 ml) was added oxalyl chloride (6.5 ml) followed by addition of one drop of DMF. The mixture was stirred at room temperature for 3 h before evaporation of solvent. The freshly made acid chloride was dissolved in THF (40 ml) and cooled to 4°C. After addition of a solution of potassium -butoxide (3.4 g, 30 mmol) in THF (10 ml), the reaction mixture was slowly warmed up to room temperature and stirred overnight. The dark red suspension was evaporated and the residue was partitioned between DCM and water. The organic phase was washed with aqueous sodium bicarbonate. The DCM phase was dried over Na2Spsi4and evaporated to give 1.658 g of tert-butyl 2-chloroisonicotinate as a red oil (purity ca. 90percent), which was used in the next step without further purification. 1H NMR (DMSO-dbeta) delta (ppm) 8.62 (d, IH), 7.81 (s, IH), 7.79 (d, IH), 1.52 (s, 9H).

Reference： [1]Patent: WO2007/75896,2007,A2 .Location in patent: Page/Page column 132

8
[ 6313-54-8 ]
[ 36805-97-7 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	In chloroform; for 2.0h;Heating / reflux;	A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]+ 1H-NMR (300 MHz, CDCl3): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%	In toluene; at 90℃; for 20.0h;	a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.

Reference： [1]Patent: US2008/132477,2008,A1 .Location in patent: Page/Page column 28
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 110 - 130
[3]Patent: WO2014/141171,2014,A1 .Location in patent: Page/Page column 17; 18

10
[ 295349-62-1 ]
[ 1338990-46-7 ]

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 414 - 418

11
[ 295349-62-1 ]
[ 603-35-0 ]
C₂₈H₂₇N₂O₂P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; In dimethyl sulfoxide; at 120℃;	General procedure: A round bottom flask equipped with reflux condenser and magnetic stirring bar was charged with substituted heteroaryl chloride (5 mmol), sodium azide (10 mmol), triphenylphosphine (10 mmol) and DMSO (40 ml). The reaction mixture was stirred at 120 °C. Reaction progress was monitored by TLC. In 3-5 hours starting material was disappeared and new product was confirmed by TLC. 1N HCl (8 mL) was added to the reaction mixture and continued to stir at 120 °C for additional 1-2 hour. Reaction mixture was cooled to room temperature and diluted with 1N HCl (8 mL). The resulting mixture was poured into distilled water (100 mL) and aqueous layer was washed with EtOAc (2 X 50 mL) to remove triphenylphosphine oxide. Aqueous layer was slowly neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc (2 X 50 mL). The combined organic layers were washed with water (40 mL), brine(40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford substituted heteroaryl amine with high purity without column purification (purity was achieved in some products by washing solid compound with n-Pantane).

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 414 - 418

12
[ 6313-54-8 ]
[ 67098-46-8 ]
[ 295349-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 16.0h;Reflux;	General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N?-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28percent ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65percent hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84percent ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

13
[ 557-21-1 ]
[ 295349-62-1 ]
[ 887579-37-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc; In N,N-dimethyl acetamide; at 120℃; for 3.0h;Inert atmosphere;	General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N?-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28percent ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65percent hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84percent ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

14
[ 295349-62-1 ]
[ 1312770-56-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

15
[ 295349-62-1 ]
2-[(1R)-1-([(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]isonicotinic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

16
[ 295349-62-1 ]
[ 1444199-70-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

17
[ 295349-62-1 ]
C₁₃H₁₉NO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

18
[ 295349-62-1 ]
[ 1444199-87-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

19
[ 295349-62-1 ]
[ 889856-82-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

20
[ 295349-62-1 ]
[ 1312771-54-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4233 - 4249

21
[ 295349-62-1 ]
[ 1610742-53-4 ]