5-Chloro-2(1H)-pyridinone | GAK

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Quality Control of 5-Chloro-2(1H)-pyridinone Purity: 98% SDS Specification

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Product Details of 5-Chloro-2(1H)-pyridinone

CAS No. :	4214-79-3
Formula :	C₅H₄ClNO
M.W :	129.54
SMILES Code :	O=C1C=CC(Cl)=CN1
MDL No. :	MFCD00040278
InChI Key :	SZFUWUOHDRMCKD-UHFFFAOYSA-N
Pubchem ID :	77889

Safety of 5-Chloro-2(1H)-pyridinone

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of 5-Chloro-2(1H)-pyridinone

* 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 [ 4214-79-3 ]

[ 4214-79-3 ] Synthesis Path-Downstream 1~35

1
[ 1072-98-6 ]
[ 4214-79-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; water; sodium nitrite; at 10℃; for 0.666667h;Green chemistry;	In a 25 ml reaction flask, first add 3.4 ml of a solution consisting of 17 ml of H2O and 17 ml of concentrated sulfuric acid (50%, volume fraction), then add 1 g (0.01 mol) of 2-amino-5-chloropyridine and cool with an ice salt bath. Below 10 C, after stirring for a few minutes, the reaction solution turned white.Then, a solution consisting of (1.72 g of NaNO2 and 3 mL of H 2 O) was slowly added dropwise, and when it was added dropwise, an irritating gas was generated. After the dropwise addition, the reaction solution became a pale yellow solution, and TCL (thin layer chromatography) was monitored until the reaction was completed ( About 40min).Then, 8 mL of H2O was added, and the reaction was stirred under reflux for 15 min, cooled, and anhydrous Na2CO3 was added under stirring to make the reaction liquid neutral (a yellow-brown solid was produced), filtered, and the obtained filtrate was dried, and then filtered and dissolved with absolute ethanol. The obtained filtrate was dried to give a yellow-brown solid, 5-chloro-2(1H)pyridone, 0.70 g.

References: [1]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1928,vol. 60,p. 689.
Chemisches Zentralblatt,1928,vol. 99,p. 1671.
[2]Patent: CN110256405,2019,A .Location in patent: Paragraph 0109; 0112-0114.

2
[ 16110-09-1 ]
[ 4214-79-3 ]

References: [1]Patent: US1778784,1928, .

3
[ 623-73-4 ]
[ 4214-79-3 ]
[ 63305-94-2 ]

References: [1]Journal of Organic Chemistry,1958,vol. 23,p. 1614.

4
[ 4214-79-3 ]
[ 98-88-4 ]
benzoic acid-(5-chloro-[2]pyridyl ester) [ No CAS ]

References: [1]Zhurnal Obshchei Khimii,1937,vol. 7,p. 1749,1750.
Chem.Abstr.,1938,p. 560.
Chemisches Zentralblatt,1938,vol. 109,p. 894.

5
[ 4214-79-3 ]
[ 122-04-3 ]
4-nitro-benzoic acid-(5-chloro-[2]pyridyl ester) [ No CAS ]

References: [1]Zhurnal Obshchei Khimii,1937,vol. 7,p. 1749,1750.
Chem.Abstr.,1938,p. 560.
Chemisches Zentralblatt,1938,vol. 109,p. 894.

6
[ 4214-79-3 ]
[ 74-88-4 ]
[ 4214-78-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1931,vol. 486,p. 71,78.
[2]Journal of Organic Chemistry,2015,vol. 80,p. 296 - 303.

7
[ 421-83-0 ]
[ 4214-79-3 ]
[ 87412-10-0 ]

References: [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 1696 - 1701.

8
[ 4214-79-3 ]
[ 3497-00-5 ]
[ 74546-80-8 ]

References: [1]Synthesis,1983,p. 731 - 733.

9
[ 4214-79-3 ]
[ 16110-09-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1980,p. 1370 - 1380.

10
[ 4214-79-3 ]
[ 137628-16-1 ]

Yield	Reaction Conditions	Operation in experiment
66%		A mixture of 5-CHLORO-2-HYDROXYPYRIDINE (20.1 g, 155.4 MMOL) and bromine (11.9 ml) in acetic acid (250 m) was stirred at r. t. for 2 hours. Then, the solvent was evaporated in vacuo and ethyl acetate (600 ML) and saturated sodium bicarbonate (300 ML) were added. The organic layer was washed with saturated sodium bicarbonate (2X200 ML), brine and was dried (NA2SO4) and concentrated to give a solid that was crystallized from hexane/ diethyl ether. The solid 3-bromo-<strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (21.3 g, 66percent) so obtained was used in the subsequent reaction.
	With bromine; In water; acetic acid;	Step 1: 3-Bromo-<strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> A mixture of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (100 g) and bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The mixture was poured into 3 L of water and stirred for 30 min then filtered. The residual solid was washed with 2 L of cold water, air dried and then coevaporated with toluene three times and with benzene two times. The white solid (81 g) so obtained was used in the subsequent reaction.
	With bromine; In water; acetic acid;	Step 1 3-Bromo-<strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> A mixture of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (100 g) and bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The mixture was poured into 3 L of water and stirred for 30 min then filtered. The residual solid was washed with 2 L of cold water, air dried and then coevaporated with toluene three times and with benzene two times. The white solid (81 g) so obtained was used in the subsequent reaction.

4.4 g	With bromine; acetic acid; at 20℃;	To a stirred solution of <strong>[4214-79-3]5-chloropyridin-2-ol</strong> (4 g, 31 mmol) in acetic acid (35 mL) at room temperature was added bromine (2.55 mL, 49.6 mmol) dropwise. After stirring the reaction mixture for overnight at room temperature, water was added and the mixture was extracted twice with ethyl acetate (2 x 150 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and was concentrated under reduced pressure to afford crude product. The crude product was purified by column chromatography by using silica (100-200 mesh) using 22percent EtOAc-hexane as eluent to afford the 3-bromo-<strong>[4214-79-3]5-chloropyridin-2-ol</strong> (4.4 g) as yellow solid.
	With bromine; In acetic acid; at 20℃; for 48h;	5-CHLORO-2-PYRIDINOL (5.18g, 40MMOL) was dissolved in glacial acetic acid (50ml) and bromine (7. 51 G, 2. 41ml, 47mmol) added. The mixture was stirred at room temperature for 48 hours. Ethyl acetate and water were added and the organic layer washed with water (*3), dried (MGS04) and evaporated. The residue was triturated with diethyl ether and the buff solid filtered and dried (5.59g). 1H NMR (CDCI3) 7.52 (1 H, d J=3Hz), 7.87 (1 H, d J=3Hz).
	With bromine; In acetic acid; at 20℃;	At room temperature, bromine (1.2 mL, 24 mmol) was added dropwise to a solution of <strong>[4214-79-3]5-chloro-2-pyridinol</strong> (2.9 g, 20 mmol) in glacial acetic acid (25 mL). After stirred at room temperature overnight, ethyl acetate and water were added. The organic layer was washed with water, dried and concentrated. The residue was triturated with diethyl ether and the precipitate was filtered and dried to give the title compound (1.5 g).

References: [1]Patent: WO2004/72037,2004,A1 .Location in patent: Page 11.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 2777 - 2782.
[3]Patent: US5861419,1999,A .
[4]Patent: US6245797,2001,B1 .
[5]Patent: WO2014/141110,2014,A2 .Location in patent: Page/Page column 83; 84.
[6]Patent: WO2004/39753,2004,A2 .Location in patent: Page 83-84.
[7]Patent: US2010/204257,2010,A1 .Location in patent: Page/Page column 6.

11
[ 358-23-6 ]
[ 4214-79-3 ]
[ 87412-10-0 ]

References: [1]Journal of Organic Chemistry,2019,vol. 84,p. 11799 - 11812.
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 1274 - 1281.
[3]Journal of Organic Chemistry,2009,vol. 74,p. 5111 - 5114.

12
[ 4214-79-3 ]
[ 176770-19-7 ]
5-chloro-2-pyridyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4161 - 4171.

13
[ 4214-79-3 ]
[ 189956-34-1 ]
3-(5-chloro-pyridin-2-yloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3187 - 3192.

14
[ 4214-79-3 ]
[ 213764-20-6 ]
2-benzyl-4-(5-chloro-2-pyridyloxy)-5-(4-methylsulfonyl)phenyl-2H-pyridazin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 70 - 80℃; for 4h;	A suspension of the bromide from step 4, Example 21 (0.419 g, 1 mmol), <strong>[4214-79-3]5-chloro-2-pyridinol</strong> (0.194 g, 1.5 mmol), CH3CN (5 mL) and DBU (0.304 g, 2 mmol) was warmed to 70-80 °C and reacted for 4 h. It was cooled to r.t., poured over H2O (20 mL) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with MgSO4 and the solvent was removed in vacuo. The residue was purified by chromatography on SiO2 using EtOH and EtOAc (1:100) to yield a mixture of the O-linked and N-linked derivatives. The mixture was again purified by chromatography on SiO2 using EtOAc and hexanes (1:2) to yield the title compound (0.038 g, 8 percent).1H NMR (CD3COCD3) d 3.15(3H, s), 5.30(2H, s), 7.10(1H,m),7.25-7.45(5H, m), 7.90(3H, m), 8.05(2H, m), 8.10(1H,s), 8.15(1H,s). MS(CI, CH4): m/z 468 (M+H)+

References: [1]Patent: EP975604,2004,B1 .Location in patent: Page 41.
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 597 - 600.

15
[ 600-00-0 ]
[ 4214-79-3 ]
[ 32177-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 50℃;	REFERENCE EXAMPLE 5; 2-Methyl-2-(5-chloro-2-pyridyloxy)propionic acid; Step A: Ethyl 2-Methyl-2-(5-chloro-2-pyridyloxy)propionate; A mixture of 5-chloro-2- hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL of acetonitrile was heated at 500C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5percent ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): delta 7.99 (d, IH), 7.67 (dd, IH), 6.68 (d,IH), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M + H)+ (3.41 min).
	With caesium carbonate; In acetonitrile; at 50℃;	A mixture of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 50C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5percent EtOAc in hexane to give the title compound. 1H NMR (500 MHZ, CD30D) : 8 7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M + H) + (3.41 min).
	With caesium carbonate; In acetonitrile; at 50℃;	A mixture of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 ML, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 ML of acetonitrile was heated at 50°C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 ML) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5percent EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD30D) : 8 7.99 (d, 1H), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: M/E 244 (M + H) + (3.41 min).

With caesium carbonate; In acetonitrile; at 50℃;

Step A; Ethyl 2-Methyl-2-(5-chloro-2-pyridyloxy)propionate; A mixture of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 5O0C overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer Was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5percent EtOAc in hexane to give the title compound. ^H NMR (500 MHz, CD3OD): delta 7.99 (d, IH), 7.67 (dd, IH), 6.68 (d, IH), 4.13 (q, 2H), 1.64 (s, 6H), 1.14(t, 3H). LC-MS: m/e 244 (M + H)+ (3.41 min).

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7584 - 7587.
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 3427 - 3430.
[3]Patent: WO2007/136571,2007,A1 .Location in patent: Page/Page column 42.
[4]Patent: WO2004/48317,2004,A1 .Location in patent: Page 40-41.
[5]Patent: WO2005/9479,2005,A1 .Location in patent: Page/Page column 38.
[6]Patent: WO2006/41797,2006,A2 .Location in patent: Page/Page column 44.

16
[ 119072-55-8 ]
[ 4214-79-3 ]
[ 123-38-6 ]
[ 107-11-9 ]
2-(N-allyl-N-(5-chloropyridin-2-yl)amino)-N-tert-butylbutanamide [ No CAS ]

References: [1]Journal of Organic Chemistry,2007,vol. 72,p. 4169 - 4180.
[2]Organic Letters,2006,vol. 8,p. 4019 - 4021.

17
[ 419572-18-2 ]
[ 4214-79-3 ]
C₁₆H₂₁ClN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dibenzyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Product distribution / selectivity;	In a flame-dried flask under N2, was combined 807 mg (6.24 mmol, 1.33 eq) of 5- chloro 2-pyridyl phenol and 1.64 g (6.23 mmol, 1.33 eq) of triphenylphosphine in 20 mL of anhydrous THF at room temperature. To this solution was added 1.86 g (6.233 mmol, 1.33 eq) of DBAD, followed by 1.0 g (4.69 mmol, 1.0 eq) of 6-hydroxymethyl-3-aza- <n="58"/>bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 5 ml_ of anhydrous THF. The yellow solution was stirred at room temperature overnight. To this solution was added 6.3 mL (25.2 mmol, 5.4 eq) of 4M HCI in 1 ,4-dioxane and the resulting solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the resulting residue was dissolved in 95 mL methylene chloride. The solution was extracted with 63 mL of 15percent aqueous citric acid. The aqueous layer was extracted with 95 mL of methylene chloride. The aqueous layer was basified with 32 mL of cone. NH4OH and extracted three times with 65 mL of methylene chloride. The combined organic layers were dried over anhydrous MgSO4, filtered and stripped in vacuo to give yellow oil which crystallized while drying under high vaccum (588 mg). The crude material was purified via flash chromatography, eluting with 5percent methanol/ methylene chloride- with 0.1 percent triethyl amine to yield 242 mg of desired compound. 400 MHz 1H NMR (CDCI3) delta 8.0 (d, 1 H), 7.5 (m, 1H), 6.7 (d, 1 H), 4.1 (d, 2H), 3.1 (d, 2H), 2.9-3.0 (m, 3H), 1.5 (m, 2H), 1.2 (m, 1H); MS (M+1) 225, 227.
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 64h;Product distribution / selectivity;	19.5 mmol of triphenyl phosphine was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 mul (0.15 mmol) of this solution was added to each 0.1 mmol of varying phenols of general foumula (III) in 2-dram vials. 13.0 mmol of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3- <n="59"/>aza-bicycio[3.1.0]hexane-3-carboxylate (Preparation 1 ) was dissolved in 6.5 mL of anhydrous THF and vortexed. 50 muL (0.10 mmol) of this solution was added to each vial. 19.5 mmol of Diethylazodicarboxylate (DEAD) was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 muL (0.15 mmol) of this solution was added to each vial. The vials were sealed and placed on shaker at room temperature for 64 hours. 200 muL of 4 M HCI in 1 ,4-dioxane was then added to each vial and the vials were placed on a shaker at room temperature for 16 hours. The reactions were evaporated under nitrogen. MCX SPE columns were conditioned by eluting twice with 4 mL of CH3OH. The reaction residues were dissolved with 1.0 mL of CH3OH, vortexed, and the reaction residues were added to the MCX columns. The reaction vials were rinsed two times with 1.0 mL of CH3OH, vortexed, and the reaction residues were added to the columns. The columns were eluted three times with 4.0 mL of CH3OH. 4.0 mL of 2 M NH3 in CH3OH was added to each vial with the eluent collected in tared 2-dram vials. The vials were evaporated under nitrogen, tared, and used without further purification in the next reaction. To each of the vials prepared above were added 500 muL of 1 ,2-dichloroethane and 28 muL (0.2 mmol) of triethylamine. 4.3 mmol of an aldehyde of general formula (V) was dissolved in 4.3 mL of 1 ,2-dichloroethane and 0.1 mL (0.1 mmol) was added to the vials. 0.3 mmol of sodium triacetoxyborohydride was added to vials. The vials were sealed and placed on shaker at room temperature for 16 hours. 1.5 mL of 1 N NaOH, followed by 1.0 mL of 1 ,2- dichloroethane was added to each vial and vortexed for 4 minutes. The layers were allowed to separate and 1.5 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added and the mixture was vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into the tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added to the each vial and vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. The combined SPE eluents remaining in the 2 dram tared vials were evaporated in a Savant SpeedVac Plus. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).Alternatively, compounds of formula I can be prepared as highlighted below in method C, utilizing parallel chemistry or high-speed synthesis methods.
	With triphenylphosphine on polystyrene; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 17h;Product distribution / selectivity;	Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxyiate (Preparation 1 ) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) <n="60"/>in THF. Prepared a 0.5 M stock solution of DEAD in toluene. To each reaction vial, added 0.200 ml_ of the varying phenol followed by 0.075 mL of (1S,5R,6R)-tert-butyl 6- (hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate. Added 0.600 mL of the DEAD solution, followed by 0.750 mL of toluene. Added 140 mg of triphenylphosphine-polystyrene resin. Vials were capped and shaken at room temperature for 17 hours. Added 2.5 mL of THF to each reaction vial. The top layer was transferred to empty 6 mL SPE cartridges over collection tubes. Added 3.0 mL of THF to the reaction vials and then aspirated the top layer to the SPE cartridges over collection tubes. Transferred solutions from collection tubes to new reaction vials and evaporated. Added 0.600 mL of CH3OH followed by 0.300 mL of 4 M HCI in 1 ,4-dioxane to each reaction vial. Vials were capped and shaken at room temperature for 24 hours. The solvent was evaporated and the intermediates used without further purification in the next reaction.Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in 1 ,2- dichloroethane. Added 0.600 mL of the aldehyde solution to each of the reaction vials from the step above, followed by 0.070 mL of DIPEA. Added 2.0 mL of the sodium triacetoxyborohydride solution, capped vials and shaken at room temperature for 17 hours. Added 1.0 mL of 1 ,2-dichloroethane followed by 2.0 mL of 10percent NaOH. Vials were vortexed and/or shaken and removed top layer. Added 2.0 mL of 10percent NH4OH, with vials shaken well and/ or vortexed. The bottom layers were aspirated to empty 6 mL SPE cartridges over tared collection tubes. Added 1.0 mL of 1 ,2-dichloroethane to the aqueous layer and aspirated the bottom layer to the SPE cartridge over the collection tubes. Evaporated solutions to dryness. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl) Alternatively, compounds of formula I can be prepared as highlighted below in method D utilizing parallel chemistry or high-speed synthesis methods.

With triphenylphosphine on polystyrene; di-tert-butyl-diazodicarboxylate; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity;

Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (Preparation 1) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) in THF. Prepared a 2 M stock solution of DBAD (di-t- butylazodicarboxylate) in THF. To each reaction vial, added 0.075 mL of the varying phenol followed by 0.075 mL of 2 M solution of triphenylphosphine in THF. The prepared solutions of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate and DBAD were mixed in 3:4 ratio and 0.1313 mL of this mixture was added to each reaction vial. Vials are capped and shaken at room temperature for 1 hour. Added 0.15 mL of 4 M HCI in 1 ,4- dioxane to each reaction vial. Vials are capped and shaken at room temperature for 16 hours. The solvent was evaporated and to each vial was added 3 mL of dichloromethane and 2 mL <n="61"/>of 15percent aqueous citric acid solution. The vials were shaken and centrifuged followed by removal of the lower organic layer. 3 mL of dichloromethane was added too each via) and the vials were shaken and centrifuged followed by removal of the lower organic layer. The last operation was repeated. To each vial was added 2 mL of 28percent aqueous NH4OH. After cooling, 2 mL of dichloromethane was added. The vials were shaken and centrifuged followed by collecting of the lower organic layer. The solvent was evaporated and the obtained products were used in the next step without further purification.Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in chloroform. To each vial from the step above was added 0.45 mL of 1 ,2-dichoroethane and, following dissolution, 0.45 mL of the aldehyde followed by 1.51 mL of the sodium triacetoxyborohydride solution. The vials were capped and shaken at room temperature for 17 hours. To each vial was added 2 mL of 10percent aqueous NaOH. Vials were shaken and centrifuged followed by transfer of the lower organic layer to phase separation cartridges. Organic layer was collected and the solvent was removed by evaporation. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).Alternatively, compounds of formula I can be prepared as highlighted below in method E, utilizing parallel chemistry or high-speed synthesis methods.

References: [1]Patent: WO2007/135527,2007,A2 .Location in patent: Page/Page column 56-57.
[2]Patent: WO2007/135527,2007,A2 .Location in patent: Page/Page column 57-58.
[3]Patent: WO2007/135527,2007,A2 .Location in patent: Page/Page column 58-59.
[4]Patent: WO2007/135527,2007,A2 .Location in patent: Page/Page column 59-60.

18
[ 119072-55-8 ]
[ 4214-79-3 ]
[ 123-38-6 ]
[ 22483-09-6 ]
2-(N-(5-chloropyridin-2-yl)-N-(2,2-dimethoxyethyl)amino)-N-tert-butylbutanamide [ No CAS ]

References: [1]Journal of Organic Chemistry,2007,vol. 72,p. 4169 - 4180.

19
[ 931-53-3 ]
[ 4214-79-3 ]
[ 123-38-6 ]
[ 104-86-9 ]
2-(N-(4-chlorobenzyl)-N-(5-chloropyridin-2-yl)amino)-N-cyclohexylbutanamide [ No CAS ]

References: [1]Journal of Organic Chemistry,2007,vol. 72,p. 4169 - 4180.

20
[ 4214-79-3 ]
[ 32230-08-3 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3427 - 3430.
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 7584 - 7587.

21
[ 4214-79-3 ]
[ 883858-22-8 ]