[ CAS No. 99464-83-2 ] {[proInfo.proName]}

Name: 99464-83-2|1-Chloroethyl cyclohexyl carbonate|97%
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Quality Control of [ 99464-83-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 99464-83-2 ]

Product Details of [ 99464-83-2 ]

CAS No. :	99464-83-2	MDL No. :	MFCD04038149
Formula :	C₉H₁₅ClO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ONZWFHWHTYZZLM-UHFFFAOYSA-N
M.W :	206.67	Pubchem ID :	11229529
Synonyms :

Calculated chemistry of [ 99464-83-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.82
TPSA :	35.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.89
Log Po/w (XLOGP3) :	3.45
Log Po/w (WLOGP) :	3.06
Log Po/w (MLOGP) :	1.71
Log Po/w (SILICOS-IT) :	2.02
Consensus Log Po/w :	2.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.03
Solubility :	0.193 mg/ml ; 0.000931 mol/l
Class :	Soluble
Log S (Ali) :	-3.88
Solubility :	0.0274 mg/ml ; 0.000133 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.8
Solubility :	3.25 mg/ml ; 0.0157 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.06

Safety of [ 99464-83-2 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P210-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405	UN#:	1760
Hazard Statements:	H227-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 99464-83-2 ]

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

Upstream synthesis route of [ 99464-83-2 ]
Downstream synthetic route of [ 99464-83-2 ]

[ 99464-83-2 ] Synthesis Path-Upstream 1~3

1
[ 50893-53-3 ]
[ 108-93-0 ]
[ 99464-83-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridine In dichloromethane at 0 - 20℃;	EXAMPLE 4 Synthesis of PGB-03 (3-Aminomethyl-5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester) Procedure: Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH₂Cl₂ (15 mL) under the treatment in a nitrogen atmosphere (0-5° C.). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH₂Cl₂ (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22 g, 15.42 mmol) and CH₂Cl₂(2 mL) were added dropwise. After stirring overnight at room temperature, CH₂Cl₂ (20 mL) and water (20 mL) were added to the reaction solution. The product was extracted to the CH₂Cl₂ phase and washed with water (3*20 mL). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94percent). ¹H-NMR (CDCl₃, 500 MHz) δ 1.22-1.30 (m, 1H), 1.32-1.41 (m, 2H), 1.42-1.58 (m, 3H), 1.71-1.80 (m, 2H), 1.83 (d, J=6.0 Hz, 3H), 1.89-2.00 (m, 2H), 4.65-4.72 (m, 1H), 6.43 (q, J=6.0 Hz, 1H).
94%	With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere	Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH₂CI₂ (15 mL) under the treatment in a nitrogen atmosphere (0 -5°C). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH₂CI₂ (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22g, 15.42 mmol) and CH₂CI₂ (2 mL) were added dropwise. After stirring overnight at room temperature, CH₂CI₂ (20 mL) and water (20 mL) were added to the <n="19"/>reaction solution. The product was extracted to the CH₂CI₂ phase and washed with water (3 x 20 ml_). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94percent). ¹HNMR(CDCI₃, 500 MHz) δ 1.22-1.30(m, 1 H), 1.32-1.41 (m, 2H), 1.42-1.58(m, 3H), 1.71-1.80(m, 2H), 1.83(d, J=6.0 Hz, 3H), 1.89-2.00(m, 2H), 4.65-4.72(m, 1H), 6.43(q, J=6.0 Hz, 1H).
80%	With pyridine In dichloromethane at -78℃;	Cyclohexanol (0.50 g, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to -78 ºC. a solution of 1-chloroethyl carbonochloridate (0.54 ml, 5.0 mmol) dissolved in 2 ml dichloromethane was added drop-wise and with stirring. The mixture was stirred for 30 min at -78ºC and then overnight, warming to room temperature and forming a precipitate. The mixture was diluted with dichloromethane and was washed sequentially with twice with water, once with 0.1N hydrochloric acid, once with water and once with brine. The organics were dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.82 g (4.0 mmol, 80percent) of the title compound as a colourless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.43 (1 H, q, J=5.9 Hz), 4.69 (0 H, tt, J=9.0, 4.5 Hz), 1.89 - 2.01 (2 H, m), 1.83 (3 H, d, J=5.9 Hz), 1.70 - 1.81 (2 H, m), 1.45 - 1.58 (2 H, m), 1.22 - 1.44 (4 H, m).

70%

With pyridine In dichloromethane at 0 - 20℃; for 16.25 h;

Preparation Example 2: ; Preparation of 1 -iodoethyl cyclohexylcarbonate(1) Preparation of 1-chloroethyl cyclohexylcarbonateCyclohexanol (19 ml, 0.18 mol) was dissolved in methylene chloride (300 ml), and pyridine (14.8 ml, 0.18 mol) was added thereto while ice-cooling. 1-Chloroethyl chloroformate (20 ml, 0.185 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 16 hours. The reaction mixture was sequentially washed with water, brine, and 5percent sodium thiosulfate solution, dried over anhydrous magnesium, and then filtered. The filtrate was distilled under a reduced pressure to obtain 26.06 g of 1-chloroethyl cyclohexylcarbonate (yield: 70percent). <n="20"/>bpδδmmHg: 101 -103 ^°C ;¹H-NMR(200MHz, CDCI₃) δ 1.0-2.3(m, 10H), 1.38(d, J=5.8Hz, 3H), 4.60-4.80(m, 1 H), 6.40(q, J=5.8Hz, 1 H).

Reference： [1] Patent: US2008/125483, 2008, A1, . Location in patent: Page/Page column 6-7
[2] Patent: WO2009/118580, 2009, A2, . Location in patent: Page/Page column 17-18
[3] Patent: EP2526945, 2012, A1, . Location in patent: Page/Page column 66
[4] Patent: WO2009/66917, 2009, A2, . Location in patent: Page/Page column 17-18
[5] Patent: EP1477482, 2004, A1, . Location in patent: Page 30
[6] Patent: EP1630157, 2006, A1, . Location in patent: Page/Page column 55
[7] Patent: WO2004/52841, 2004, A1, . Location in patent: Page 87
[8] Patent: EP1445249, 2004, A1, . Location in patent: Page 114
[9] Patent: WO2006/63578, 2006, A2, . Location in patent: Page/Page column 24
[10] Patent: US2013/244958, 2013, A1, . Location in patent: Paragraph 0123

2
[ 123-63-7 ]
[ 108-93-0 ]
[ 503-38-8 ]
[ 99464-83-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: at -10 - 0℃; for 8 h; Stage #2: at 20℃; for 3 h;	1) In a 1000 ml reaction flask,238 g of trichloromethyl chloroformate was added,Open stirring, cooling to -10 ~ 0 by adding 2.4g pyridine,Dropping 106 g of triacetaldehyde, dropping the process for 6 hours,After the addition was complete, stirring was continued for 2 h,247 g of pyridine was added,The temperature to be mixed is 20 ° CAfter the addition of cyclohexanol 240 g,After completion of the dropwise addition, stirring was continued for 3 h.After completion of the reaction, 120 g of water was added,The organic phase was separated from crude 1-chloroethylcyclohexylpropyl carbonate.(2) The crude product of 1-chloroethylcyclohexylpropyl carbonate was put into a distillation reaction flask,Control the bottle temperature below 130 ,Vacuum vacuum distillation,That is to get1-chloroethylcyclohexylpropylCarbonate461g,The yield was 93percent and the purity was greater than 99.5percent.

Reference： [1] Patent: CN104496822, 2016, B, . Location in patent: Paragraph 0030-0033

3
[ 75-07-0 ]
[ 13248-54-9 ]
[ 99464-83-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1921 - 1926

[ 99464-83-2 ] Synthesis Path-Downstream 1~87

1
[ 99464-83-2 ]
ammonium thiocyanate [ No CAS ]
[ 117972-03-9 ]
[ 117972-11-9 ]

Reference： [1]Tetrahedron,1988,vol. 44,p. 1619 - 1630

2
[ 99464-83-2 ]
2-butyl-1-<<2'-<N-(triphenylmethyl)-1H-tetrazol-5-yl>biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylic acid [ No CAS ]
2-Butyl-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2343 - 2349

3
[ 99464-83-2 ]
[ 894806-43-0 ]
[ 886999-34-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2343 - 2349

4
[ 99464-83-2 ]
[ 626-62-0 ]

Reference： [1]Tetrahedron Letters,1985,vol. 26,p. 5445 - 5446

5
[ 99464-83-2 ]
[ 60846-23-3 ]
1-(cyclohexyloxycarbonyloxy)ethyl 7β-<2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido>-3-acetoxymethyl-3-cephem-4-carboxylate [ No CAS ]

Reference： [1]Synthetic Communications,1998,vol. 28,p. 4345 - 4354

6
[ 99464-83-2 ]
[ 95789-69-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium iodide; In acetonitrile; at 50℃; for 5.5h;	Sodium iodide (4.48 g, 29.88 mmol) was dissolved in anhydrous CH3CN (30 mL). Compound 6 (1.20 g, 5.98 mmol) and anhydrous CH3CN (3 mL) were added and stirred for 5.5 hours at 50 C. After filtering and concentration, the residue was diluted with ether and re-concentrated to give 1.21 g of carbonic acid cyclohexyl ester 1-iodo-ethyl ester 7 (Yield: 69%). 1H-NMR (CDCl3, 500 MHz) delta 1.25-1.40 (m, 3H), 1.41-1.58 (m, 3H), 1.70-1.78 (m, 2H), 1.85-1.95 (m, 2H), 2.22 (d, J=7.0 Hz, 3H), 4.66-4.71 (m, 1H), 6.77 (q, d=7.0 Hz, 1H).
69%	With sodium iodide; In acetonitrile; at 50℃; for 5.5h;	Sodium iodide (4.48g, 29.88 mmol) was dissolved in anhydrous CH3CN (30 mL). Compound 6 (1.2Og, 5.98 mmol) and anhydrous CH3CN (3 mL) were added and stirred for 5.5 hours at 500C. After filtering and concentration, the residue was diluted with ether and re-concentrated to give 1.21 g of carbonic acid cyclohexyl ester 1-iodo-ethyl ester 7 (Yield: 69%). 1HNMR(CDCI3, 500 MHz) delta 1.25-1.40(m, 3H), 1.41-1.58(m, 3H), 1.70-1.78(m, 2H), 1.85-1.95(m, 2H), 2.22(d, J=7.0 Hz, 3H), 4.66-4.71 (m, 1H), 6.77(q, d=7.0 Hz, 1 H).
	With sodium iodide; In acetonitrile; at 60℃; for 2h;	Chloroethyl chloroformate (4 ml) was added to a solution of cyclohexyl alcohol (4.3 ml) and pyridine (3.3 ml) in dichloromethane (60 ml) at -78C, and they were stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to obtain crude <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (7.5 g). Sodium iodide (1.6 g) and acetonitrile (16 ml) were added to the obtained crude product (7.5 g), and they were stirred at 60C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated to obtain a mixture (420 mg) of <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> and 1-iodoethylcyclohexyl carbonate. The compound obtained in Referential Example 108 (50 mg), triethylamine (26 ul) and dichloromethane (750 ul) were added to the obtained mixture (54 mg), and they were stirred at room temperature for 16 hours. After the evaporation of the reaction mixture followed by the purification by the reversed-phase high-performance liquid chromatography (reversed-phase HPLC) [water - acetonitrile each containing 0.1 % trifluoroacetic acid (TFA)], the title compound (25 mg) was obtained. MS(ESI MH+) : 725 CHNO : C36H38Cl2N4O8

	With sodium iodide; In acetonitrile;	(a) Production of 1-Iodoethyl Cyclohexyl Carbonate A solution of 1.65 g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> and 5.0 g of sodium iodide in 50 ml of acetonitrile is stirred at 70 C. for 45 minutes and then concentrated under reduced pressure. The residue is extracted with ether. The extracts are combined and evaporated under reduced pressure to remove the solvent to give the title compound as pale yellow oil. NMR (CD3 CN, TMS(referenceexternal) delta: 0.7-2.3 (10H, m, STR71 2.18 (3 J=6 Hz, --CH3), 4.1-4.9 (1H, m, STR72 6.67 (1H, q, J=6 Hz, ICHO).
	With sodium iodide; In acetonitrile; at 60℃; for 1.16667h;	(2) Preparation of 1-iodoethyl cyclohexylcarbonate; 1-chloroethyl cyclohexylcarbonate (2.6 g, 13 mmol) prepared in Step (1) was dissolved in acetonitrile (80 ml), and sodium iodide (8.5 g, 56.7 mmol, 4.36 eq) was added thereto. The reaction mixture was stirred at 600C for 70 minutes and then filtered. The filtrate was cooled to room temperature and then distilled under a reduced pressure to remove the solvent. The resulting residue was extracted with water and diethyl ether. The separated organic layer was washed with 5% sodium thiosulfate solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was distilled under a reduced pressure to obtain 2.68 g of 1-iodoethyl cyclohexylcarbonate. The product was immediately used in subsequent reactions due to its instability. 1H-NMR(200MHz, CDCI3) delta 0.9-2.2(m, 10H), 2.20(d, J=5.8Hz, 3H), 4.60-4.80(m,1 H), 6.81 (q, J=5.8Hz, 1 H).
	With sodium iodide;zinc(II) chloride; In carbon disulfide; at 20℃; for 3h;	To a solution (25 mL) of 1-chloroethyl cyclohexylcarbonate (5.0 g) in carbon disulfide were added sodium iodide (6.8 g) and zinc chloride (0.25 g) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was poured into ice water (100 mL) and the mixture was extracted twice with diethyl ether (50 mL). The organic layers were combined and washed with 10% aqueous sodium sulfite solution (30 mL), saturated aqueous sodium hydrogen carbonate (30 mL) and water (30 mL). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give cyclohexyl 1-iodoethylcarbonate (6.10 g) as a liquid.
	With sodium iodide; In acetonitrile; at 60℃; for 1h;	(1) 9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> as colorless oil. 5.00 g of this <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
1.05 kg	With sodium iodide; calcium chloride; In acetonitrile; at 40 - 45℃;Molecular sieve;	To a 10 L dry reactor, anhydrous acetonitrile 3.29 L, anhydrous sodium iodide 947 g,Under the condition of water bath, the temperature is controlled to be 20-25 DEG C, 313 g of molecular sieve anhydrous calcium chloride is slowly added under stirring, and the mixture is stirred for 20 min after addition, heated to 45-50 DEG C, and rapidly dropped<strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> 947g, the reaction 1.0h (respectively 30min and 1h sampling monitoring, GC detection of the control) to stop the reaction, the reaction solution was dark, the control was concentrated under reduced pressure at 20 ~ 25 until no liquid dripped .Take petroleum ether 4.48L, cooled to 0 ~ 5 , and then the cold petroleum ether was added to the above concentrate,The solution was transferred to a 10L reactor, the temperature was controlled at 0 ~ 5 slowly added cold purified water 2.12kg, Canada completed,Stirring for 15min, standing stratified, the aqueous layer was extracted once with petroleum ether 2.46L, the two ether layers were combined,Add 25% sodium thiosulfate solution 4.07kg, the temperature was controlled at 0 ~ 10 C for 30min, the color of the reaction solution disappeared completely,Still stratified, divided into the lower aqueous phase, adding 6.54% sodium bicarbonate solution 2.54kg, stirring 15min, standing to separate the lower aqueous phase. The organic phase is evaporated under reduced pressure at low temperature to remove the petroleum ether at 20 ~ 25 C, to obtain about 1.05kg light yellow oil. Add 10% dichloromethane, -20 dark reserve for use.

Reference： [1]Patent: US2008/125483,2008,A1 .Location in patent: Page/Page column 7
[2]Patent: WO2009/118580,2009,A2 .Location in patent: Page/Page column 18
[3]Patent: WO2006/63578,2006,A2 .Location in patent: Page/Page column 24-25
[4]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1921 - 1926
[5]Patent: EP1477482,2004,A1 .Location in patent: Page 30
[6]Patent: US5120841,1992,A
[7]Patent: WO2009/66917,2009,A2 .Location in patent: Page/Page column 18
[8]Patent: EP1437352,2004,A1 .Location in patent: Page 28
[9]Patent: EP1445249,2004,A1 .Location in patent: Page 114
[10]Patent: CN106749334,2017,A .Location in patent: Paragraph 0045; 0046; 0047

7
[ 75-07-0 ]
[ 13248-54-9 ]
[ 99464-83-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1921 - 1926

8
C₂₀H₁₉Cl₂NO₇ [ No CAS ]
[ 99464-83-2 ]
C₂₉H₃₃Cl₂NO₁₀ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4193 - 4207

9
[ 820244-80-2 ]
[ 99464-83-2 ]
C₂₉H₃₂Cl₂FNO₁₀ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4193 - 4207

10
[ 161715-21-5 ]
[ 99464-83-2 ]
3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester [ No CAS ]

Reference： [1]Journal of Antibiotics,2006,vol. 59,p. 241 - 247

11
[ 99464-83-2 ]
5-{(R)-2-[(R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(1-cyclohexyloxycarbonyloxy-ethyl) ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1921 - 1926

12
[ 99464-83-2 ]
[ 117972-11-9 ]

Reference： [1]Tetrahedron,1988,vol. 44,p. 1619 - 1630

13
[ 103577-40-8 ]
[ 99464-83-2 ]
cyclohexyl 1-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 69℃; for 34h;	To a solution (50 mL) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]benzimidazole (2.12 g) and 1-chloroethyl cyclohexylcarbonate (1.86 g) in acetonitrile were added sodium iodide (0.45 g) and potassium carbonate (1.66 g) and the mixture was stirred at 60C for 34 hrs. Acetonitrile was evaporated under reduced pressure and the residue was extracted with ethyl acetate (150 mL) and water (50 mL). The organic layer was separated and washed with 10% aqueous sodium sulfite solution (30 mL). It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with ethyl acetate:hexane=1:1) to give cyclohexyl 1-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol-1-yl]ethyl carbonate (1.00 g) as an amorphous form.1H-NMR(CDCl3): 1.08-1.98 (10H,m) , 1.86 (3H,d,J=6.5Hz) , 2.35 (3H, s), 4.44(2H,q,J=7.5Hz), 4.54(1H,m), 4.86(2H,s), 6.65(1H,d,J=5.8Hz), 6.86(1H,q,J=6.5Hz), 7.17-7.29(2H,m), 7.56-7.72 (2H,m) , 8.36(1H, d, J=5.8Hz).

Reference： [1]Patent: EP1437352,2004,A1 .Location in patent: Page 27

14
[ 50893-53-3 ]
[ 108-93-0 ]
[ 99464-83-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridine; In dichloromethane; at 0 - 20℃;	EXAMPLE 4 Synthesis of PGB-03 (3-Aminomethyl-5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester) Procedure: Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2Cl2 (15 mL) under the treatment in a nitrogen atmosphere (0-5 C.). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2Cl2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22 g, 15.42 mmol) and CH2Cl2(2 mL) were added dropwise. After stirring overnight at room temperature, CH2Cl2 (20 mL) and water (20 mL) were added to the reaction solution. The product was extracted to the CH2Cl2 phase and washed with water (3*20 mL). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94%). 1H-NMR (CDCl3, 500 MHz) delta 1.22-1.30 (m, 1H), 1.32-1.41 (m, 2H), 1.42-1.58 (m, 3H), 1.71-1.80 (m, 2H), 1.83 (d, J=6.0 Hz, 3H), 1.89-2.00 (m, 2H), 4.65-4.72 (m, 1H), 6.43 (q, J=6.0 Hz, 1H).
94%	With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Cyclohexy alcohol (1.4 g, 13.97 mmol) was dissolved in CH2CI2 (15 mL) under the treatment in a nitrogen atmosphere (0 -5C). 1-Chloroethyl chloroformate (2.0 g, 13.97 mmol) and CH2CI2 (10 mL) were slowly added. The solution was stirred for 15 minutes and pyridine (1.22g, 15.42 mmol) and CH2CI2 (2 mL) were added dropwise. After stirring overnight at room temperature, CH2CI2 (20 mL) and water (20 mL) were added to the <n="19"/>reaction solution. The product was extracted to the CH2CI2 phase and washed with water (3 x 20 ml_). The residue was dried and concentrated to give 2.64 g of Carbonic acid cyclohexyl ester 1-chloro-ethyl ester 6 (Yield: 94%). 1HNMR(CDCI3, 500 MHz) delta 1.22-1.30(m, 1 H), 1.32-1.41 (m, 2H), 1.42-1.58(m, 3H), 1.71-1.80(m, 2H), 1.83(d, J=6.0 Hz, 3H), 1.89-2.00(m, 2H), 4.65-4.72(m, 1H), 6.43(q, J=6.0 Hz, 1H).
80%	With pyridine; In dichloromethane; at -78℃;	Cyclohexanol (0.50 g, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) were dissolved in 10 ml dichloromethane and the mixture cooled to -78 ºC. a solution of 1-chloroethyl carbonochloridate (0.54 ml, 5.0 mmol) dissolved in 2 ml dichloromethane was added drop-wise and with stirring. The mixture was stirred for 30 min at -78ºC and then overnight, warming to room temperature and forming a precipitate. The mixture was diluted with dichloromethane and was washed sequentially with twice with water, once with 0.1N hydrochloric acid, once with water and once with brine. The organics were dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.82 g (4.0 mmol, 80%) of the title compound as a colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 6.43 (1 H, q, J=5.9 Hz), 4.69 (0 H, tt, J=9.0, 4.5 Hz), 1.89 - 2.01 (2 H, m), 1.83 (3 H, d, J=5.9 Hz), 1.70 - 1.81 (2 H, m), 1.45 - 1.58 (2 H, m), 1.22 - 1.44 (4 H, m).

70%	With pyridine; In dichloromethane; at 0 - 20℃; for 16.25h;	Preparation Example 2: ; Preparation of 1 -iodoethyl cyclohexylcarbonate(1) Preparation of 1-chloroethyl cyclohexylcarbonateCyclohexanol (19 ml, 0.18 mol) was dissolved in methylene chloride (300 ml), and pyridine (14.8 ml, 0.18 mol) was added thereto while ice-cooling. 1-Chloroethyl chloroformate (20 ml, 0.185 mol) was slowly added to the reaction mixture over 15 minutes. The reaction mixture was slowly heated to room temperature and then stirred for 16 hours. The reaction mixture was sequentially washed with water, brine, and 5% sodium thiosulfate solution, dried over anhydrous magnesium, and then filtered. The filtrate was distilled under a reduced pressure to obtain 26.06 g of 1-chloroethyl cyclohexylcarbonate (yield: 70%). <n="20"/>bpdeltadeltammHg: 101 -103 C ;1H-NMR(200MHz, CDCI3) delta 1.0-2.3(m, 10H), 1.38(d, J=5.8Hz, 3H), 4.60-4.80(m, 1 H), 6.40(q, J=5.8Hz, 1 H).
	With pyridine; In dichloromethane; at -78 - 20℃; for 15h;	Chloroethyl chloroformate (4 ml) was added to a solution of cyclohexyl alcohol (4.3 ml) and pyridine (3.3 ml) in dichloromethane (60 ml) at -78C, and they were stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to obtain crude 1-chloroethylcyclohexyl carbonate (7.5 g). Sodium iodide (1.6 g) and acetonitrile (16 ml) were added to the obtained crude product (7.5 g), and they were stirred at 60C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated to obtain a mixture (420 mg) of 1-chloroethylcyclohexyl carbonate and 1-iodoethylcyclohexyl carbonate. The compound obtained in Referential Example 108 (50 mg), triethylamine (26 ul) and dichloromethane (750 ul) were added to the obtained mixture (54 mg), and they were stirred at room temperature for 16 hours. After the evaporation of the reaction mixture followed by the purification by the reversed-phase high-performance liquid chromatography (reversed-phase HPLC) [water - acetonitrile each containing 0.1 % trifluoroacetic acid (TFA)], the title compound (25 mg) was obtained. MS(ESI MH+) : 725 CHNO : C36H38Cl2N4O8
	With pyridine; In chloroform; at -78 - 20℃; for 24h;	Step 1 1-chloroethyl cyclohexyl carbonate Cyclohexanol (4.58 g) was dissolved in chloroform (75 ml), pyridine (3.63 g) was added, and the mixture was cooled to -78C. 1-Chloroethyl chlorocarbonate (5.0 ml) was added. The reaction mixture was gradually returned to room temperature and stirred for one day. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (8.85 g).
	With pyridine; In dichloromethane; at 20℃; for 1h;	[00388] To a mixture of cyclohexanol (10.9 G, 10.9 MMOL), pyridine (8.62 g, 10.9 mmol) in dichloromethane was added 1-CHLOROETHYL CHLOROFORMATE (15.59, 10. 9 mmol) AT C. The resulting mixture was stirred at room temperature for 60 min. The mixture was partitioned between hexane and 10% citric acid. The organic phase was separated and dried over MGS04. Removal of the solvent gave the title compound, which was used in the next reaction without further purification.
	With pyridine; In dichloromethane; at 0 - 20℃; for 2h;	(1) 9.15 g of cyclohexanol was dissolved in 150 ML of methylene chloride, to which 7.4 ML of pyridine was added followed by dropwise addition of 10 ML of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature.. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom.. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
	With pyridine; In dichloromethane; at -78℃; for 3h;	Example 8 1-(Cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate [0122] cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at -78 C. for 3 h to give 1-chloroethyl cyclohexyl carbonate. A portion of 1-chloroethyl cyclohexyl carbonate (253 mg, 1.22 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 0.244 mmol) in the presence of cesium carbonate (487.4 mg, 1.5 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (135.4 mg, 70% yield). MS (ES+) m/z calcd. for C40H44Cl2F2N3O7: [(M+H)+]: 786, found: 786

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[10]Patent: US2013/244958,2013,A1 .Location in patent: Paragraph 0123

15
[ 139481-72-4 ]
[ 99464-83-2 ]
[ 170791-09-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In tetrahydrofuran; at 20 - 65℃; for 6h;Product distribution / selectivity;	Example/STEP 1; Preparation of 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (i.e., Candesartan cilexetil trityl); Example/Step 1-ATo a 1 L, three-necked round-bottomed spherical flask equipped with a reflux condenser and a thermometer, were added 100.0 g of 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (146.5 mmol), chloroethyl cyclohexyl carbonate (approximately 36.32 g, 175.8 mmol), potassium carbonate (approximately 24.29 g, 175.8 mmol), benzyltriethylammonium chloride (approximately 8.340 g, 36.62 mmol) and tetrahydrofuran (approximately 350 mL). The suspension is heated to reflux (approximately 63-65 C.) over approximately 30 minutes and maintained at this temperature for approximately 5 hours. The heating was stopped, and the suspension was cooled to approximately 20-25 C. over approximately 30 minutes. The suspension was filtered, and the resulting white solid was washed with tetrahydrofuran (2× approximately 100 mL). The solid was discarded, and the yellow mother liquors were concentrated by distilling off the tetrahydrofuran under vacuum. Isopropyl alcohol (approximately 500 mL) was added to the concentrated solution, and the suspension was heated to reflux (approximately 76-78 C.). After reaching reflux temperature, the solution was allowed to cool to approximately 20-25 C. over approximately 3 hours during which time a solid precipitates. The resulting suspension was then stirred at approximately 20-25 C. for approximately 1 hour. The suspension was then filtered, and the resulting solid was washed with isopropyl alcohol (2× approximately 50 mL) to yield 171.0 g (loss on drying (?LOD?)=23.21%, 131.3 g (dry), quantitative yield) of crude 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (i.e., candesartan cilexetil trityl). Table 1 illustrates the results of an HPLC analysis of the crude candesartan cilexetil trityl obtained in Example/Step 1-A.
98%	With potassium carbonate; In ISOPROPYLAMIDE; at 60℃; for 4h;	20.40 g (30 mmol) of trityl candesartan (III), 30 mL of dimethylacetamide (DMA); 4.95 g (235.9 mmol) K2CO3 and 10.2 g (49.4 mmol) of 1 -chloroethyl cycfohexyf carbonate are heated at 600C for 4 hours. The reaction mixture is cooled to room temperature, and 240 ml of isopropyl acetate and 240 mi of water are added. The organic phase is separated from the aqueous phase and the aqueous phase is <n="22"/>extracted again with 240 m. of isopropyi acetate. The combined organic phases are washed with 2x240 ml of water, filtered and the volatile components are evaporated in vacuum. To the oily residue 150 m. of tert-butyl methyl ether are added and the mixture is stirred at room temperature for at least 15 hours. The precipitate is filtered and dried for 2 hours at 400C in a vacuum dryer. 25.09 g (98%) of compound (II) are obtained (HPLC: more than 98%).
96%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;Flow reactor; Alkaline conditions; Large scale;	II.The reactor was charged with DMF (68 kg), triphenyl candesartan prepared in Step I (14 kg, 20.50 mol), sodium iodide (1.5 kg, 10.00 mol) and anhydrous potassium carbonate (3.8 kg, 27.53 mol) were added. ,Then add chloroethyl cyclohexyl carbonate (5.6kg, 27.18mol), warmed to 60 C, incubated for 4 hours;TLC (dichloromethane:methanol=20:1) was detected and the reaction was completed. The temperature was lowered to 25 C., 35 L of ethyl acetate and 93 L of water were added to the reactor, and 152 L of ethyl acetate was added for extraction to separate the organic layer. , add anhydrous sodium sulfate to dry;The desiccant was filtered off, the filtrate was transferred to a vacuum oven, and the ethyl acetate was recovered by distillation under reduced pressure at 35 C. The residue in the kettle was viscous.Add 70kg of anhydrous ethanol, raise the temperature to 45C, stir for 3 hours, reduce to room temperature, until a large amount of solids are generated; filter rejection, solid drying at 50C for 12 hours to obtain triphenylcandesartan cilexetil (white sticky solid () 16.8kg. Calculated according to the following formula, the yield of this step is 96%.

95%	With potassium carbonate; In N,N-dimethyl-formamide; at 55 - 60℃; for 3h;	A mixture of trityl Candesartan, dimethylformamide (DMF) and potassium carbonate at was heated at 60-70 C. Cyclohexyl 1-chloroethylcarbonate was added at 55-60 C. to the reaction mixture and maintain for 3 hours at 55-60 C. The reaction mixture was cooled at ambient temperature. The reaction mixture was poured in water at 0-10 C. and stirred for one hour at 0-10 C. The mixture was filtered and washed with D. M. water. A mixture of wet cake and acetone was stirred and heated for 30 minutes at 55-60 C. The reaction mixture was cooled and stirred at ambient temperature for 30 minutes. The mixture was filtered and washed with acetone. The solid was dried to obtain tritylated Candesartan cilexetil.Yield: 92-95%
92 - 95%	With potassium carbonate; In N,N-dimethyl-formamide; at 55 - 70℃; for 3h;	Exaniples-4; Preparation of tritylated Candesartan cilexetilA mixture of trityl Candesartan, dimethylformamide (DMF) and potassium carbonate at was heated at 60-700C. Cyclohexyl 1-chloroethylcarbonate was added at 55-600C to the reaction mixture and maintain for 3 hours at 55-600C. The reaction mixture was cooled at ambient <n="16"/>temperature. The reaction mixture was poured in water at 0-100C and stirred for one hour at 0-100C. The mixture was filtered and washed with D. M. water. A mixture of wet cake and acetone was stirred and heated for 30 minutes at 55-600C. The reaction mixture was cooled and stirred at ambient temperature for 30 minutes. The mixture was filtered and washed with acetone. The solid was dried to obtain tritylated Candesartan cilexetil. Yield: 92-95 %
84.8%	With potassium carbonate; In acetonitrile; at 40℃; for 8h;Product distribution / selectivity;	EXAMPLES; Example 1: Method of Making Cilexetil Trityl Candesartan in a Low Boiling Solvent; A suspension of trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (0.81 g, 5.86 mmol) and acetonitrile (19 g) was stirred at 40C for about 8 h, and the reaction was monitored by TLC. The acetonitrile was removed at 30C to 35 C under reduced pressure (10 mbar), and the residue was mixed with water (20 ml) and ethyl acetate (30 ml). The water layer was separated and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (10 ml x 2), dried over sodium sulfate, and evaporated to give cilexetil trityl candesartan crude, as a semi-solid, 94.38 % pure by HPLC. The crude product was triturated with hexane (30 ml) at 25C to 27C for about 3 h. Thereafter, the solids were filtered off, washed on the filter with hexane (5 g x 2) and dried at 25 C to 27C under reduced pressure (10 mbar) to give cilexetil trityl candesartan (12 g, 84.8 %) 94.64% pure by HPLC.
67.2%	With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In toluene; at 50 - 55℃; for 8.5h;Product distribution / selectivity;	Example 2: Method of Making Cilexetil Trityl Candesartan with a PTC; A suspension of trityl candesartan (2.0 g, 2.93 mmol), cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (1.22 g, 8.83 mmol), and tetrabutylammoniumhydrogensulfate (0.2 g) in toluene (20 ml) was stirred at 50C to 55 C for about 8. 5 h. The reaction progress was monitored by TLC. The mixture was poured into water (100 ml) and neutralized with citric acid (solid). The organic layer was separated, washed with water, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, and evaporated. The residue was triturated with hexane (20 ml) at 20-25C for about 30 min, filtered and dried at 40C and at less than about 30mbar to give white powder (1.68 gr, 67.2%), with 97.90% purity by HPLC.
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 25 - 65℃;	13,6 kg candesartan is dissolved 43,3 kg DMF at temperature bellow 25C; thereto add 4,1 kg Threeethylamine and 10,4 kg trityl chloride and heat up to 60-650C. After the reaction has completed the reaction mixture is poured into ethanol preheated to 50 +/-2C and thereto water is added. Upon cooling pH is adjusted with aqueous HCI to 4.6. Isolated tritylcandesartan is dissolved in 50kg DMF, and mixed at 25C; whereupon 2,2 kg potassium iodide, 4,4 kg potassium carbonate and 6,6 kg cilexetil chloride are added and mixture is heated to 60-65 0C until the reaction is completed. The product is isolated.
	With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 60 - 65℃; for 2.5h;Product distribution / selectivity;	Step-2: Preparation of Trityl candesartan cilexetil; Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at temperature of 60 - 65C over 30 min. Reaction mass is maintained at 60-650C for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60 - 650C and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60 - 650C. Toluene is distilled off from water washed organic layer at temperature below 6O0C under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 600C under vacuum. Residue is cooled to 30 - 35C, ethanol (300 ml) is added, mixed for 2 hrs at 25 - 300C and filtered the product. Wet cake is washed with ethanol (100 ml) and suck dried. Wet weight of Cilexetil trityl candesartan is 180 g; Example 2: Preparation of Candesartan cilexetil (without isolation of cilexetil trityl candesartan); Carbohexyl 1-chloroethyl carbonate (36 g) is added to a suspension of trityl candesartan (100 g), potassium carbonate (24 g) and potassium iodide (12 g) in DMSO (500 ml) at <n="8"/>temperature of 60 - 65C over 30 min. Reaction mass is maintained at 60-650C for 2 hrs, added toluene (300 ml) and water (300 ml). Reaction mass is mixed for 15 min., allowed to settle, the layers are separated at 60 - 650C and aqueous layer is extracted with toluene (200 ml). Water (200 ml) washings are given to the combined organic layer and toluene extractions twice at temperature of 60 - 650C. Toluene is distilled off from water washed organic layer at temperature below 6O0C under vacuum, ethanol (100 ml) is added, mixed for about 30 min and distilled off solvents under vacuum at temperature below 6O0C under vacuum. Residue is cooled to 30 - 350C, ethanol (1000ml) and boric acid (9.0 g) is added at temperature of 25 - 300C, temperature of reaction mass is raised and maintained at reflux temperature for 8 hrs. Reaction mass is concentrated to one third of its original volume by distillation of solvent and cooled the solution to 25 - 3O0C.n-Hexane (500 ml) is added to the reaction mass, mixed for 8hrs at 25 - 3O0C and filtered the product. Wet cake is washed with n-hexane (100 ml) and dried the material at temperature of 45-500C till becomes constant weight. Dry weight of Cilexetil candesartan is 65 g (Yield: 72.5%)
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 75℃;	Potassium carbonate (60 gm), 1-chloroethylcyclohexyl carbonate (60 gm) and potassium iodide (20 gm) were added to the solution of 2-Ethoxy-1-[[2'-(N- triphenylmethyltetrazole-5-yl)biphenyl)-4-yl]methyl]benzimidazole-7-carboxylic acid (100 gm) in dimethylformamide (500 ml) at room temperature. Raised the temperature to 750C, stirred for 2 hours, cooled to room temperature and 5% sodium chloride solution (2000 ml) was added. Maintained for 15 minutes, ethyl acetate (400 ml) was added, stirred and separated the layers. Aqueous layer was extracted with ethyl acetate (400 ml), organic layer was taken, washed with 10% sodium chloride solution (400 ml), concentrated, and co-distilled with ethyl acetate (100 ml). Mixture of ethyl acetate (500 ml) and n-hexane (500 ml) were added to the residual mass, stirred for 6 hours at room temperature, cooled to 50C, stirred for 1 hour, filtered, then washed with mixture of ethyl acetate (50 ml) and n-hexane (200 ml) and dried for 6 hours to obtain 1-(Cyclohexyloxy <n="6"/>carbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylate (110 gm, HPLC Purity: 99%).
	With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 2.5h;	Step I: Preparation of N-trityl candesartan cilexetilA mixture of N-trityl candesartan (Form A: 120 gm), potassium carbonate (48.58 gm), cilexetil chloride (54.48 gm) and dimethyl formamide (180 mL) at ambient temperature was heated to 60 C to 65 C followed by stirring at the same temperature for 2 hours and 30 minutes. The reaction mixture was cooled to 25 C to 30 C followed by addition of dichloromethane (600 mL) and ice cooled de-ionized water (1200 mL) at 10 C to 15 C to the reaction mass. The reaction was further stirred at 15 C to 20 C for 30 minutes followed by extraction of the aqueous layer with dichloromethane (120 mL) at 15 C to 30 C and washing with de-ionized water (2x600 mL) at ambient temperature.The organic layer was concentrated completely under vacuum at 30 C to 35 C followed by removal of traces of dichloromethane with cyclohexane (120 mL) and the further addition of cyclohexane (360 mL) to the residue at the ambient temperature. The reaction mixture was stirred at the same temperature for 14 hours followed by filtration and washing of the solid with cyclohexane (120 mL) which was suck dried under vacuum for 1 hour. Dichloromethane was again added (360 mL) at ambient temperature to the isolated solid followed by heating and stirring of the reaction mass at 30 C to 35 C for 30 minutes. The organic layer was concentrated under vacuum at 30 C to 35 C, cyclohexane (300 mL) added and the reaction mass was stirred further for 5 hours at the same temperature. The solid was filtered, washed with cyclohexane (120 mL) and suck dried under vacuum for 1 hour followed by further drying under vacuum for 16 hours at 35 C to 40 C.Chromatographic purity: 98.8%N-trityl desethylcandesartan cilexetil- 0.28%

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Yield	Reaction Conditions	Operation in experiment
96.9%	With pyridine; In dichloromethane; at -20 - 20℃; for 3h;	General procedure: Chloromethyl chloroformate (10 g, 78.2 mmol) was dissolved in dichloromethane (200 mL).Cool down to -20 C,And added ethanol (5 mL, 85.9 mmol)And a solution of pyridine (7.5 mL, 93.2 mmol) in dichloromethane (50 mL).After the reaction solution was stirred at 0 C for 1 hour,Return to room temperature and continue stirring for 2 hours.The mixture was sequentially treated with 1N aqueous HCl (300 mL) and brine.Wash with water (200 mL), dry over anhydrous Na2SO4,The title compound was obtained as a colorless oil (8.75 g, 81.1%).The compound was used directly in the next reaction without purification.
88%		REFERENCE EXAMPLE 2-1 1-Chloroethyl Cyclohexyl Carbonate A solution of 1.83 g of cyclohexanol and 1.45 g of pyridine in 30 ml of methylene chloride is cooled to -78 C. and, with stirring, 2.0 ml of 1-chloroethyl chloroformate is added dropwise to the solution over a period of 10 minutes. After completion of addition, the cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 3.31 g (yield 88%) of the title compound as colorless oil. bp 100-113 C./5-6 mmHg. IR(filmliquid) cm-1: 1760, 1455, 1390, 1360, 1260. NMR (CDCl3)delta: 1.0-2.3 (10H, m, STR21 1.83 (3H, d, J=6 Hz, CH3), 4.68 (1H, m, STR22 6.40 (1H, q, J=6H, STR23
88%		(a) Production of 1-Chloroethyl Cyclohexyl Carbonate A solution of 1.83 g of cyclohexanol and 1.45 g of pyridine in 30 ml of methylene chloride is cooled to -78 C. and 2.0 ml of 1-chloroethyl chloroformate is added dropwise, while stirring, over 10 minutes. Thereafter, the cold bath is removed and the mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 3.31 g (88% in yield) of the title compound as a colorless oil. bp 100-113 C./5-6 mm Hg IR numaxliquid film cm-1: 1760, 1455, 1390, 1360, 1260 NMR(CDCl3)delta: 1.0-2.3(10H, m), 1.83(3H, d, J=6 Hz), 4.68(1H, m), 6.40(1H, q, J=6 Hz)

		1-Chloroethyl Cyclohexyl Carbonate To twenty grams of cyclohexanol dissolved in 500 ml of anhydrous methylene chloride is added 18.4 ml of pyridine. The solution is cooled to -78 C. under an argon flush, 24.2 ml of 1-chloroethyl chloroformate in 160 ml of anhydrous methylene chloride is added dropwise. After the addition the milky reaction mixture is allowed to warm to room temperature. The now clear solution is stirred at room temperature for two hours, poured into a mixture of 100 ml of ice/100 ml of saturated sodium chloride, the layers are separated and the organic layer is dried and concentrated in vacuo to give 41.03 g of an oily yellow product. The yellow oil is purified by distillation (2.1 mm Hg at 82 C.) to give 38.54 g of a colorless oil. 1 H-NMR(CDCl3): delta6.5-6.4(q,1H,Cl--CH); 4.75-4.64(m,1H, C(=O)--O--C H in ring); 1.83(d,3H,J=5.8,Me); 1.23-2.02 (m,10H).
	With pyridine; In dichloromethane; at -20 - 20℃; for 3h;	General procedure: Step 1) chloromethyl ethyl carbonate To a solution of chloromethyl chloroformate (10 g, 78.2 mmol) in DCM (200 mL) was added a mixture of ethanol (5 mL, 85.9 mmol) and pyridine (7.5 mL, 93.2 mmol) in DCM (50 mL) at -20 C. The reaction was stirred at 0 C. for 1 h, then at rt for another 2 h. The resulting mixture was washed with 1N HCl solution (300 mL), followed by brine (200 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (8.75 g, 81.1%). The compound was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below: 1H NMR (400 MHz, CDCl3) delta 1.32-1.36 (t, J=7.2 Hz, 3H), 4.26-4.31 (m, J=7.2 Hz, 2H), 5.72 (s, 2H).

17
3-(6-amino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid dihydrochloride [ No CAS ]
[ 99464-83-2 ]
3-(6-amino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester [ No CAS ]

Reference： [1]Patent: WO2005/105781,2005,A1 .Location in patent: Page/Page column 55

18
[ 872866-01-8 ]
[ 99464-83-2 ]
{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid 1-cyclohexyloxycarbonyloxy-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 3h;	Example 6; Synthesis of {l-[l-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (compound 1-071); A suspension of {l-[l-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid hydrochloride (300 mg), <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (293 mg), potassium carbonate (196 mg) and Nal(213 mg) in DMF (3 mL) was heated at 60C for 3 hours. After cooling to roomtemperature, water was added and the mixture was extracted with ethyl acetate.The organic phase was washed with brine and concentrated under reducedpressure. The residue was purified with column chromatography (silica gel: Wakogel C200, eluent: hexane : ethyl acetate = 4 / 1) to obtain the title compound (225mg) as a colorless oil.

Reference： [1]Patent: WO2006/1511,2006,A1 .Location in patent: Page/Page column 49; 60

19
1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid [ No CAS ]
[ 99464-83-2 ]
[ 1307853-85-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 4h;	Step 6 A mixture of the carboxylic acid form (compound 24b, 3.71 g, 6.99 mmol), <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (compound 25a, 1.73 g), potassium carbonate (1.54 g) and DMF (20 mL) was stirred at 65 C. for 4 hr. Water was added to the reaction solution, and the resultant product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column (hexane?hexane :AcOEt =4:1?2:1?3:2?4:1) to give the objective compound (compound 26b) (4.9 g, quantitative) as a yellow amorphous solid.IR: 1751, 1549, 1458 cm-1 1H-NMR (CDCl3): delta=7.74-7.76 (m, 1H), 7.57-7.61 (m, 2H), 7.48-7.50 (m, 1H), 7.30-7.40 (m, 2H), 7.13-7.18 (m, 3H), 6.87-7.02 (m, 5H), 6.70-6.72 (m, 2H), 5.56-5.67 (m, 2H), 4.61-4.71 (m, 6H), 1.85-1.93 (m, 2H), 1.65-1.80 (m, 2H), 1.20-1.62 (m, 13H).MS: m/z=701 (MH+)
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 4h;	Example 6-6 (0428) (0429) A mixture of the carboxylic acid compound (3.71 g, 6.99 mmol), <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (1.73 g), potassium carbonate (1.54 g) and DMF (20 mL) was stirred at 65 C. for 4 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (hexane?hexane:ethyl acetate=4:1?2:1?3:2?1:1) to give BCAN of the object compound as a yellow amorphous product (4.9 g, quant.). (0430) IR: 1751, 1549, 1458 cm-1 (0431) 1H NMR (CDCl3): delta=7.74-7.76 (m, 1H), 7.57-7.61 (m, 2H), 7.48-7.50 (m, 1H), 7.30-7.40 (m, 2H), 7.13-7.18 (m, 3H), 6.87-7.02 (m, 5H), 6.70-6.72 (m, 2H), 5.56-5.67 (m, 2H), 4.61-4.71 (m, 6H), 1.85-1.93 (m, 2H), 1.65-1.80 (m, 2H), 1.20-1.62 (m, 13H). (0432) MS: m/z=701 (NH+)
	With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 2 - 3h;	3-[2'-(1-Benzyl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2-ethoxy-3H-benzoimidazole-4-carboxylic acid (19.5 grams) potassium carbonate (7.5 grams)and N, N-dimethylformamide (39 ml) were charged in a round bottom flask. 1-chlorbethylcyclohexylcarbonate (8.4 grams) was added followed by heating thereaction suspension to about 60-65C and was maintained for about 2-3 hours.The resultant reaction mixture was cooled to about 25-30C and was quenchedwith 10% sodium chloride solution (390 ml) and was extracted with 2x98 ml ofdichloromethane. Organic and aqueous layers were separated and organic layerwas washed with 4x98 ml of water. Organic and aqueous layers were separatedand organicjayer was distjjjed completely.

Reference： [1]Patent: US2012/232283,2012,A1 .Location in patent: Page/Page column 49-50
[2]Patent: US2015/239854,2015,A1 .Location in patent: Page/Page column 50
[3]Patent: WO2006/15134,2006,A1 .Location in patent: Page/Page column 19

20
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate [ No CAS ]
[ 99464-83-2 ]
1-[(cyclohexyloxy)carbonyl]oxyethyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-benzyl-N,N,N-triethylammonium chloride; In N,N-dimethyl-formamide; at 50℃; for 1h;	Example 3 Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.43g) was dissolved in dry DMF (4.3ml) and thereto was added triethylbenzylammonium chloride (0.25g). Thereto was dropped 1-chloroethylcyclohexylcarbonate (0.62g) and the mixture was stirred under heating to 50C. One hour later, the mixture was cooled to room temperature and thereto was added ethyl acetate. The mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (hexane: ethyl acetate = 1:2?1:3?ethyl acetate only) to give 1-[(cyclohexyloxy)carbonyl]oxylethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.12g, yield 20%). 1H NMR (400 MHz, CDCl3) delta 1.13-1.99 (m, 17H), 3.17-3.31 (m, 3H), 3.82 (s, 3H), 4.19-4.26 (m, 2H), 4.60-4.65 (m, 1H), 6.83-6.90 (m, 3H), 7.39 (t, 2H, J=8.0Hz)

Reference： [1]Patent: EP1612211,2006,A1 .Location in patent: Page/Page column 54-55

21
hydrochloric acid ethyl acetate [ No CAS ]
1-[3-(7-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol [ No CAS ]
sodium iodide(O_.17 g) [ No CAS ]
[ 99464-83-2 ]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide; water; ethyl acetate;	4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride To a solution of product of example 118 (1.1 g) in dimethylformamide (15 ml) were added sodium iodide(O.17 g), potassium carbonate (0.38 g) and <strong>[99464-83-2]cyclohexyl 1-chloroethyl carbonate</strong> (J. Antibiotics, 1987, 40, 81.) (0.579) at room temperature. The mixture was stirred at 70 C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3). The obtained oil was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl acetate solution (0.8 ml) was added. The precipitation was filtered to give the titled compound (0.96 g). 1H-NMR (DMSO-d6) d: 1.22-1.47 (6H,m), 1.58 (3H,d), 1.63-1.81 (6H,m), 2.38-3.30 (10H,m), 4.07-4.59 (1H,m), 5.80 (2H,brs), 6.28 (1H,t), 6.87 (1H, q), 6.97 (1H,d), 7.40-7.49 (4H,m), 7.64 (1H,dd), 7.79 (1H,dd), 7.96 (1H,d), 8.03 (1H,dd), 8.65 (1H,dd), 11.07 (1H,brs).

Reference： [1]Patent: US2002/119973,2002,A1

22
hydrochloric acid ethyl acetate [ No CAS ]
1-[3-(7-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol [ No CAS ]
[ 99464-83-2 ]
4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; potassium carbonate; In N-methyl-acetamide; water; ethyl acetate;	4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride To a solution of product of example 118 (1.1 g) in dimethylformamide (15 ml) were added sodium iodide(0.17 g), potassium carbonate (0.38 g) and <strong>[99464-83-2]cyclohexyl 1-chloroethyl carbonate</strong> (J. Antibiotics, 1987, 40, 81.) (0.57 g) at room temperature. The mixture was stirred at 70 C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3). The obtained oil was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl acetate solution (0.8 ml) was added. The precipitation was filtered to give the titled compound (0.96 g). 1H-NMR (DMSO-d6) delta: 1.22-1.47 (6H, m), 1.58 (3H, d), 1.63-1.81 (6H, m), 2.38-3.30 (10H, m)), 4.07-4.59 (1H, m), 5.80 (2H, brs), 6.28 (1H, t), 6.87 (1H, q), 6.97 (1H, d), 7.40-7.49 (4H, m), 7.64 (1H, dd), 7.79 (1H, dd), 7.96 (1H, d), 8.03 (1H, dd), 8.65 (1H, dd), 11.07 (1H, brs). MS m/z: 661[(M-2HCl)+1]
	With sodium iodide; potassium carbonate; In N-methyl-acetamide; water; ethyl acetate;	Example 306 4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol Dihydrochloride To a solution of product of example 118 (1.1 g) in dimethylformamide (15 ml) were added sodium iodide (0.17 g), potassium carbonate (0.38 g) and <strong>[99464-83-2]cyclohexyl 1-chloroethyl carbonate</strong> (J. Antibiotics, 1987, 40, 81.) (0.57 g) at room temperature. The mixture was stirred at 70 C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3). The obtained oil was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl acetate solution (0.8 ml) was added. The precipitation was filtered to give the titled compound (0.96 g). 1H-NMR (DMSO-d6) delta: 1.22-1.47(6H,m), 1.58(3H,d), 1.63-1.81(6H,m), 2.38-3.30(10H,m), 4.07-4.59(1H,m), 5.80(2H,brs), 6.28(1H,t), 6.87(1H, q), 6.97(1H,d), 7.40-7.49(4H,m), 7.64(1H,dd), 7.79(1H,dd), 7.96(1H,d), 8.03(1H,dd), 8.65(1H,dd), 11.07(1H,brs).

Reference： [1]Patent: US6509346,2003,B2
[2]Patent: US2005/70549,2005,A1

23
(S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid [ No CAS ]
(S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid [ No CAS ]
[ 99464-83-2 ]
[ 189365-94-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium iodide; triethylamine; In ethyl acetate; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 43 (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester (another name: (s,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester). In DMF (5.8 ml) were dissolved (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid (another name: (S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid) (0.58 g, 0.88 mmol) and triethylamine (0.49 ml, 3.52 mmol). To the solution were added, while stirring at room temperature, carbonic acid 1-chloroethyl ester cyclohexyl ester (0.73 g, 3.52 mmol) and potassium iodide (0.58 g, 3.52 mmol). The mixture was stirred for 38 hours at room temperature, which was then poured into water. To the mixture was added ethyl acetate, and the mixture was shaken for extraction. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate=2/5) to afford the title compound (0.43 g, 59%) as a colorless amorphous powdery product. IR nu max cm-1: 3410, 2930, 1755, 1710, 1645, 1510, 1450, 1240, 1075; NMR(CD3 OD) delta: 1.10-2.10(14H,m), 1.52(3H,d,J=5.4 Hz), 2.80-5.20(15H,m), 3.77(3H,s), 5.07(2H,s), 5.09(2H,s), 5.64(1H,d,J=7.8 Hz), 6.67-6.87(2H,m), 7.08(2H,d,J=8.4 Hz), 7.33(10H,s).

Reference： [1]Patent: US5935963,1999,A

24
(S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid [ No CAS ]
(S,S)-›4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl)-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid [ No CAS ]
[ 99464-83-2 ]
[ 189365-94-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium iodide; triethylamine; In N,N-dimethyl-formamide;	Reference Example 91 (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester (another name: (S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester) In DMF (5.8 ml) was dissolved (S,S)-?4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl)-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid (another name: (S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid) (0.58 g, 0.88 mmol) produced in Reference Example 78 and triethylamine (0.49 ml, 3.52 mmol). To the solution was added, while stirring at room temperature, carbonic acid 1-chloroethyl ester cyclohexyl ester (0.73 g, 3.52 mmol) and potassium iodide (0.58 g, 3.52 mmol). The mixture was stirred for 38 hours at room temperature, then poured into water. To the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of silica gel column chromatography (hexane/ethyl acetate=2/5) to afford the title compound (0.43 g, 59%) as a colorless amorphous powdery product. IR nu max cm-1: 3410, 2930, 1755, 1710, 1645, 1510, 1450, 1240, 1075 NMR(CD3 OD) delta: 1.10-2.10(14H,m), 1.52(3H,d,J=5.4 Hz), 2.80-5.20(15H,m), 3.77(3H,s), 5.07(2H,s), 5.09(2H,s), 5.64(1H,d,J=7.8 Hz), 6.67-6.87(2H,m), 7.08(2H,d,J=8.4 Hz), 7.33(10H,s).

Reference： [1]Patent: US5876756,1999,A

25
[ 160130-40-5 ]
[ 99464-83-2 ]
1-[trans-4-[[1-(Cyclohexyloxycarbonyloxy)ethyl]oxycarbonyl]-cyclohexyl]-3-[4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl]-imidazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; potassium carbonate; In water; acetic acid; dimethyl sulfoxide; ethyl acetate;	EXAMPLE 21 1-[trans-4-[[1-(Cyclohexyloxycarbonyloxy)ethyl]oxycarbonyl]-cyclohexyl]-3-[4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl]-imidazolidin-2-one 2.0 g of 1-(trans-4-carboxycyclohexyl)-3-[4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl]-imidazolidin-2-one, 4.5 g of (1-chloroethyl)-cyclohexylcarbonate and 0.2 g of sodium iodide in 10 ml of dimethylsulfoxide are stirred for 1 hour at ambient temperature. 1.1 g of potassium carbonate are added and the mixture is stirred for 16 hours at 60 C. After cooling the reaction mixture is poured onto 100 ml of water, to which 1 ml of glacial acetic acid has been added. The mixture is extracted 3 times with ethyl acetate, the combined organic phases are washed with saline solution, dried and evaporated down. The residue is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (1:1). Yield: 0.8 g (30% of theory), Rf value: 0.54 (Silica gel; cyclohexane/ethyl acetate=1:1) Mass spectrum: M+ =675

Reference： [1]Patent: US5681841,1997,A

26
[ 117423-04-8 ]
[ 99464-83-2 ]
[ 1025828-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide;	EXAMPLE 1 1-(Cyclohexyloxycarbonyloxy)ethyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(3-tetrahydrofuryl)methylpenem-3-carboxylate (Compound 7): The mixture of sodium (5R,6S)-6-[(R)-1-hydroxy-ethyl]-2-(3-tetrahydrofuryl)methylpenem-3-carboxylate 2.5 hydrate (Compound 1, 1 g), 1-chloroethyl cyclo-hexylcarbonate (0.6 ml) and N,N-dimethylformamide (6 ml) was heated at 70 C. for one hour. The reaction mixture was then diluted with ethyl acetate and washed with water. The organic layer was dried and then concentrated. The residue was purified by passing it through a silica gel column, whereby 0.32 g of the title compound was obtained.

Reference： [1]Patent: US5703068,1997,A

27
2'-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carboxylic acid [ No CAS ]
[ 99464-83-2 ]
1-(cyclohexyloxycarbonyloxy)ethyl 2'-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy)ethyl]biphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃; for 24h;	Step 3 1-(cyclohexyloxycarbonyloxy)ethyl 2'-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carboxylate 1-Chloroethyl cyclohexyl carbonate (149 mg) obtained in Step 1 was dissolved in N,N-dimethylformamide (5.0 ml), 2'-[1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carboxylic acid (300 mg) obtained in Step 2, potassium carbonate (99 mg) and potassium iodide (50 mg) were successively added and the mixture was stirred at 60C for 1 day. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water (3 times) and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give the title compound (381 mg). 1H-NMR (300MHz, deltappm, DMSO-d6) 8.05 (2H, d, J=8.1Hz), 7.87-7.76 (3H, m), 7.66 (1H, s), 7.60-7.55 (1H, m), 7.50-7.33 (7H, m), 7.21-7.19 (1H, m), 6.93-6.88 (1H, m), 4.62-4.53 (1H, m), 4.44-4.38 (1H, m), 3.60-3.52 (1H, m), 3.45-3.29 (1H, m), 3.13-3.09 (2H, m), 2.78 (2H, brs), 2.70-2.45 (2H, m), 1.88-1.76 (2H, m), 1.68-1.58 (5H, m), 1.50-1.12 (9H, m), 0.99-0.97 (6H, m). MS(ESI, m/z) 668 (M+H)+.

Reference： [1]Patent: EP1630157,2006,A1 .Location in patent: Page/Page column 55-56

28
3-[(4-dipropylamino-butyl)-(4-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-propionic acid hydrochloride [ No CAS ]
[ 99464-83-2 ]
3-[(4-dipropylamino-butyl)-(4-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-amino]-propionic acid-1-(cyclohexyloxycarbonyloxy)-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 60℃; for 15h;	The compound (352.4 mg) obtained in Example 51-1, potassium carbonate (420.2mg), and potassium iodide (41.5mg) were suspended in anhydrous DMF (7.0 ml). The suspension was added with a DMF solution (3.5 ml) containing 1-chloro-ethyl ester cyclohexyl ester carboxylic acid (152.9 mg) and the whole was stirred at 60C for 15 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with water and the whole was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (199.6 mg) as a colorless oily substance. MS(FAB,Pos.):m/z=566[M+H]+ 1H-NMR(500MHz,CDCl3):delta=0.85(6H,t,J=7.3Hz),1.22-1.43(15H,m),1.48(3H,d,J=5.4Hz),1.53-1.54(1H,m),1.73(2H,m),1.91(2H,m),2.18-2.34(6H,m),2.42(2H,t,J=6.8Hz),2.48(2H,t,J=7.6Hz),2.79(2H,t,J=7.8Hz),3.46(2H,s),3.55(5H,s),3.62(2H,s),3.67(2H,s),4.59-4.64(1H,m),6.75(1H,q,J=5.4Hz),6.87(1H,d,J=1.2Hz),6.99(1H,d,J=1.2Hz),7.10(2H,d,J=20.8Hz),7.26(2H,d,J=8.1Hz),7.33(2H,d,J=8.1Hz),12.34(1H,br).

Reference： [1]Patent: EP1724263,2006,A1 .Location in patent: Page/Page column 82

Yield	Reaction Conditions	Operation in experiment
		(b) Production of 1-Iodoethyl Cyclohexyl Carbonate A solution of 1.65 g of 1-chloroethyl cyclohexyl carbonate obtained by the procedure (a) and 5.0 g of sodium iodide in 50 ml of acetonitrile is stirred at 70 C. for 45 minutes and then concentrated under reduced pressure. The residue is extracted with ether. The extracts are combined and the solvent is distilled off under reduced pressure to give the title compound as a light-yellow oil. NMR(CD3 CN, TMS(external standard))delta: 0.7-2.3(10H, m), 2.18(3H, d, J=6 Hz), 4.1-4.9(1H, m), 6.67(1H, q, J=6 Hz)

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 7 alpha-Chloroethyl Cyclohexyl Carbonate By the method of Preparation 1, cyclohexanol (4.90 g, 49.0 mmol) was converted to title product, distillation at 73-77 C. (1 mm) affording 8.3 g as a clear oil (40.4 mmol, 82.4%): 1 H NMR (CDCl3) delta 0.80-2.30 (br m, 10H), 1.83 (d, J=6 Hz, 3H), 4.40-5.00 (br m, 1H), 6.42 (q, J=6 Hz, 1H).

31
[ 854538-90-2 ]
[ 99464-83-2 ]
1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 1-(4-bromobenzyl)-2-ethoxy-1H-benzimidazole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate; potassium iodide; In 1,2-dimethoxyethane; at 60 - 70℃; for 10h;	Example 6. Obtaining cilexetil 1- (4-bromobenzylamine) -2- ethoxybenzimidazole-7-carboxylate (III)(in) (III) To a solution made of 1.8 g of l-(4- bromobenzylamine) -2-ethoxybenzimidazole-7-carboxylic acid in dimethylformamide potassium iodide (0.44 g) and anhydrous potassium carbonate (0.89 g) are added. (+/-) 1- chloroethyl cyclohexyl carbonate (6.43 g) is added to the resulting mixture and stirred at 60-70C for approximately 10 hours. Ethyl acetate (20 ml) and water (30 ml) are then added successively. The organic phase is separated, washed with water and concentrated at reduced pressure. This provides 2.05 g of dry product in the form of an oil (79% yield) .

Reference： [1]Patent: WO2006/134078,2006,A1 .Location in patent: Page/Page column 13-14

32
[ 947331-10-4 ]
[ 99464-83-2 ]
[ 947331-20-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a 100 ml of one-necked flask, 0.662g of material, 0.161g of potassium carbonate, 5 ml of N,N-dimethylacelamide were added in turn. The solution was stirred at room temperature for 20 minutes. 0.584g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was added and the mixture was reacted at 45-50C for 16 hours. After the reaction was completed, the resulting solution was filtered, and 30ml of water was added into the filtrate. The resulting mixture was extracted with 30ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.456g of oil, which was directly used in the next reaction without purification. 10ml of dioxane and 5ml of 4mol/L HCl were added to react at room temperature for 16 hours. The solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.412g of the final product. 1H-NMR (CDCl3) delta H (ppm): .87(t,3H,J=14.1), 1.2-1.6(m,15H), 1.73(m,2H,J=7.5), 2.07(s,1H), 2.69(t,2H,J=13.1), 4.05(q,3H,J=22.0), 5.54(s,2H), 6.80-7.70(8H), 8.08(d,1H,J=8.6) ESI(-)m/z: 605.7
	With potassium carbonate; In N,N-dimethyl acetamide; at 20 - 50℃; for 16.3333h;	To a 100 ml of one-necked flask, 0.662 g of material, 0.161 g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. 0.584 g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was added and the mixture was reacted at 45-50 C. for 16 hours. After the reaction was completed, the resulting solution was filtered, and 30 ml of water was added into the filtrate. The resulting mixture was extracted with 30 ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.456 g of oil, which was directly used in the next reaction without purification.

Reference： [1]Patent: EP1988090,2008,A1 .Location in patent: Page/Page column 15
[2]Patent: US2009/36505,2009,A1 .Location in patent: Page/Page column 13

33
[ 632322-61-3 ]
[ 99464-83-2 ]
[ 632322-62-4 ]

Yield	Reaction Conditions	Operation in experiment
97.43%	Reflux;	To the reaction solution was added KOH (11.8 g, 0.21 mol)The reaction was continued until the saponification was complete by TLC (about 3 to 5 hours).1-Chloroethylcyclohexyl carbonate (31.0 g, 0.15 mol) was added, the temperature was raised to reflux,The reaction was monitored by TLC to complete the reaction (about 8-10 hours). The reaction mixture was allowed to cool to room temperature and the inorganic salt was removed by filtration. About 100 g of solvent was removed by concentration,Cooling to 0 C, crystallization 1h,2-ethoxy-1 - [(2'-cyanobiphenyl-4-yl) methyl] -1H-benzimidazole-7--1 - [[(cyclohexyloxy) carbonyl] oxy] ethyl ester (XII) 51.8 g,Yield 91.3% (relative to XIII) with a purity of 97.43%.
64%	With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 3h;Product distribution / selectivity;	b) 1 -(cyclohexy.oxycarbonyloxy)ethyl 1 -((2'-cyanobiphenyl-4-yl)methyl-2-ethoxy-1 H- benzo[dJimidazole-7-carboxyiate; 1 1.8 g (29.7 mmol) of 2-ethoxy-1 -[(2'-cyanobiphenyl-4-yl)-me1hyl]-1 /-/-benzimidazole- 7-carboxylic acid, 30 ml of dimethylacetamide, 4.68g (34 mmol) of K2CO3 and 10.1 g (49 mmoi) of (+/-)i -chloroethyl cyclohexyi carbonate were heated at 6O0C for 3 hours. The reaction mixture was then cooled and 300 ml of isopropy. acetate and 300 mi of water were added. The phases were separated water phase was extracted again with 300 ml of isopropyi acetate. Collected organic phases were washed with 66 ml of water, dried over Na2SO4, filtered and concentrated to oily residue. To this residue 10 ml of methylene chloride were added and the precipitated product was filtered off and suspended in 50 ml of terf-butyl methyl ether. The product was collected by filtration, washed and dried at reduced pressure (10.7 g, 64%).IR: 2930, 2227, 1755, 1726, 1550, 1280, 1245, 1082, 1038, 910, 7641H NMR (300 MHz, DMSO, delta): 7.91 m (1 H), 7.75 m (2H), 7.45-7.60 m (5H), 7.22 m (1 H), 7.10 d (2H), 6.81 q (1 H), 5.63 d (1 H), 5.57 d (1 H), 4.46-4.68 m (3H)1 1 .15-1.80 m (16H).

Reference： [1]Patent: CN107089972,2017,A .Location in patent: Paragraph 0033; 0034; 0035; 0036; 0038; 0039
[2]Patent: WO2008/129077,2008,A2 .Location in patent: Page/Page column 26

34
[ 1070890-09-3 ]
[ 99464-83-2 ]
[ 1070891-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 24h;	A mixture of 3-(2-[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)- benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (500 mg, 0.95 mmol), <strong>[99464-83-2]carbonic acid 1-chloroethyl cyclohexyl ester</strong> (393 mg, 1.9 mmol), triethylamine (399 muL, 2.85 mmol), and NaI (142.5 mg, 0.95 mmol) in DMF (5 mL) were stirred at 60 C for 1 day. Ethyl acetate was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 3-(2-[4-Chloro-3- (4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid i-cyclohexyloxycarbonyloxy-ethyl ester 37-1. MS [M+H]+ : 674.2 ; tR = 35.7 min (method 5).

Reference： [1]Patent: WO2008/124610,2008,A1 .Location in patent: Page/Page column 118

35
[ 99464-83-2 ]
[ 61070-20-0 ]
Nα-tert-butoxycarbonyl-Nϖ-methyl-L-histidine 1-(cyclohexyloxycarbonyloxy)ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Example 47 Production of Nalpha-tert-butoxycarbonyl-N?-methyl-L-histidine 1-(cyclohexyloxycarbonyloxy)ethyl ester Into a suspension of potassium carbonate (2.1 g, 14.9 mmol) in DMF (20 mL) was dropped a solution of Nalpha-tert-butoxycarbonyl-N?-methyl-L-histidine (2.0 g, 7.4 mmol) in DMF (20 mL) at 0 C. followed by stirring at room temperature for 0.5 hour. 1-Chloroethylcyclohexyl carbonate (1.8 g, 8.9 mmol) was dropped into the above mixture at 0 C. followed by stirring at room temperature for 20 hours. The reaction solution was poured over ice water, the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The residue prepared by evaporation of the solvent therefrom in vacuo was purified by silica gel column chromatography (chloroform methanol=30:1) to give the title compound (1.7 g, 53%) as an oily substance. MS (EI) m/z: 440 (M+). 1H-NMR (DMSO-d6) delta: 1.32-1.44 (m, 15H), 1.62-1.64 (m, 2H), 1.81-1.83 (m, 2H), 2.89-2.94 (m, 2H), 3.31 (s, 3H), 3.52-3.53 (m, 3H), 4.21-4.23 (m, 1H), 4.54-4.56 (m, 1H), 6.62-6.66 (m, 2H), 7.39-7.41 (m, 1H), 7.48-7.49 (m, 1H).

Reference： [1]Patent: US2010/152459,2010,A1 .Location in patent: Page/Page column 10

36
[ 1239349-13-3 ]
[ 99464-83-2 ]
[ 1239349-15-5 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 5402 - 5406

37
[ 1239349-14-4 ]
[ 99464-83-2 ]
[ 1239349-15-5 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 5402 - 5406

38
[ 99464-83-2 ]
[ 18162-48-6 ]
[ 139481-59-7 ]
[ 145040-37-5 ]

Yield	Reaction Conditions	Operation in experiment
		To 50.0 grams (0.113 moles) of 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid were added 250 ml of dry chloroformand 46 grams of triethylamine. Then, a solution of 25.5 grams tert-butyldimethylchlorosilane in dry chloroform was slowly added to the resultingsolution at ambient temperature and the mixture was stirred for 3 hours. Thereaction mass was cooled to 57C and 25.8 grams (1.1 moles) of 1-chloroethylcyclohexylcarbonate and 46 grams of triethylamine were added simultaneously, and the resulting mixture was stirred for 24 hours. The reactionmass was washed with aqueous saturated sodium bicarbonate solution followedby water, and the chloroform layer was separated and evaporated under reducedpressure. To the residue, diisopropyl ether was added and stirred to form acomplete solution. The ether solution was dried over magnesium sulfate and thesolvent was evaporated under reduced pressure. The precipitated solid wasfiltered and dried at 60C to get the product (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Reference： [1]Patent: WO2006/15134,2006,A1 .Location in patent: Page/Page column 17-18

39
[ 1174039-19-0 ]
[ 99464-83-2 ]
(R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy) ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.4%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 65℃; for 2h;In a sealed tube;	(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added to the reaction tube. After stirring until 2a was dissolved, <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (0.124 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were then added to the solution successively. Upon completion of the addition, the reaction tube was sealed up. The reaction mixture was reacted at 65 C in an oil bath for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials, and then the oil bath was removed. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with 30 mL of water and 30 mL of saturated brine successively. The combimed organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester 38a (0.25 g, yield 69.4%) as a white solid. MS m/z (ESI): 721.0 [M+1].

Reference： [1]Patent: EP2230241,2010,A1 .Location in patent: Page/Page column 60

40
[ 1176736-62-1 ]
[ 99464-83-2 ]
[ 1176738-87-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 26. Production of 1-Cyclohexyloxycarbonyloxyethyl 4-(1-methylpiperidin-4-ylidene)-9,10-dihydro-4H-1-thiabenzo[f]azulene-2-carboxylate hydrochloride [Compound 176] Triethylamine (6.2 mL, 44.2 mmol), potassium iodide (4.4 g, 26.5 mmol), and <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (2.2 g, 10.6 mmol) were added to a DMF (50 mL) solution of the compound 4 (3.0 g, 8.84 mmol), and the mixture was stirred at 80C overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1). The resulting free amino acids were dissolved in dioxane (20 mL), 4 mol/L hydrogen chloride-dioxane was added thereto, and the mixture was stirred for 1 hour. The solvents were distilled off under a reduced pressure, and ether was added thereto to allow crystallization of a hydrochloride. The crystals were separated by filtration and dried, to give 1.8 g (2 steps, 37%) of the captioned compound.

Reference： [1]Patent: EP2243778,2010,A1 .Location in patent: Page/Page column 23

41
[ 1073117-27-7 ]
[ 99464-83-2 ]
[ 1073117-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 6h;	The mixture of 13.4 g of 2-((tert-Butoxycarbonyl)((2?-(l -trityl-1 H-tetrazol-5-yl)-[1 , 1 ?-biphenyl]4-yl)methyl)ammno)-3-nitrobenzoic acid (the product of previous reaction), 11.2 ml of N,Ndimethylacetamide, 4.06 g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> and 2.35 g of K2C03 is heated at 60C for 6 hours. Then the reaction mixture is cooled 82 ml of isopropyl acetate and 82 ml of water are added. The phases are separated and aqueous phase is reextracted with 82 ml of isopropyl acetate. Collected organic phases are washed with water (2 x 82 ml). Isolated organic phase is a solution of the title product in isopropyl acetate.HPLC purity: 87.5% of the title product

Reference： [1]Heterocycles,2010,vol. 81,p. 1503 - 1508
[2]Patent: WO2015/90635,2015,A1 .Location in patent: Page/Page column 13; 14

42
[ 1190221-98-7 ]
[ 99464-83-2 ]
[ 1190220-93-9 ]

Yield	Reaction Conditions	Operation in experiment
28%	With sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 2h;	0.69 g (1.5 mmol) of 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid · sodium salt, 0.37 g (1.8 mmol) of carbonic acid-1-chloro-ethylcyclohexyl, and 0.25 g (1.65 mmol) of sodium iodide were stirred in DMF (7 mL) at 60C for 2 hours. After completion of the reaction, ethyl acetate was added thereto, and the mixture was washed with a sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give the target 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid · 1-([(cyclohexyloxy)carbonyl]oxy)ethyl ester (yield: 28%). 1H-NMR (CDCl3) delta: 1.38 (3H, d, J = 5.5 Hz), 1.25-1.86 (10H, m), 4.28 (2H, s), 4.31 (2H, s), 4.51-4.60 (1H, m), 6.73 (1H, q, J = 5.5 Hz), 7.42-7.68 (6H, m), 8.00 (1H, d, J = 2.4 Hz), 8.11-8.12 (1H, m), 8.64-8.67 (2H, m), 8.79 (1H, d, J= 9.2 Hz), 8.85 (1H, s), 11.7 (1H, br).

Reference： [1]Patent: EP2272822,2011,A1 .Location in patent: Page/Page column 51

43
[ 139481-72-4 ]
[ 99464-83-2 ]
1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazole-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 75℃; for 2h;	Potassium carbonate (60 gm), <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (60 gm) and potassium iodide (20 gm) were added to the solution of 2-Ethoxy-l-[[2'-(N- triphenylmethyltetrazole-5-yl)biphenyl)-4-yl]methyl]benzimidazole-7-carboxylic acid (100 gm) in dimethylformamide (500 ml) at room temperature. Raised the temperature to 75C, stirred for 2 hours, cooled to room temperature and 5% sodium chloride solution (2000 ml) was added. Maintained for 15 minutes, ethyl acetate (400 ml) was added, stirred and separated the layers. Aqueous layer was extracted with ethyl acetate (400 ml), organic layer was taken, washed with 10% sodium chloride solution (400 ml), concentrated, and co-distilled with ethyl acetate (100 ml). Mixture of ethyl acetate (500 ml) and n-hexane (500 ml) were added to the residual mass, stirred for 6 hours at room temperature, cooled to 5C, stirred for 1 hour, filtered, then washed with mixture of ethyl acetate (50 ml) and n-hexane (200 ml) and dried for 6 hours to obtain 1 10 gm of 1- (cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(lH-tetrazole-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate.

Reference： [1]Patent: WO2011/145100,2011,A1 .Location in patent: Page/Page column 8

44
[ 1350551-90-4 ]
[ 99464-83-2 ]
[ 1350551-98-2 ]
[ 1350551-34-6 ]

Yield	Reaction Conditions	Operation in experiment
		[0173] Example 3-1; Carbonic acid l -(5-{(i?V("4-{amino benzoyliminolmethv phenylamino)- 2-fluoro-3-(2-hy droxyethoxy')-5-rnethoxyphenyllmethyl)-2-pyrimidin-2-yl-2H-r i ,2,41triazol -3-yloxy)ethyl ester cyclohexyl ester (Diastereomer 1); Example 3-2; Carbonic acid1 -(5- { (R)-(4- { amino [benzoylimino]methyU phenylamino -[2-fluoro-3 -(2-hy droxyethoxyV5-methoxyphenyllmethyl}-2-pyrimidin-2-yl-2H-f l ,2,41triazol -3-yloxy")ethyl ester cyclohexyl ester ("Diastereomer 2; (3a) Carbonic acid l -(5- {(4-{amino[benzoylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydro xyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[l ,2,4]triazol-3- yloxy)ethyl ester cyclohexyl esterTo a mixture ofN- [ 1 -amino- 1 -(4- { [[2-fluoro-3 -(2-hydroxyethoxy)-5 -methoxyphenyl] -(5-ox o-l -pyrimidin-2-yl-4,5-dihydro-lH-[l ,2,4]triazol-3-yl)methyl]amino}pheny l)methylidene]benzamide (Example la, 1.0 g) and DMF (20 mL), potassium hydrogen carbonate (1.67 g) and 1 -chloroethyl cyclohexyl carbonate (2.76 g) were added, and the resulting mixture was stirred at 55C for 26 hours. The reaction solution was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (680 mg).Mass spectrum (ESI) m/z: 769 (M+H)+ [0174] (3b) Carbonic acid l -(5-{(i?)-(4-{amino[benzoyliniino]methyl}phenylamino)-[2-fluoro-3-(2-hy droxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[l ,2,4]triazol - -yloxy)ethyl ester cyclohexyl esterUsing SUMICHIRAL OA-2500 column, carbonic acid 1 -(5- { (4- { amino[benzoylimino]methyl }phenylamino)- [2-fluoro-3 -(2-hydro xyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[l ,2,4]triazol-3- yloxy)ethyl ester cyclohexyl ester (680 mg) was optically resolved under the conditions below to obtain the captioned compounds in the second fraction and the third fraction as a crudely purified product.HPLC retention time; (the second fraction) 14 min, (the third fraction) 17 min (column name: SUMICHIRAL OA-2500, 30 rnmcp x 25 cm, mobile phase: methanol, elution rate: 30 mL/min)The crudely purified product obtained (the second fraction) was purified using SUMICHIRAL OA-2500S column (20 mm(p x 25 cm, mobile phase: methanol, elution rate: 30 mL/min) to obtain Diastereomer 1 (48.22 mg).The second fraction (Diastereomer 1)1H-NMR (CD3OD) delta = 1.15-1.90 (m, 13H), 3.71 (s, 3H), 3.84-3.94 (m, 2H), 4.02-4.13 (m, 2H), 4.45-4.57 (m, 1H), 6.08 (s, 1H), 6.59 (dd, J = 2.8, 7.2 Hz, 1H), 6.73 (dd, J = 2.8, 4.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.91 (q, J = 5.6 Hz, 1 H), 7.36-7.54 (m, 4H), 7.96 (d, J = 8.8 Hz, 2H), 8.16-8.30 (m, 2H), 8.84 (d, J = 4.4 Hz, 2H)Mass spectrum (ESI) m/z: 769 (M+H)+ The crudely purified product obtained (the third fraction) was purified using SUMICHIRAL OA-2500S column (20 mm

Reference： [1]Patent: WO2011/145747,2011,A1 .Location in patent: Page/Page column 50-52

45
[ 99464-83-2 ]
[ 1394048-74-8 ]

Reference： [1]Patent: US2012/213806,2012,A1

46
[ 99464-83-2 ]
C₂₇H₃₅NO₆*ClH [ No CAS ]

Reference： [1]Patent: US2012/213806,2012,A1

47
[ 1394050-13-5 ]
[ 99464-83-2 ]
C₃₂H₄₃NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 80℃; for 2h;Inert atmosphere; Microwave irradiation;	F. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (R7=-CH(CH3)OCOO-cyclohexyl) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (50 mg, 120 mumol, 1.0 eq.), DMA (1 mL), DIPEA (0.13 mL, 0.75 mmol) and <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (52 mg, 250 mumol, 2.0 eq.) were combined. The reaction vessel was capped and microwaved at 80 C. for 2 hours. The mixture was dried under vacuum, dissolved in MeCN (2 mL), and combined with 4 M of HCl in dioxane (500 muL). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and discarded, and the filtrate containing the intermediate was concentrated down and submitted to next step. 1,2,3-triazole-4-carboxylic acid (14 mg, 120 mumol, 0.5 eq.) and HATU (48 mg, 120 mumol, 1.0 eq) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (44 muL) and the intermediate from last step. The mixture was stirred for 5 minutes. The reaction was quenched with water and the product dried under vacuum. The product was then purified by preparative HPLC to yield the title compound (4.8 mg, 95% purity. MS m/z [M+H]+ calc'd for C30H36N4O7, 565.26. found 565.4.

Reference： [1]Patent: US2012/213806,2012,A1 .Location in patent: Page/Page column 46

48
[ 1394050-24-8 ]
[ 99464-83-2 ]
C₃₃H₄₅NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetone; for 24h;Inert atmosphere; Reflux;	ZD. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (S)-1-cyclohexyloxycarbonyloxy-ethyl ester (R4=H; R7=-CH(CH3)OC(O)O-cyclohexyl) 1-Chloroethyl cyclohexyl carbonate (240 mg, 1.2 mmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 726 mumol) and Et3N (106 muL, 762 mumol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. The individual isomers were separated (~1:1) and purified (Interchim reverse phase chromatography column) the solvent was removed under vacuum. MeCN (2 mL) and 4 M HCl in 1,4-dioxane (3 mL, 10 mmol) was added and the resulting mixture was stirred for 30 minutes. The solvent was evaporated under vacuum and the product was azeotroped with toluene (1*) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester.

Reference： [1]Patent: US2012/213806,2012,A1 .Location in patent: Page/Page column 66

49
[ 1307853-76-4 ]
[ 99464-83-2 ]
[ 1307853-79-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 4h;	Step 7 A mixture of the carboxylic acid form (compound 24a, 804 mg, 1.4 mmol), <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (compound 25a, 346 mg, 1.7 mmol), potassium carbonate (309 mg, 2.2 mmol) and DMF (5 ml) was stirred at 65 C. for 4 hr. Water was added to the reaction mixture, and the resultant product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (hexane?hexane :AcOEt =4:1?2:1?3:2?1:1) to give the objective compound (compound 26a) (972 mg, 93%) as a colorless amorphous solid.IR: 1751, 1550, 1462 cm-1 1H-NMR (CDCl3): delta=7.74-7.76 (m, 1H), 7.59-7.62 (m, 2H), 7.49-7.51 (m, 1H), 7.38-7.40 (m, 1H), 7.31-7.33 (m, 1H), 7.16-7.20 (m, 1H), 7.01 (d, J=8 Hz, 2H), 6.96 (d, J=8 Hz, 2H), 6.87-6.89 (m, 1H), 6.62-6.68 (m, 4H), 5.56-5.68 (m, 2H), 4.60-4.69 (m, 6H), 3.70 (s, 3H), 1.91-1.93 (m, 2H), 1.71-1.73 (m, 2H), 1.15-1.63 (m, 13H).MS: m/z=731 (MH+)

Reference： [1]Patent: US2012/232283,2012,A1 .Location in patent: Page/Page column 46

50
[ 1382326-04-6 ]
[ 99464-83-2 ]
[ 1401719-79-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 30℃;	B. Preparation of Cbz-D-Glu(D-Tphi-0-CH(CH3)-0-CO-0-cyclohexyl)-0-Bzl To a mixture of Cbz-D-Glu(D-Trp-OH)-0-Bzl (6.00 g, 10.8 mmol), potassium carbonate (5.94 g, 43.0 mmol) and sodium iodide (28.50 g , 190.1 mmol) in W,W-dimethylformamide (40 mL) was added 1 -chloroethyl-cyclohexyl carbonate (8.90 g, 43.0 mmol) at RT. After stirring at 30C for overnight, the reaction mixture was diluted with ethyl acetate. The mixture was then washed with water (x3) and brine. The residue was subjected to purification by column chromatography on silica gel using a solvent gradient consisting of a mixture of ethyl acetate in hexanes (20 to 40%) as eluant. Fractions rich in product were combined, and volatiles were removed in vacuo. Thus, the alkylated productCBz-D-Glu(D-Trp-0-CH(CH3)-0-CO-0-cyclohexyl)-0-Bzl (3.77 g) was obtained as a pale-yellow foam. Yield = 48%; 1H NMR (DMSO-D6> 400 MHz) delta ppm: 10.86 (s, 1 H), 8.35 (dd, J = 17.7, 7.6 Hz, H), 7.78 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1 H), 7.34 (br. s, 11H), 7.14 (d, J = 3.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1 H), 6.94 - 7.00 (m, 1H), 6.62 (q, J = 5.1 Hz, 0.5H), 6.51 (q, J = 5.1 Hz, 0.5H), 5.12 (d, J = 3.0 Hz, 2H), 4.97 - 5.09 (m, 2H), 4.40 - 4.59 (m, 2H), 4.05 - 4.15 (m, 1H), 2.93 - 3.18 (m, 2H), 2.15 - 2.27 (m, 2H), 1 .91 - 1 .97 (m, 1H), 1.71 - 1.86 (m, 3H), 1.57 - 1.68 (m, 2H), 1.13 - 1.49 (m, 9H); MS-ESI (m/z): 728 [M+lf .

Reference： [1]Patent: WO2012/129671,2012,A1 .Location in patent: Page/Page column 41-42

51
[ 1382326-14-8 ]
[ 99464-83-2 ]
[ 1401719-90-1 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20 - 40℃;	Example 19 Preparation of H-D-Glu(D-Trp-0-CH(CH3)0-CO-0-cyclohexyl)-0-Et hydrochloride salt, Apo854.HCI Cbz-D-Glu(OH)-0-Et (12.1 g, 39.1 mmol), HOSu (4.60 g, 40.0 mmol) andEDCI.HCI (7.67 g, 40.0 mmol) were mixed in DMF (100 mL) under ice-water bath temperature. The reaction mixture was allowed to warm to RT then stirred for overnight. The reaction mixture was cooled again in an ice-water bath and D-Trp- OH (8.17 g, 40.0 mmol) was added. The mixture was stirred at room temperature for overnight. The mixture was poured into a beaker containing 0.5N HCI (200 mL) and ice pellets. The mixture was extracted with ethyl acetate (2x200 mL + 1x100 mL). The organic layers were combined and washed with a 0.5N HCI solution (100 mL), water (2x100 mL) and brine (100 mL), dried over MgS04, then filtered. The filtrate was concentrated via rotary evaporation under reduced pressure and the resulting solid Cbz-D-Glu(D-Trp-OH)-0-Et was triturated with10% ethyl acetate in hexanes. The precipitated white solid was collected via suction filtration (17.6 g). Yield = 90 %; 1H NMR (DMSO-D6l 400 MHz) delta ppm: 12.58 (br. s, 1 H), 10.82 (s, 1H), 8.12 (d, J = 8.1 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 1H), 7.23 - 7.42 (m, 6H), 7.12 (s, 1 H), 7.06 (t, J = 7.6 Hz, 1 H), 6.97 (t, J = 7.6 Hz, 1H), 4.97 - 5.10 (m, 2H), 4.41 - 4.51 (m, 1H), 3.95 - 4.15(m, 3H), 3.15 (dd, J = 14.1 , 5.1 Hz, 1H), 2.99 (dd, J = 15.2, 8.1 Hz, 1 H), 2.09 - 2.26 (m, 2H), 1.83 - 1.96 (m. 1 H), 1.65 - 1.81 (m, 1 H), 1.16 (t, J - 7.1 Hz, 3H); MS-ESI (m/z): 496 [ +1f. To a mixture of Cbz-D-Glu(D-Trp-OH)-0-Et {4.95 g, 0.0 mmol) with potassium carbonate (4.15 g, 30.0 mmol) and sodium iodide (6.00 g, 40.0 mmol) in Lambda/,/V-dimethylformamide (30 mL) at room temperature, 1-chtoroethylcyclohexyl carbonate (6.20 g, 30.0 mmol) was added. After being stirred at room temperature for overnight, additional W,/V-dimethylformamide (30 mL) was added and the reaction mixture was stirred at 40C for overnight. The reaction mixture was diluted with ethyl acetate then washed with water (3x) then with brine. The crude product Cbz-D-Glu(D-Trp-0-CH(CH3)-0-CO-0-cyclohexyl)-0-Et was purified by column chromatography on silica gel using a solvent gradient of a mixture of ethyl acetate in hexanes (20 to 40%) as eluant. Fractions rich in product were combined together and evaporated to dryness. Thus, the desired compound Cbz-D-Glu(D-Trp-0-CH(CH3)-0-CO-0-cyclohexyl)-0-Et (4.43 g) was obtained as a pale-yellow foam. Yield = 66 %; 1H NMR (DMSO-D6> 400 MHz) delta ppm: 10.86 (or. s, 1H), 8.36 (dd, J = 17.2, 7.1 Hz, 1 H), 7.66 - 7.77 (m, 1 H), 7.46(t, J = 8.0 Hz., 1H), 7.22 - 7.42 (m, 6H), 7.10 - 7.20 (m, 1 H), 7.02 - 7.10 (m, 1 H), 6.90 - 7.02 (m, 1 H), 6.58 - 6.70 (m, 0.5H), 6.46 - 6.58 (m, 0.5H), 5.04 (br. s, 2H), 4.38 - 4.61 (m, 2H), 3.93 - 4.15 (m, 3H), 2.90 - 3.17 (m, 2H), 2.20 (br. s, 2H), 1.54 - 1.96 (m, 6H), 1.02 - 1.53 (m, 12H); MS-ESI (m/z): 666 [M+1f. Cbz-D-Glu(D-Trp-0-CH(CH3)-0-CO-0-cyclohexyl)-0-Et (2.0 g, 3.0 mmol) and 10 % Pd/C (wet, 0.6 g) was mixed in ethanol (50 mL) and 2 HCI in ether (1.7 mL, 3.4 mmol). The reaction mixture was hydrogenated in a Parr apparatus at 20-25 psi of hydrogen pressure for an hour. The mixture was filtered through Celite and the cake was washed with ethanol. The filtrate was concentrated by rotary evaporation and the residue was triturated with a mixture of ether and hexanes. Thus, H-D-Glu(D-Trp-O-CH(CH3)-0-CO-0-cyclohexyl)-0-Ethydrochloride salt (Apo854.HCI, 0.80 g) was obtained as a pink solid foam. Yield = 47%; *H NMR (DMSO-D6, 400 MHz) delta ppm: 0.94 (br. s, 1 H), 8.57 (br. s, 4H), 7.47 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.19 (s, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 6.88 - 7.03 (m, 1 H), 6.58 - 6.72 (q, J = 5.1 Hz, 0.5H), 6.53 (q, J = 5.1 Hz,0.5H), 4.39 - 4.63 (m, 2H), 4.00 - 4.26 (m, 2H), 3.78 - 4.00 (m, 1 H), 2.93 - 3.18 (m, 2H), 2.18 - 2.41 (m, 2H), 1.88 - 2.02 (m, 2H), 1.82 (br. s, 2H), 1.63 (br. s, 2H), 1.13 - 1.53 (m, 12H); MS-ESI (m/z): 532 [M+1]+ (free base).

Reference： [1]Patent: WO2012/129671,2012,A1 .Location in patent: Page/Page column 53-54

52
[ 1415043-08-1 ]
[ 99464-83-2 ]
[ 1415043-84-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	The title compound of Example 4 (150 mg, 0.33 mmol) and potassium carbonate (114 mg, 0.82 mmol) were suspended in 3 ml dimethylformamide. The title compound of Preparation 102 (163 mg, 0.79 mmol) was added and the mixture was stirred at room temperature overnight. Additional potassium carbonate (114 mg, 0.82 mmol) and title compound of Preparation 102 (163 mg, 0.79 mmol) and the mixture was stirred at room temperature for 6 h. The mixture was partitioned between ethyl acetate and water. The organics were washed sequentially three times with water and once with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was triturated with ether to give 120 mg (0.19 mmol, 58%) of the title compound as a white solid. Purity 96%. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.21 (1 H, d, J=7.8 Hz), 7.95 (2 H, dd, J=8.8, 4.9 Hz), 7.41 (1 H, t, J=7.0 Hz), 7.32 (1 H, t, J=7.6 Hz), 7.18 (2 H, t, J=8.6 Hz), 7.06 (1 H, d, J=7.4 Hz), 6.76 (1 H, q, J=5.2 Hz), 4.96 (1 H, br. s.), 4.61 (1 H, tt, J=9.0, 4.5 Hz), 4.52 (2 H, s), 4.36 (2 H, s), 3.50 - 3.58 (2 H, m), 2.75 (2 H, t, J=6.8 Hz), 1.89 (3 H, s), 1.83 - 1.95 (2 H, m), 1.68 - 1.78 (1 H, m), 1.53 (3 H, d, J=5.5 Hz), 1.39 - 1.50 (2 H, m), 1.17 - 1.41 (4 H, m). HPLC/MS (30 min) retention time 17.98 min. LRMS: m/z 627 (M+1).

Reference： [1]Patent: EP2526945,2012,A1 .Location in patent: Page/Page column 107-108

53
Cilazapril [ No CAS ]
[ 99464-83-2 ]
cilazapril 1-(cyclohexyloxycarbonyloxy) ethyl ester [ No CAS ]
(1S,9S)-1-(cyclohexyloxycarbonyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl] amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;	(1S,9S)-1-(cyclohexyloxycarbonyloxy)ethyl 9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl] amino]-10-oxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate Cilazapril 1-(cyclohexyloxycarbonyloxy)ethyl ester (2) was prepared according to the general procedure using cilazapril (0.60 mmol, 0.25 g), K2CO3 (0.72 mmol, 0.10 g) and 1-chloroethyl(cyclohexyl)carbonate (0.78 mmol, 0.16 g) in anhydrous dimethylformamide (3 ml) and was obtained after flash chromatography (petroleum ether/ethyl acetate 3/2 v/v) as a yellowish oil (0.26 g, 74 %).

Reference： [1]Patent: EP2537534,2012,A1

54
[ 761404-85-7 ]
[ 99464-83-2 ]
[ 1337980-10-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1347 - 1350

55
(2R)-3-(1-amino-7-trifluoromethoxyisoquinolin-6-yl)-2-[(3S)-2-oxo-3-[(2-pyrrolidin-1-ylthiazole-5-sulfonyl)amino]pyrrolidin-1-yl]propionic acid hydrochloride [ No CAS ]
[ 99464-83-2 ]
[ 1445563-86-9 ]

Yield	Reaction Conditions	Operation in experiment
14%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 432h;Inert atmosphere;	To a solution of (2R)-3-[1 -amino-7-(trifluoromethoxy)isoquinolin-6-yl]-2-[(3S)-2-oxo-3-([2- (pyrrolidin-1 -yl)-1 ,3-thiazol-5-yl]sulfonyl}amino)pyrrolidin-1 -yl]propanoic acid hydrochloride (compound of example 4) (0.13 g, 0.19 mmol) in anhydrous dimehtylformamide (1 ml) were added diisopropyl ethyl amine (0.1 1 ml, 0.61 mmol) and carbonic acid 1 -chloro-ethyl ester cyclohexyl ester (0.04 ml, 0.21 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 days, it was then concentrated under reduced pressure. The crude product was purified using a silica gel column chromatography (acetone/methylene chloride) to afford the title compound (0.021 g, 14%) as a white solid. M.p. : 147C. 1H-NMR (d6-DMSO, 400 MHz, delta ppm) : 1 .1 -1 .7 (13 H, m), 1 .75-1 .89 (2 H, m), 1 .92-2.05 (4 H, m), 2.1 -2.25 (1 H, m), 3.05-3.25 (2 H, m), 3.4 (4 H, s), 3.42-3.55 (1 H, m), 3.7-3.9 (1 H, m), 4.55 (1 H, m), 4.9-5.1 (1 H, m), 6.63 (1 H, m), 6.87 (1 H, d, J=5.6 Hz), 6.94 (2 H, s), 7.56 (1 H, d, J=8Hz), 7.7 (1 H, s), 7.83 (1 H, d, J=6 Hz), 8.1 (1 H, s), 8.2 (1 H, s).

Reference： [1]Patent: WO2013/92756,2013,A1 .Location in patent: Page/Page column 60

56
[ 1229705-06-9 ]
[ 99464-83-2 ]
[ 1456545-46-2 ]

Yield	Reaction Conditions	Operation in experiment
135.4 mg	With caesium carbonate; In N,N-dimethyl-formamide;	Example 8 1-(Cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at -78 C. for 3 h to give 1-chloroethyl cyclohexyl carbonate.

Reference： [1]Patent: US2013/244958,2013,A1 .Location in patent: Paragraph 0123

57
(R)-3-[N'-(1-allyloxy-1H-[1,2,3]-triazole-4-carbonyl)-N-(2',5'-dichlorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxypropionic acid [ No CAS ]
[ 99464-83-2 ]
C₃₁H₃₅Cl₂N₅O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With 2,6-dimethylpyridine; sodium iodide; at 50℃; for 5h;	Example 9K (R)-3-[N-(2',5'-Dichlorobiphenyl-4-ylmethyl)-N'-(1-hydroxy-1H-[1,2,3]-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid 1-cyclohexyloxycarbonyloxyethyl Ester To a mixture of (R)-3-[N'-(1-allyloxy-1H-[1,2,3]triazole-4-carbonyl)-N-(2',5'-dichlorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxypropionic acid (300 mg, 590 mumol) and <strong>[99464-83-2]carbonic acid 1-chloro-ethyl ester cyclohexyl ester</strong> (1.5 mL) were added NaI (178 mg, 1.2 mmol) and lutidine (124 mg, 1.2 mmol). The mixture was stirred at 50 C. for 5 hours. After cooling to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (2*15 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (PE:EtOAc=5:1 to 2:1) to yield Compound 1 as a light yellow solid (200 mg). LC-MS: 676 [M+H]+.

Reference： [1]Patent: US2013/330365,2013,A1 .Location in patent: Paragraph 0527-0528

58
C₂₆H₁₉ClF₂N₃O₅^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 99464-83-2 ]
(R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid 1-cyclohexyloxycarbonyloxyethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 mg	With 2,6-dimethylpyridine; at 90℃; for 0.5h;Sealed tube; Microwave irradiation;	(R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid 1-Cyclohexyloxycarbonyloxyethyl Ester To a solution of (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (1.5 g, 3.7 mmol), EDC (928 mg, 4.8 mmol), HOBt (653 mg, 4.8 mmol) and 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (848 mg, 4.1 mmol) in DCM (20 mL) was added DIPEA (1.9 mL, 11.2 mmol) under nitrogen. The resulting mixture was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in EtOAc (20 mL), washed with 0.5N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc, 10:1?3:1) to yield Compound 1 as a solid (1.4 g). LC-MS: 556 [M+H]+.

Reference： [1]Patent: US2013/330365,2013,A1 .Location in patent: Paragraph 0324

59
C₂₁H₁₈ClFN₃O₆^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 99464-83-2 ]
(R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 1-cyclohexyloxycarbonyloxyethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-dimethylpyridine; In ethyl acetate; at 90℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 4R (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid 1-Cyclohexyloxycarbonyloxyethyl Ester To a solution of compound (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (1.2 g, 3.0 mmol), EDC (742 mg, 3.9 mmol), HOBt (523 mg, 3.9 mmol) and 3-methoxyisoxazole-5-carboxylic acid (468 mg, 3.3 mmol) in DCM (20 mL) was added DIPEA (1.48 mL, 8.9 mmol) under nitrogen. The resulting mixture was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in EtOAc (20 mL), washed with 0.5N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc, 10:1?3:1) to yield Compound 1 as a solid (970 mg). LC-MS: [M+H]+: 492.

Reference： [1]Patent: US2013/330365,2013,A1 .Location in patent: Paragraph 0360-0362

60
vemurafenib [ No CAS ]
[ 99464-83-2 ]
[ 1567347-27-6 ]

Yield	Reaction Conditions	Operation in experiment
51.9%		N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (5g, 10.2mmol)Dissolved in tetrahydrofuran (36 mL),Potassium hydroxide (1.1 g, 20.4 mmol) was added thereto.After the reaction solution was stirred at room temperature for 0.5 hour,A solution of 1-chloromethylcyclohexyl carbonate (2.3 g, 11.2 mmol) in tetrahydrofuran (9 mL) was added.The reaction solution was refluxed for 16 hours, and the reaction was completed.Cool the mixture to room temperature,It was diluted with tetrahydrofuran (50 mL).Filtered, and the filtrate was concentrated under reduced pressure.The residue obtained was subjected to silica gel column chromatography (Petroleum ether / ethyl acetate (v/v) = 8 / 1) purification,The title compound was obtained as a white solid ( 3.49 g, 51.9%).
3.49 g		Step 2) 1-(5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl cyclohexyl carbonate To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (5 g, 10.2 mmol) in THF (36 mL) was added KOH (1.1 g, 20.4 mmol). The reaction was stirred at rt for 0.5 h, followed by the addition of a solution of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (2.3 g, 11.2 mmol) in THF (9 mL). The mixture was refluxed for 16 h, then cooled to rtand diluted with THF (50 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound as a white solid (3.49 g, 51.9%). The title compound was characterized by LC-MS and 1H NMR as shown below: LC-MS (ESI, neg. ion) m/z 657.5 [M-H]-; 1H NMR (400 MHz, CDCl3) delta 1.05-1.08 (t, J=7.4 Hz, 3H), 1.20-1.58 (m, 8H), 1.72 (m, 2H), 1.89-1.94 (m, 5H), 3.10-3.14 (m, 2H), 4.59 (m, 1H), 6.40-6.50 (d, J=1.7 Hz, 1H), 7.04-7.09 (m, 1H), 7.30-7.33 (m, 1H), 7.46-7.48 (m, 1H), 7.58-7.60 (m, 1H), 7.71-7.74 (m, 1H), 7.79 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.81-8.82 (d, J=2.0 Hz, 1H).

Reference： [1]Patent: CN103626765,2016,B .Location in patent: Paragraph 0611; 0612; 0616; 0617
[2]Patent: US2014/56849,2014,A1 .Location in patent: Paragraph 0455-0457

61
[ 99464-83-2 ]
(1S)-1-chloroethyl cyclohexyl carbonate [ No CAS ]
(1R)-1-chloroethyl cyclohexyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Chiralpak ID column; In n-heptane; tert-butyl methyl ether;Resolution of racemate;	<strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was resolved by HPLC on a preparative Chiralpak ID column using Heptane/TBME 98:2 and a polarimetric detector. From this resolution, Peak 2 was determined to have 98% ee on a Chiralpak ID column and was used in the subsequent step. To a solution of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (second-eluting isomer from a Chiralpak ID column Heptane/TBME 98:2) (1.75 g, 8.47 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-4-(5?-chloro-2?-fluoro-[1,1?-biphenyl]-4-yl)butanoic acid (1.5 g, 3.68 mmol) in 35 mL anhydrous DMF at 0 C. was added cesium carbonate (1.2 g, 3.68 mmol). After the reaction mixture was stirred for 5 min, the ice-bath was removed and the reaction mixture was stirred at 23 C. for 4.5 hours. LCMS showed that the reaction was approximately 40% complete. The reaction mixture was stirred approximately 18 hours, at which point LCMS showed the reaction was approximately 95% complete. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride (pH of aqueous layer approximately 6-7). After separation, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography on an Isco RediSep 120 g silica cartridge (0-20% ethyl acetate-heptane) to afford (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5?-chloro-2?-fluoro-[1,1?-biphenyl]-4-yl)butanoate (2.07 g, 97% yield, 95.8% ee as determined on analytical supercritical fluid HPLC using a Chiralpak AD-H 5-55% MeOH with 20 mM NH4OH in CO2. LCMS (ES+) C30H37ClFNO7: Calc.: 577.2; Found: 578.3[M+H]+.

Reference： [1]Patent: US2014/228323,2014,A1 .Location in patent: Paragraph 0210

62
[ 1621527-49-8 ]
[ 99464-83-2 ]
(1S,3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 23℃; for 22.5h;Cooling with ice;	B: (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)butanoate <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was resolved by HPLC on a preparative Chiralpak ID column using Heptane/TBME 98:2 and a polarimetric detector. From this resolution, Peak 2 was determined to have 98% ee on a Chiralpak ID column and was used in the subsequent step. To a solution of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (second-eluting isomer from a Chiralpak ID column Heptane/TBME 98:2) (1.75 g, 8.47 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)butanoic acid (1.5 g, 3.68 mmol) in 35 mL anhydrous DMF at 0 C. was added cesium carbonate (1.2 g, 3.68 mmol). After the reaction mixture was stirred for 5 min, the ice-bath was removed and the reaction mixture was stirred at 23 C. for 4.5 hours. LCMS showed that the reaction was approximately 40% complete. The reaction mixture was stirred approximately 18 hours, at which point LCMS showed the reaction was approximately 95% complete. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride (pH of aqueous layer approximately 6-7). After separation, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography on an Isco RediSep 120 g silica cartridge (0-20% ethyl acetate-heptane) to afford (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)butanoate (2.07 g, 97% yield, 95.8% ee as determined on analytical supercritical fluid HPLC using a Chiralpak AD-H 5-55% MeOH with 20 mM NH4OH in CO2. LCMS (ES+) C30H37ClFNO7: Calc.: 577.2; Found: 578.3[M+H]+.

Reference： [1]Patent: US2014/228323,2014,A1 .Location in patent: Paragraph 0210

63
C₃₁H₂₆N₆O₃*C₁₂H₂₃N [ No CAS ]
[ 99464-83-2 ]
[ 1307853-85-5 ]

Reference： [1]ACS Catalysis,2014,vol. 4,p. 4047 - 4050

64
[ 915-79-7 ]
[ 99464-83-2 ]
1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 3β-acetoxyurs-12-en-28-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.8 g	With potassium carbonate; potassium iodide; In acetone; at 20℃; for 24h;	EXAMPLE 3 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 3beta-acetoxy-urs-12-en-28-oate 1.0 g of the compound obtained from Reference Example 1 was dissolved in 20 ml of acetone. 0.9 g of potassium carbonate and 0.4 g of potassium iodide (KI) were added thereto, and 0.65 g of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> was added thereto. The mixture was reacted at room temperature for 24 hours and concentrated. 10 ml of ethyl acetate was added to the concentrate, the concentrate was washed with 10 ml of water and brine, respectively, and dried over anhydrous sodium sulfate. After filtration under reduced pressure and concentration to obtain residue, the residue was separated and purified by column chromatography to thereby obtain 0.8 g of a target compound. 1H-NMR(DMSO-d6, 500 MHz) 5.74?5.87(1H, dd) 5.17(1H, t), 3.0(1H, m) 2.11?2.13(1H, d, J=11.0 Hz), 2.00(3H,s), 1.45(3H,d), 1.06(3H, s), 0.90?0.92(6H, d), 0.81?0.86(9H, m), 0.76(3H,s), 1.00?2.20(10H, m); IR(cm-1) 2925 1756 1732, 1697, 1466, 1373, 1245, 983.

Reference： [1]Patent: US2015/218206,2015,A1 .Location in patent: Paragraph 0064-0067
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5524 - 5527

65
1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid [ No CAS ]
[ 99464-83-2 ]
[ 145040-37-5 ]

Reference： [1]Patent: US2015/239854,2015,A1

66
1-[3-(7-carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol [ No CAS ]
[ 99464-83-2 ]
4-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.96 g	With potassium carbonate; sodium iodide; In water; at 70℃; for 1h;	Example 306 4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol dihydrochloride To a solution of product of example 118 (1.1 g) in dimethylformamide (15 ml) were added sodium iodide (0.17 g), potassium carbonate (0.38 g) and <strong>[99464-83-2]cyclohexyl 1-chloroethyl carbonate</strong> (J. Antibiotics, 1987, 40, 81.) (0.57 g) at room temperature. The mixture was stirred at 70 C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3). The obtained oil was dissolved with ethyl acetate, and 4 N hydrochloric acid ethyl acetate solution (0.8 ml) was added. The precipitation was filtered to give the titled compound (0.96 g). 1H-NMR (DMSO-d6) delta: 1.22-1.47 (6H, m), 1.58 (3H, d), 1.63-1.81 (6H, m), 2.38-3.30 (10H, m), 4.07-4.59 (1H, m), 5.80 (2H, brs), 6.28 (1H, t), 6.87 (1H, q), 6.97 (1H, d), 7.40-7.49 (4H, m), 7.64 (1H, dd), 7.79 (1H, dd), 7.96 (1H, d), 8.03 (1H, dd), 8.65 (1H, dd), 11.07 (1H, brs). MS m/z: 661[(M-2HCl)+1]

Reference： [1]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 0788; 0789; 0790

67
C₂₃H₁₅ClFN₇O₄S [ No CAS ]
[ 99464-83-2 ]
1-[(cyclohexyloxy)carbonyl]oxy}ethyl4-(2-{-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-7-hydroxy-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl}-1H-imidazol-5-yl)-3-fluorothiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃;	EXAMPLE 124 l-{ [(cyclohexyloxy)carbonyl]oxy}ethyl 4-(2-{-3-[5-chloro-2-(lH-tetrazol-l-yl)phenyl]-7- hydroxy-l-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl}-lH-imidazol-5-yl)-3- fluorothiophene-2-carboxylate 7-(4-(5-Carboxy-4-fluorothiophen-3-yl)-lH-imidazol-2-yl)-3-(5-chloro-2-(lH-tetrazol-l- yl)phenyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1 -oxide (EX-50, 100 mg, 0.185 mmol) was mixed with <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong> (153 mg, 0.74 mmol), KI (123 mg, 0.74 mmol), and K2C03 (102 mg, 0.741 mmol) in DMF (1 ml). The mixture was stirred at 60 C overnight. The mixture was diluted with ethyl acetate (50 mL), and washed with brine. After being dried over anhydrous sodium sulfate, the solution was filtered and concentrated. The crude was purified by column chromatography on a silica gel column, eluting with 0 ~ 5% CH2Cl2/MeOH gradient to give the title product. MS (ESI) m/z: 710.1 (M+H).

Reference： [1]Patent: WO2016/168098,2016,A1 .Location in patent: Page/Page column 130-131

68
[ 144690-04-0 ]
[ 99464-83-2 ]
1-ethylcyclohexylcarbonyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		After dissolving 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylic acid (5 g, 23.6 mmol) in 40 ml of dimethylacetamide at room temperature, diisopropylethylamine (4.52 ml, 28.3 mmol) was slowly added dropwise. After 15 minutes, <strong>[99464-83-2]1-chloroethylcyclohexyl carbonate</strong> (4.52 ml, 24.7 mmol) was slowly added dropwise, and the mixture was stirred at 60 C for 1.5 to 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and distilled water, and separated without purification. (6.39 g, 71%).

Reference： [1]Patent: KR101628758,2016,B1 .Location in patent: Paragraph 0038; 0039

69
[ 123-63-7 ]
[ 108-93-0 ]
[ 503-38-8 ]
[ 99464-83-2 ]

Yield	Reaction Conditions	Operation in experiment
93%		1) In a 1000 ml reaction flask,238 g of trichloromethyl chloroformate was added,Open stirring, cooling to -10 ~ 0 by adding 2.4g pyridine,Dropping 106 g of triacetaldehyde, dropping the process for 6 hours,After the addition was complete, stirring was continued for 2 h,247 g of pyridine was added,The temperature to be mixed is 20 CAfter the addition of cyclohexanol 240 g,After completion of the dropwise addition, stirring was continued for 3 h.After completion of the reaction, 120 g of water was added,The organic phase was separated from crude 1-chloroethylcyclohexylpropyl carbonate.(2) The crude product of 1-chloroethylcyclohexylpropyl carbonate was put into a distillation reaction flask,Control the bottle temperature below 130 ,Vacuum vacuum distillation,That is to get1-chloroethylcyclohexylpropylCarbonate461g,The yield was 93% and the purity was greater than 99.5%.

Reference： [1]Patent: CN104496822,2016,B .Location in patent: Paragraph 0030-0033

70
[ 34157-83-0 ]
[ 99464-83-2 ]
C₃₈H₅₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 16. ERX1016, 2 isomers P1 (less polar) and P2 (more polar) [0222] To a solution of celastrol (300 mg, 0.666 mmol) in DMF (4 mL) was added K2C03 (184 mg, 1.332 mmol) followed by <strong>[99464-83-2]carbonic acid 1-chloroethyl cyclohexyl ester</strong> (151 mg, 0.134 mL, 0.732 mmol). The reaction was stirred at room temperature overnight. Then the solution was diluted with CH2C12 (200 mL), washed with brine (100 mL), dried over MgS04 and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ ethyl acetate =5:2) twice to afford isomerl (less polar, 29.7 mg, 0.0478 mmol, Yield=7.2%) and isomer 2 (more polar, 20.0 mg, 0.0322 mmol, Yield=4.8%) as yellow solid. Isomer 1: 1HNMR: 5(400 MHz, CDC13) : 7.02 (IH, dd, J=7.3, 1.1 Hz), 6.98 (IH, s), 6.74 (IH, q, J=5.5 Hz), 6.55 (IH, d, J=l.l Hz), 6.35 (IH, d, J=7.3 Hz), 4.45-4.53 (IH, m), 2.41 (IH, d, J=16.1 Hz), 2.20 (3H, s), 1.00-2.20 (23H, m), 1.46 (3H, s), 1.45 (3H, d, J=5.5 Hz), 1.27 (3H, s), 1.20 (3H, s), 1.09 (3H, s), 0.93-1.00 (IH, m), 0.61 (3H,s); LC-MS: SP-0012508-089- l-01262-LCMSA043Mobile Phase: A: water(10mM Ammonium hydrogen carbonate); B: ACN; Gradient: 5%-95% B in 1.5min; Flow Rate: 2.0ml/min; Column: XBridge C18,4.650mm,3.5um): rt = 3.11 min, m/z = 477.4 [M- C6H110C02]+, purity=100% (214,254 nm). Isomer 2: 1HNMR: 5(400 MHz, CDC13) : 7.02 (IH, dd, J=7.1, 1.1 Hz), 6.97 (IH, s), 6.67 (IH, q, J=5.4 Hz), 6.52 (IH, d, J=l.l Hz), 6.35 (IH, d, J=7.1 Hz), 4.52-4.58 (IH, m), 2.41 (IH, d, J=15.9 Hz), 2.21 (3H, s), 1.05-2.25 (23H, m), 1.46 (3H, d, J=5.4 Hz), 1.45 (3H, s), 1.26 (3H, s), 1.19 (3H, s), 1.10 (3H, s), 0.94-1.01 (IH, m), 0.60 (3H, s); LC-MS (Mobile Phase: A: water(10mM Ammonium hydrogen carbonate); B: ACN; Gradient: 5%-95% B in 1.5min; Flow Rate: 2.0ml/min; Column: XBridge C18,4.650mm,3.5um): rt = 3.12 min, m/z = 477.3 [M-C6HnOC02]+, purity=94.91% (254 nm).

Reference： [1]Patent: WO2017/70615,2017,A1 .Location in patent: Paragraph 0222

71
[ 15761-38-3 ]
[ 99464-83-2 ]
C₁₇H₂₉NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Under nitrogen, Boc-L-alanine (2.0 g, 10.5 mmol) in DMF (15 ml)The solution was added dropwise to a solution of potassium carbonate (2.9 g, 21.1 mmol) in DMF (16 mL) at 0 C, and the reaction was carried out at room temperature for 30 minutes, cooled to 0 C, and compound 2 (4.3 g, 21.1 mmol) To the reaction solution, the reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by petroleum ether: ethyl acetate = 20: 1 column to give compound 3, 2.0 g, 53%

Reference： [1]Patent: CN106317116,2017,A .Location in patent: Paragraph 0086; 0090; 0091; 0092; 0093

72
[ 99464-83-2 ]
C₁₂H₂₁NO₅*ClH [ No CAS ]

Reference： [1]Patent: CN106317116,2017,A

73
[ 99464-83-2 ]
C₂₇H₃₇N₆O₈P [ No CAS ]

Reference： [1]Patent: CN106317116,2017,A

74
[ 99464-83-2 ]
C₂₇H₃₇N₆O₉P*C₄H₄O₄ [ No CAS ]

Reference： [1]Patent: CN106317116,2017,A

75
(R)-3-({5-[(tert-butyldimethylsilyl)oxy]-4,5-dihydro-1,3,4-oxadiazol-2-yl}formamido)-4-[2'-(difluoromethoxy)-5'-fluoro-[1,1'-biphenyl]-4-yl]butanoic acid [ No CAS ]
[ 99464-83-2 ]
4-(2'-difluoromethoxy-5'-chlorobiphen-4-yl)-3-[(5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-amino]-butyric acid-1-cyclohexyloxycarbonyloxyethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
563 mg	With potassium carbonate; potassium iodide; In acetonitrile; at 20℃;	(R) -3 - [5- (tert-butyl-dimethyl-silanyloxy) - [1,3,4] oxadiazole-2-carbonyl] -amino} -4- Fluoro-5'-fluoro-biphenyl-4-yl) butanoic acid (0.865 g, 1.53 mmol) was dissolved in 15 ml of acetonitrile,Potassium carbonate (800 mg) and potassium iodide (1.2 g) were added,Was added 1-chloro - ethyl carbonate cyclohexyl acrylate (1ml),Stirred overnight at room temperature,filter,The filtrate was evaporated by rotary evaporator,The residue was purified by column chromatography to give a pale yellow viscous oily liquid (0.803 g).The oily liquid was dissolved in 10 ml of tetrahydrofuran,TBAF (3 ml, 1 M in THF) was added at room temperature,Stir for 30 minutes,The solvent is distilled off,The residue was purified by silica gel column chromatography to give a pale yellow solid (563 mg).

Reference： [1]Patent: CN106831473,2017,A .Location in patent: Paragraph 0051; 0052; 0053

76
[ 99464-83-2 ]
C₃₂H₄₀ClNO₉ [ No CAS ]

Reference： [1]Patent: CN106831473,2017,A

77
(R)-3-tert-butoxycarbonylamino-4-(5'-chloro-2'-difluoromethoxybiphen-4-yl)butyric acid [ No CAS ]
[ 99464-83-2 ]
1-[(cyclohexyloxy)carbonyl]oxy}ethyl (3R)-3-[(tert-butoxy)carbonyl]amino}-4-[5'-chloro-2'-(propan-2-yloxy)-[1,1'-biphenyl]-4-yl]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.603 mg	With potassium carbonate; potassium iodide; In acetonitrile; at 20℃;	(R) -3- tert - butoxycarbonylamino-4- (5'-chloro-2'-difluoromethoxy - biphenyl-4-yl) butyric acid (0.650g, 1.43mmol) was dissolved in 15 ml of acetonitrile,Potassium carbonate (780 mg) and potassium iodide (1.1 g) were added,1-Chloro-ethyl ester cyclohexyl carbonate (0.85 ml) was added,Stirred overnight at room temperature,filter,The filtrate was evaporated by rotary evaporator,The residue was purified by column chromatography to give a pale yellow viscous oily liquid (0.603 g).

Reference： [1]Patent: CN106831473,2017,A .Location in patent: Paragraph 0073; 0074; 0075

78
[ 99464-83-2 ]
cefotiam hexetil dihydrochloride [ No CAS ]

Reference： [1]Patent: CN106749334,2017,A

79
[ 99464-83-2 ]
[ 95761-91-4 ]

Reference： [1]Patent: CN106749334,2017,A

80
cefotiam potassium [ No CAS ]
[ 99464-83-2 ]
[ 95761-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium iodide; In formamide; at -10 - 10℃;Large scale;	To the potassium salt of cefotiam (compound IIa) in the above step (1)The residue (theoretical yield 0.89 kg)Add formamide 8.0kg,Cooling to between -10 ~ 0 ,Lithium iodide 53g.Temperature control at 5 ~ 10 ,0.64 kg of chlorocyclohexyl carbonate (Compound III)Stir 0.5-1h.Temperature control 5 ~ 10 ,The reaction mixture was transferred to a pre-prepared 5% sodium bisulfite solution (8.9kg)Add ethyl acetate twice, each 8.9kg,The above organic phases are combined,The organic phase 1 was obtained after washing with 9 kg of saturated sodium chloride aqueous solution.Control the temperature at 5 ~ 10 ,To the organic layer 1, 10.7 kg of a 15% hydrochloric acid aqueous solution was added,Stir 10 ~ 20min after standing liquid,The aqueous phase 1 was obtained and the aqueous phase 1 was washed with 1,2-dichloroethane.The aqueous phase 1 was cooled to 0 ~ 10 ,The pH was adjusted to 6.8-7.0 with saturated potassium bicarbonate solution.Continue to control the temperature to 0 ~ 10 ,11.0kg of methylene chloride was added to stand still and separated to obtain an organic phase.Continue to control the temperature 0 ~ 10 ,The organic phase was washed with saturated brine (9.6 kg) to give an organic phase 2.After the organic phase 2 was added with anhydrous magnesium sulfate (0.9 kg) and dried,Filtration, filtrate stand-by. Temperature T?15 ,After the system is concentrated at P?-0.09 MPa to about 50% of the original volume,Slowly add cyclohexane 10.5kg.After cooling to 0 ~ 5 , stirring a lot of solid precipitation 1-2h.Filtered to give a solid cefotiam ester free base (Compound Iv), to be used.

Reference： [1]Patent: CN106349256,2017,A .Location in patent: Paragraph 0084; 0085; 0090; 0091; 0096; 0097; 0102; 0103

81
[ 99464-83-2 ]
[ 153559-49-0 ]
C₃₃H₄₂O₅ [ No CAS ]

Reference： [1]Journal of Controlled Release,2018,vol. 286,p. 10 - 19

82
[ 1361139-71-0 ]
[ 99464-83-2 ]
1-(5-[2-chloro-3-(methylsulfanyl)-4-(trifluoromethyl)benzoyl]imino}-4-methyl-4,5-dihydro-1H-tetrazol-1-yl)ethyl cyclohexyl carbonate [ No CAS ]
1-[(cyclohexyloxy)carbonyl]oxy}ethyl 2-chloro-3-(methylsulfanyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzenecarboximidate [ No CAS ]
C₂₀H₂₃ClF₃N₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; for 9h;Reflux;	General procedure: To a solution of 1.00 g (2.843 mmol) of 2-chloro-3-(methylsulfanyI)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide are in 20 ml of acetonitrile are added at room temperature 911 mg (5.97 mmol) of 1-chloroethyl ethyl carbonate and 825 mg (5.97 mmol) of potassium carbonate and the mixture is boiled under reflux for 9 h. The reaction mixture is concentrated and then dissolved in 20 ml of ethyl acetate and 20 ml of water are added and extracted. The aqueous phase is extracted twice more with 20 ml of ethyl acetate each time. The combined organic phases are washed with saturated NaCI solution, dried and concentrated. The residue is purified by RP-HPLC (acetonitrile/water).; By analogy to the abovementioned preparation method, by reacting 1.00 g (2.719 mmol) of 2-chloro-3-(methylsulfanyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide with 1234 mg (5.97 mmol) of <strong>[99464-83-2]1-chloroethyl cyclohexyl carbonate</strong>, isolated were: Compound no. 5-384 1H-NMR (400 MHz; CDCl3): 7.77 ppm (d, 1H), 7.68 ppm (d, 1H), 7.00 (q, 1H), 4.65-4.59 (m, 1H), 3.98 (s, 3H); 2.43 (s, 3H); 2.00 (d, 3H); 1.98-1.88 (m, 1H), 1.85-1.65 (m, 4H),1.59-1.18 (m, 5H). Compound no. 23-384 1H-NMR (400 MHz; CDCl3): 7.96 ppm (d, 1H), 7.73 ppm (d, 1H), 7.54 ppm (d, 1H), 7.27 (q, 1H), 4.72-4.63 (m, 1H), 3.97 (s, 3H); 2.32 (s, 3H); 2.00- 1.86 (m, 2H), 1.77-1.65 (m, 5H), 1.59-1.21 (m, 6H). Compound no. 32-384 1H-NMR (400 MHz; CDCl3): 7.81 ppm and 7.72 ppm (2d, 1H), 7.52 ppm and 7.38 (2d, 1H), 6.23 and 5.95 (2q, 1H), 4.72 and 4.56 (2m, 1H), 4.12-3.98 (3s, 3H); 2.2.46 and 2.34 (2s, 3H); 2.01- 1.766 (m, 4H), 1.59-1.1.22 (m, 8H).

Reference： [1]Patent: US2018/192650,2018,A1 .Location in patent: Paragraph 0120; 0121; 0135; 0136; 0137; 0138; 0139-0142

83
[ 99464-83-2 ]
[ 1026789-25-2 ]

Reference： [1]Patent: WO2009/118580,2009,A2

84
[ 1190307-88-0 ]
[ 99464-83-2 ]
C₃₁H₄₃FN₃O₁₂P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of <strong>[1190307-88-0]sofosbuvir</strong> (530 mg, 1.0 mmol, 1.0 eq.) in DMF(2 mL) cooled in an ice bath was added K2CO3 (138 mg, 1.0 mmol,1.0 eq.) followed with a 15 min?s stir. 1-chloroethyl- or methyl- carbonates(2.0 eq.) was added to the resulted mixture and stirred at roomtemperature for 12 h. The mixture was diluted with EA (50 mL) andthen washed with water (10 mL×3). The organic layer was dried overanhydrous Na2SO4, concentrated in vacuo and purified by silica gelchromatography to afford 8a-8b in 40% ? 60% yield.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 748 - 759

85
potassium 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4-(3H)-one [ No CAS ]
[ 99464-83-2 ]
1-(5-(4'-((2-butyl-5-(2-(dimethylamino)-2-thioxoethyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)-[1,1'-biphenyl]-2-yl)-2H-tetrazol-2-yl)ethyl cyclohexyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium iodide; In N,N-dimethyl-formamide; at 20℃;	fimasartan potassium salt monohydrate (1 g, 1.8 mmol)Was added dimethylformamide (8 mL)After dissolving,Potassium iodide (30 mg, 0.18 mmol), 1-Chloroethyl cyclohexyl carbonate(0.40 mL, 2.2 mmol) was added,The reaction mixture was stirred at room temperature overnight. After the ethyl acetate was added to the reaction mixture,The organic layer was washed with brine.The washed organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure,The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.71 g, 59%, foamy solid).

Reference： [1]Patent: KR2019/31725,2019,A .Location in patent: Paragraph 0142-0146

86
[ 99464-83-2 ]
[ 100986-85-4 ]
[ 2640005-60-1 ]

Yield	Reaction Conditions	Operation in experiment
89.3%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere;	4.2. Synthesis of levofloxacin cilexetil ester LVFX-CLX was synthesized by the modified method of Daehne et al. (1970), whoreported a method to synthesize acyloxymethyl esters of ampicillin. Anhydrous potassiumcarbonate 553 mg (4 mmo1) was added to the levofloxacin 722 mg (2 mmo1)solution dissolved in N,N-dimethylformamide (DMF) (25 mL) with vigorous stirringin round bottom flask. Then, 1-chloro ethyl cyclohexyl carbonate 1.2 mL (8 mmol)was added and stirred for 2 h at 70 °C under argon atmosphere. Crushed ice andwater (60 mL) were slowly added to the mixture after cooling. The reaction mixturewas extracted three times with ethyl acetate (50 mL x 3). The extract was washedwith distilled water and dehydrated with anhydrous sodium sulfate. Then, the organicsolvent was gradually evaporated to dryness. Recrystallization of the precipitatewas made from chloroform and cyclohexane. This method gave an 89.3% yield ofLVFX-CLX. The chemical structures of LVFX-CLX is shown together with LVFX inFig. 1. Melting point of LVFX-CLX determined on Yanagimoto micro melting pointapparatus (MP-S3, Yanaco, Kyoto, Japan) was 124-126 °C(dec.). LVFX-CLX wasdissolved in CDCl3 and proton nuclear magnetic resonance (1H NMR) spectra wererecorded on a JEOL AL-300 at 300 MHz (JEOL Ltd., Tokyo, Japan). 1H NMR chartof LVFX-CLX is shown in Fig. 4. Chemical shifts relative to Me4Si (δ 0.00) wereas follows: 1H-NMR δ: 1.29-1.39 (6H, m), 1.53-1.56 (3H, m), 1.63-1.67 (3H, m),1.73-1.76 (2H, m), 1.91-1.96 (2H, m), 2.36 (3H, s), 2.55-2.56 (4H, m), 3.30-3.40 (4H,m), 4.30-4.41 (3H, m), 4.65 (1H, td, J = 9.1, 5.1 Hz), 7.00 (1H, dq, J = 10.8, 2.7 Hz),7.64 (1H, dd, J = 12.5, 6.2 Hz), 8.27 (1H, d, J = 2.2 Hz). As lH NMR spectral data onlydisplayed the specific signals of LVFX-CLX, the purity might be more than 99%. Thepurity of the compound was also examined by thin layer chromatography (Kieselge160 F254 plates, Merck, USA) using chloroform-methanol-acetic acid-distilled water(l5:5:2:1, v/v/v/v) as a developing solvent. Detection of LVFX and LVFX-CLXwere made by short wave ultraviolet light (254 nm). The Rf values of LVFX andLVFX-CLX were 0.45 and 0.72, respectively. Taken together, the synthesized materialwas particularly pure, being completely uncontaminated by LVFX. Mass spectra wererecorded on JEOL JMS-700 spectrometers by direct inlet system, and it was m/z:531(M+).

Reference： [1]Shinmachi; Takahashi; Kaneuji; Kawamura; Kohama; Hieda; Goromaru; Eto; Murakami; Maeda [Pharmazie, 2020, vol. 75, # 11, p. 554 - 558]

87
[ 74103-06-3 ]
[ 99464-83-2 ]
[ 2756270-38-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium fluoride In dimethyl sulfoxide at 35℃; Inert atmosphere;	11 Synthesis of Compound N10 At room temperature, ketorolac (1.0 g, 3.92 mmol) was weighed into a dry two-necked reaction flask, and 3.0 ml of DMSO was added and dissolved with stirring. KF (0.5g, 8.61mmol) was weighed and added to the above reaction flask, the reaction flask was replaced with Ar twice, 1-chloroethylcyclohexyl carbonate (0.83g, 4.02mmol) was weighed and added dropwise to the above reaction flask, Dropped. The reaction flask was moved to 35°C for overnight reaction. 20ml of water and 30ml of ethyl acetate were added to the reaction flask, and the solution was separated. The EA layer was washed with 5% NaHCO3, washed with water, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, concentrated and loaded by wet method, and subjected to column chromatography (PE /EA=6:1) to obtain 0.99 g of pale yellow oil with a yield of 67%

Reference： [1]Current Patent Assignee: NANJING HERON PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO LTD; NANJING HERON PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO. - CN113831342, 2021, A Location in patent: Paragraph 0193-0198

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