Name: 99469-99-5|2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid|98%
Brand: Ambeed
SKU: A142970
Price: 10.0 USD
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1
[ 89606-11-1 ]
[ 99469-99-5 ]
[ 219922-18-6 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

2
ethyl 4-(2-amino-2-oxoethyl)-2-ethoxybenzoate [ No CAS ]
[ 220438-80-2 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

3
[ 99469-99-5 ]
1-(5-chloro-2-piperidino-phenyl)-propylamine [ No CAS ]
[ 219922-19-7 ]

Yield	Reaction Conditions	Operation in experiment
80%		(e) Ethyl 2-ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(5-chloro-2-piperidino-phenyl)-1-propylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 80% of theory. M.p. 110-112 C. Calculated: C--66.58%; H--7.24%; N--5.75%; Cl--7.28. Found: C--66.61%; H--7.34%; N--5.86%; Cl--7.35%.
80%		(e) Ethyl 2-ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(5-chloro-2-piperidino-phenyl)-1-propylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 80% of theory. M.p. 110-112 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

4
[ 99469-99-5 ]
[ 99469-97-3 ]
[ 99469-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; triphenylphosphine; In tetrachloromethane; water; ethyl acetate; acetonitrile;	EXAMPLE 1 Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}aminocarbonylmethyl]-benzoate 2 g (7.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 2.46 g (9.38 mmols) of triphenylphosphine, 1.7 ml (12.3 mmols) of triethylamine and 0.76 ml (7.9 mmols) of carbon tetrachloride were added to a solution of 1.84 g (7.9 mmols) of 1-(2-piperidinophenyl)-1-butylamine in 19 ml of acetonitrile, and the mixture was stirred for two days at room temperature. It was then evaporated in vacuo, and the residue was taken up in a mixture of ethyl acetate and water. The organic phase was dried, filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=5/1). Yield: 3 g (81% of theory). M.p. 113-115 C. (petroleum ether). Calculated: C--72.07%; H--8.21%; N--6.00%. Found: C--72.18%; H--8.27%; N--6.16%.
	With 1,1'-carbonyldiimidazole; In tetrahydrofuran;	EXAMPLE 2 Ethyl (+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}aminocarbonylmethyl]-benzoate 0.90 g (3.57 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.61 g (3.73 mmol) of N,N'-carbonyldiimidazole are refluxed for 5 hours in 9 ml of absolute tetrahydrofuran. Then a solution of 0.85 g (3.67 mmol) of (+)-1-(2-piperidino-phenyl)-1-butylamine (ee=94.2) in 9 ml of absolute tetrahydrofuran is added and the mixture is refluxed for 3 hours. It is concentrated in vacuo and the evaporation residue is distributed between chloroform and water. The organic phase is dried, filtered and evaporated in vacuo. The evaporated extract is purified by column chromatography on silica gel (toluene/acetone=10.1). Yield: 0.85 g (51.2% of theory). M.p. 118-119 C. (petroleum ether/toluene=50/2). Calculated: C--72.07%; H--8.21%; N--6.00%. Found: C--72.43%; H--8.34%; N--6.00%. Specific rotation: [alpha]D20 =+7.1 (c=1.06 in methanol).
	With 1,1'-carbonyldiimidazole; In tetrahydrofuran;	EXAMPLE 2 Ethyl (+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate 0.90 g (3.57 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid and 0.61 g (3.73 mmol) of N,N'-carbonyldiimidazole are refluxed for 5 hours in 9 ml of absolute tetrahydrofuran. Then a solution of 0.85 g (3.67 mmol) of (+)-1-(2-piperidinophenyl)-1-butylamine (ee=94.2) in 9 ml of absolute tetrahydrofuran is added and the mixture is refluxed for 3 hours. It is concentrated in vacuo and the evaporation residue is distributed between chloroform and water. The organic phase is dried, filtered and evaporated in vacuo. The evaporated extract is purified by column chromatography on silica gel (toluene/acetone=10.1). Yield: 0.85 g (51.2% of theory). M.p. 118-119 C. (petroleum ether/toluene=50/2). Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.43%; H-8.34%; N-6.00%. Specification rotation: [alpha]D20 =+7.1 (c=1.06 in methanol).

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5216167,1993,A
[4]Patent: US5312924,1994,A

5
[ 99469-99-5 ]
[ 219921-93-4 ]
[ 147770-08-9 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

6
[ 99469-99-5 ]
[ 147769-93-5 ]
[ 147770-06-7 ]

Yield	Reaction Conditions	Operation in experiment
93%		Example 11 (S)(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonyl-methyl]-benzoic acid ethyl ester 20.77 g (82.4 mmol) of 2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)-acetic acid were slowly added to a solution of N,N'-carbonyldiimidazole (13.36 g, 82.4 mmol, 97%) in dichloromethane (240 ml) at room temperature. After activation for 1.5h at 20-25C a solution of (S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butan-1-amine (19.70 g, 80.0 mmol) in dichloromethane (80 ml) was added dropwise and the resulting mixture was stirred for 2h. The reaction mixture was quenched by adding water (2 x 160 ml). The organic phase was then evaporated under reduced pressure. The yield of the crude repaglinide ester product of formula IV was 35.7 g (93%; HPLC: 97.58%).
89.5%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 0 - 20℃; for 18.5h;	To a mixture of (1 3-METHYL-1-(2-PIPERIDIN-1-YLPHENYL) BUTAN-1-AMINE (499, 0.2 MOL), [3-ETHOXY-4- (ETHOXYCARBONYL) PHENYL] acetic acid (50 g, 0.2 mol) and triethylamine (100 g, 0.99 mol) in ethyl acetate (1.0 L), a solution (50% w/w) of propane phosphonic acid anhydride (278 g, 0.44 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature at 0-5 C and stirred for 18 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCI, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to give title compound. Yield : 86 g, 89.5%
89.6%	With phenylboronic acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 2 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30 C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%).

89.6%	With phenylboronic acid; In toluene;Reflux;	Example 8Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoateIn a round bottom flask fitted with a Dean Stark condenser, 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 moles) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 moles) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 moles). The reaction mixture was refluxed for 16-18 hours. The reaction mixture was cooled at room temperature followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution. This was followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue in order to precipitate the solid and then stirred for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate (Yield: 89.6%; HPLC purity: 99.46%; and Chiral purity: 99.98%).
87.2%	With tetramethylorthosilicate; In toluene; for 11h;Inert atmosphere; Reflux;	Under nitrogen, compound 370.3g (0.285mol, 1eq), 4- carboxy-methyl-2-ethoxy ethyl benzoate 72.0g (0.285mol ,, 1eq), tetramethoxysilane 86.8g (152.22,0.57 mol, 2eq) and 285g of toluene, heated to reflux for 11 hours, HPLC control the starting material the reaction was complete, cooled, concentrated under reduced pressure, from ethanol / MTBE to give white crystalline solid 119.4g, HPLC98.8%, yield 87.2%, 99.5% ee.
73.3%	With boric acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 1 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30 C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%).
	With triethylamine; triphenylphosphine; In tetrachloromethane; acetonitrile;	EXAMPLE 1 Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate 0.48 g (1.91 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 0.60 g (2.29 mMol) of triphenylphosphine, 0.80 ml (5.73 mMol) of triethylamine and 0.18 ml (1.91 mMol) of carbon tetrachloride are added successively to a solution of 0.47 g (1.91 mMol) of (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 5 ml of anhydrous acetonitrile and the resulting mixture is stirred for 20 hours at ambient temperature. It is then evaporated down in vacuo and distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated down in vauco. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate=10/1). Yield: 0.71 g (77.3% of theory), Melting point: 110-112 C. Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.29; H 8.42; N 5.80.
	With dicyclohexyl-carbodiimide; In toluene; at 25 - 40℃;	EXAMPLE 5; PREPARATION OF REPAGLINIDE; 3-Ethoxy-4-(ethoxycarbonyl)benzene acetic acid (2.25 g, 0.0089 moles) was added to a solution of (alphaS)-alpha-(2-methylpropyl)-2-(1-piperidinyl)benzenemethanamine (2g, .008 moles) in toluene (20 ml). Then N,N-dicyclohexylcarbodiimide (1.95 g, 0.0094 moles) was added and the reaction mixture was stirred till completion of the reaction at 25-40C. The solid was filtered under suction and toluene filtrate was distilled under reduced pressure. The product was crystallized from ethanol / water and dried to yield ethyl 2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g). 1N aqueous sodium hydroxide solution (8.0 ml) in ethanol (30 ml) was added to ethyl-2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g) at 60-65C and stirred. After completion of the reaction the reaction mixture was cooled, pH was adjusted to 5 with 1N aqueous hydrochloric acid and product was filtered and dried at reduced pressure. The dried product was recrystallised from aqueous ethanol to give repaglinide. Yield: 2.27 g

Reference： [1]Patent: EP2177221,2010,A1 .Location in patent: Page/Page column 13
[2]Patent: WO2004/103983,2004,A1 .Location in patent: Page 7
[3]Patent: US2008/200684,2008,A1 .Location in patent: Page/Page column 3-4
[4]Patent: US2010/197732,2010,A1 .Location in patent: Page/Page column 13
[5]Asian Journal of Chemistry,2013,vol. 25,p. 9345 - 9350
[6]Patent: CN109970681,2019,A .Location in patent: Paragraph 0043; 0051; 0052
[7]Chimia,2006,vol. 60,p. 593 - 597
[8]Patent: US2008/200684,2008,A1 .Location in patent: Page/Page column 3
[9]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[10]Patent: US5312924,1994,A
[11]Patent: EP2019097,2009,A1 .Location in patent: Page/Page column 8

7
[ 99469-99-5 ]
[ 108157-52-4 ]
[ 108175-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; triphenylphosphine; In tetrachloromethane; water; ethyl acetate; acetonitrile;	EXAMPLE 12 Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoate 3 g (11.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmols) of triphenylphosphine, 3.3 ml (23.8 mmols) of triethylamine and 1.15 ml (11.9 mmols) of carbon tetrachloride were added successively to a solution of 2.9 g (11.9 mmols) of 3-methyl-1-(2-piperidino-phenyl)-1-butylamine in 29 of acetonitrile. The mixture was then stirred for 15 hours at room temperature, the solvent was removed in vacuo, and the residue was taken up in a mixture of ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silaca gel (toluene/acetone=10/1). Yield: 4.9 g (85% of theory). M.p. 143-145 C. (petroleum ether).

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A

8
[ 99469-99-5 ]
2-(5-chloro-2-piperidino-phenyl)-2-propylamine [ No CAS ]
ethyl 2-ethoxy-4-<2-<<1-<5-chloro-2-(1-piperidinyl)phenyl>propyl>amino>-2-oxoethyl>-benzoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

9
[ 99469-99-5 ]
[ 219921-60-5 ]
[ 219922-22-2 ]

Yield	Reaction Conditions	Operation in experiment
63%		(F) Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-pentylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 63% of theory. M.p. 113-115 C. Calculated: C--72.47%; H--8.39%; N--5.83%. Found: C--72.66%; H--8.26%; N--5.99%.
63%		(f) Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-pentylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 63% of theory. M.p. 113-115 C.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

10
[ 99469-99-5 ]
[ 89606-14-4 ]
[ 219922-23-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 100 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-4-penten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 117-120 C. Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.73; H 7.97; N 6.07.
		EXAMPLE 100 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-4-penten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 117-12020

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

11
[ 99469-99-5 ]
[ 219921-63-8 ]
[ 219922-24-4 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

12
[ 99469-99-5 ]
[ 219922-85-7 ]
[ 219922-27-7 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 80 Ethyl 2-ethoxy-4-[N-(alpha-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from alpha-cyclopropylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 126-127 C. Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.85; H 7.74; N 5.84.
		EXAMPLE 80 Ethyl 2-ethoxy-4-[N-(alpha-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from alpha-cyclopropylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 126-127 c. Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.85; H 7.74; N 5.84.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

13
[ 99469-99-5 ]
[ 99469-98-4 ]
[ 99469-91-7 ]

Yield	Reaction Conditions	Operation in experiment
87%		(t) Ethyl (-)-2-ethoxy-4-[N-(alpha-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate Prepared from (-)-alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 87% of theory. M.p. 110-111 C. Calculated: mol peak m/e=500 Found: mol peak m/e=500. Specific rotation: [alpha]D20 =-6.3 (c=1, methanol).
87%		(t) Ethyl (-)-2-ethoxy-4-[N-(alpha-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from (-)-alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 87% of theory. M.p. 110-111 C. Calculated: mol peak m/e=500 Found: mol peak m/e=500 Specification rotation: [alpha]D20 -6.3 (c=1, methanol).
77%		(b) Ethyl 2-ethoxy-4-[N-(alpha-phenyl-2-piperidino-benzyl)aminocarbonylmethyl}-benzoate Prepared from alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 77% of theory. M.p. 149-151 C. Calculated: C--7.437%; H--7.25%; N--5.60%. Found: C--74.69%; H--6.44%; N--5.59%.

77%

(b) Ethyl 2-ethoxy-4-[N-(alpha-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate Prepared from alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 77% of theory. M.p. 149-151 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[4]Patent: US5216167,1993,A
[5]Patent: US5312924,1994,A

14
[ 99469-99-5 ]
[ 219921-61-6 ]
[ 219922-25-5 ]

Yield	Reaction Conditions	Operation in experiment
43%		EXAMPLE 27 Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-n-hexyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-n-hexylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogous to Example 1. Yield: 43% of theory. M.p. 101-105 C.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5312924,1994,A

15
[ 99469-99-5 ]
[ 107362-46-9 ]
[ 107362-11-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 48 Ethyl 2-ethoxy-4-[N-(alpha-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from alpha-benzyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 102-105 C. (petroleum ether). Calculated: C 74.68; H 7.44; N 5.44. Found: C 74.73; H 7.68; 5.39.
		EXAMPLE 48 Ethyl 2-ethoxy-4-[N-(alpha-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from alpha-benzyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 102-105 C. (petroleum ether) Calculated: C 74.68; H 7.44; N 5.44. Found: C 74.73; H 7.68; N 5.39.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

16
[ 99469-99-5 ]
[ 219922-86-8 ]
[ 219922-28-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 82 Ethyl 2-ethoxy-4-[N-(alpha-cyclobutylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from alpha-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid. Melting point: 116-118 C. Calculated: C 73.14; H 8.18; N 5.69. Found: C 73.14; H 8.32; N 5.64.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A

17
[ 99469-99-5 ]
[ 219921-62-7 ]
[ 219922-26-6 ]

Yield	Reaction Conditions	Operation in experiment
79%		(aa) Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-heptylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 79% of theory. M.p. 101-104 C. Calculated: C--73.19%; H--8.72%; N--5.51%. Found: C--73.00%; H--8.90%; N--5.28%.
79%		(aa) Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-piperidino-phenyl)-1-heptylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 79% of theory. M.p. 101-104 C.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

18
[ 99469-99-5 ]
[ 219921-65-0 ]
[ 219922-29-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 84 Ethyl 2-ethoxy-4-[N-(alpha-cyclopentylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from alpha-cyclopentylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid. Melting point: 120-121 C. Calculated: C 73.49; H 8.36; N 5.53. C 73.31; H 8.55; N 5.39.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5312924,1994,A

19
[ 99469-99-5 ]
[ 107362-45-8 ]
[ 107362-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; triphenylphosphine; In tetrachloromethane; acetonitrile;	EXAMPLE 47 Ethyl 2-ethoxy-4-[N-(alpha-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate To a solution of alpha-cyclohexylmethyl-2-piperidinobenzylamine (1.13 g, 3.96 mmol) in acetonitrile (11 ml) are added, successively, 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid (1 g, 3.96 mmol), of triphenylphosphine (1.25 g, 4.76 mmol), triethylamine (1.11 ml, 7.92 mmol) and carbon tetrachloride (0.38 ml, 3.96 mmol) and the mixture is stirred for 15 hours at ambient temperature. It is then concentrated by evaporation in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=10/1). Yield: 1.4 g. Melting point: 95-97 C. (petroleum ether/cyclohexane=1/1). Calculated: C 73.81; H 8.52; N 5.38. Found: C 73.98; H 8.49; N 5.61.
	With triethylamine; triphenylphosphine; In tetrachloromethane; acetonitrile;	EXAMPLE 47 Ethyl 2-ethoxy-4-[N-(alpha-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate To a solution of alpha-cyclohexylmethyl-2-piperidino-benzylamine (1.13 g, 3.96 mmol) in acetonitrile (11 ml) are added, successively, 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid (1 g, 3.96 mmol), of triphenylphosphine (1.25 g, 4.76 mmol), triethylamine (1.11 ml, 7.92 mmol) and carbon tetrachloride (0.38 ml, 3.96 mmol) and the mixture is stirred for 15 hours at ambient temperature. It is then concentrated by evaporation in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=10/1). Yield: 1.4 g, Melting point: 95-97 C. (petroleum ether/cyclohexane=1/1) Calculated: C 73.81; H 8.52; N 5.38. Found: C 73.98; H 8.49; N 5.61.

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Patent: US5216167,1993,A
[3]Patent: US5312924,1994,A

20
[ 99469-99-5 ]
[ 219921-66-1 ]
[ 219922-30-2 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

21
[ 99469-99-5 ]
(R)-3-Methyl-1-(2-piperidin-1-yl-phenyl)-butylamine; compound with pentanedioic acid [ No CAS ]
[ 147770-08-9 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

22
[ 99469-99-5 ]
3-methyl-1-(2-piperidino-phenyl)-3-butenylamine glutarate [ No CAS ]
[ 219922-24-4 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

23
[ 99469-99-5 ]
(S)-3-Methyl-1-(2-piperidin-1-yl-phenyl)-butylamine; compound with (S)-2-acetylamino-pentanedioic acid [ No CAS ]
[ 147770-06-7 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

24
[ 332347-69-0 ]
[ 99469-99-5 ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With hydrogenchloride; In water;pH 3;Large scale;	The reaction kettle was charged with ethyl 4-methyl-2-ethoxybenzoate (1kg, 4.8mol), ethanol (38kg, 836.5mol), potassium persulfate (4.5kg, 7.2mol), and triruthenium dodecylcarbonyl (93.2 g, 144 mmol), 2-bis (diphenylphosphine) methylenepyridine (39.5 g, 144 mmol), charged with 2.0 MPa of CO, heated to 100 C, stirred for 10 hours, cooled to room temperature, and depressurized A 2 mol / L potassium hydroxide aqueous solution (4.80 L) was added to the reaction solution, and the reaction was stirred at 10 C for 6 hours. Then, cyclohexane (24 L × 3) was added to wash the reaction solution. The reaction solution was neutralized with hydrochloric acid to pH 7 and concentrated under reduced pressure to About 24 L, hydrochloric acid was acidified to pH 3, a yellow solid was precipitated, and the residue was recrystallized from toluene-petroleum ether to obtain a white solid intermediate (I) (1095.4 g, yield: 90.5%).
77.8%		A solution of 15 ml of water and 1.4 g (0.98 mol.) of sodium hydroxide was added slowly to a slowly to a solution of 25 ml of methanol and 10 g (1.0 mol) of Ethyl-2-ethoxy-4-ethoxy carbonyl methyl benzoate at a temperature of 10-15 C. Stirred for 1-2 hrs at 10-15 C., then the solvent was distilled off from reaction solution under reduced pressure at below 60 C. Cooled to 25-35 C. and charged 20 ml of water and 20 ml of toluene. Then stirred for 15-30 min, separated the aqueous phase and organic phase. Washed the aqueous phase with 20 ml of toluene. Aqueous layer pH was adjusted to 34 with hydrochloric acid at temperature of 0-5 C. Product was extracted with toluene (2×30 ml) from acidified aqueous layer at temperature of 50-60 C. Washed the total organic phase with water (3×30 ml), and concentrated under reduced pressure at below 70 C. The title compound was isolated from residue with 20 ml of cyclohexane at a temperature of 10-15 C. Dried the product at 45-50 C. The yield is 7 g (77.8%). [0046] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR
	With water; sodium hydroxide; In ethanol; at 30℃; for 1h;	Anhydrous ethanol (35.0 mL) and 5 (10.0 g, 35.7 mmol) were stirredat room temperature. A solution of sodium hydroxide (1.4 g, 35.7mmol) in water (6 mL) was then added dropwise at a uniform rate.The reaction temperature was maintained below 30 C for 1 h. Theresulting mixture was adjusted with sodium bicarbonate to pH = 7and extracted with ethyl acetate (20 mL × 3). The aqueous layer wasseparated and adjusted with 20% hydrochloric acid to pH = 1. Then theresulting mixture was extracted with dichloromethane (20 mL × 3).The combined organic layer was dried over anhydrous magnesiumsulfate for several hours and filtered. The dichloromethane solvent wasevaporated from the filtrate under reduced pressure to give transparentpale yellow liquid (8.0 g) with the yield of 89.0%. The resulting residuewas dissolved in petroleum ether/ethyl acetate (5:1, v/v) and stirred for30 min. The precipitate was filtered to obtain white powder 1, m.p.:78.01 C (70-75 C in literature30). Analysis of 1 shows as follows.1H NMR (CDCl3, 500 Hz, delta: ppm): 7.75-7.74 (d, 1H, J = 8.0 Hz),6.89-6.88 (d, 2H, J = 5.5 Hz), 4.37-4.32 (q, 2H, J = 7.0 Hz), 4.13-4.08(q, 2H, J = 7.0 Hz), 3.65 (s, 2H), 1.46-1.44 (t, 3H, J = 7.0 Hz), 1.38-1.35(t, 3H, J = 7.0 Hz). 1H NMR data is in accordance with the literature.5

Reference： [1]Patent: CN110483292,2019,A .Location in patent: Paragraph 0039-0042; 0049-0064
[2]Patent: US2004/249188,2004,A1 .Location in patent: Page 4; 5
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[4]Journal of Chemical Research,2016,vol. 40,p. 506 - 510

25
1-(5-methoxy-2-piperidino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		(o) Ethyl 2-ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(5-methoxy-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 31% of theory. M.p. 117-120 C. Calculated: Mol. peak m/e=496 Found: Mol. peak m/e=496.
31%		(o) Ethyl 2-ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate Prepared from 1-(5-methoxy-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 31% of theory. M.p. 117-120 C. Calculated: Mol. peak m/e=496 Found: Mol. peak m/e=496

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

26
[ 50-85-1 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Patent: WO2016/34673,2016,A1
[4]Patent: WO2016/34673,2016,A1

27
[ 88709-17-5 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Patent: CN110483292,2019,A
[4]Patent: CN110483292,2019,A

28
[ 110017-07-7 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

29
[ 99470-01-6 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

30
[ 99469-99-5 ]
4-[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

31
[ 99469-99-5 ]
2-ethoxy-4-[1-(2-piperidin-1-yl-phenyl)-ethylcarbamoyl]-methyl}-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

32
[ 99469-99-5 ]
[ 219921-27-4 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

33
[ 99469-99-5 ]
2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

34
[ 99469-99-5 ]
[ 99469-93-9 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

35
[ 99469-99-5 ]
[ 108157-53-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

36
[ 99469-99-5 ]
[ 1026614-00-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

37
[ 99469-99-5 ]
[ 135062-02-1 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

38
[ 99469-99-5 ]
(R)-(-)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

39
[ 99469-99-5 ]
[ 99469-95-1 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

40
[ 99469-99-5 ]
4-[2-cyclopropyl-1-(2-piperidin-1-yl-phenyl)-ethylcarbamoyl]-methyl}-2-ethoxy-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

41
[ 99469-99-5 ]
2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

42
[ 99469-99-5 ]
2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

43
[ 99469-99-5 ]
[ 147770-06-7 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

44
[ 99469-99-5 ]
[ 147770-08-9 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

45
[ 99469-99-5 ]
2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-1-yl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

46
[ 99469-99-5 ]
2-Ethoxy-4-[N-(α-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

47
[ 99469-99-5 ]
2-Ethoxy-4-[N-(α-cyclobutylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

48
[ 99469-99-5 ]
2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-n-hexyl}-aminocarbonyl-methyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

49
[ 99469-99-5 ]
2-Ethoxy-4-[(S)-3-methyl-1-(2-piperidin-1-yl-phenyl)-but-3-enylcarbamoyl]-methyl}-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

50
[ 99469-99-5 ]
2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

51
[ 99469-99-5 ]
(S)-(+)-ethyl 2-ethoxy-4-<2-<<3-methyl-1-<2-(1-piperidinyl)phenyl>-3-buten-1-yl>amino>-2-oxoethyl>-benzoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

52
[ 99469-99-5 ]
2-Ethoxy-4-[N-(α-cyclopentylmethyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

53
[ 99469-99-5 ]
2-Ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

54
[ 99469-99-5 ]
2-Ethoxy-4-[N-(α-cycloheptylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

55
[ 799255-62-2 ]
(R)-1-(2-piperidino-phenyl)-1-pentyl-N-[4-methoxybenzyl]amine [ No CAS ]
[ 99469-99-5 ]
C₂₉H₄₀N₂O₄ [ No CAS ]
C₂₉H₄₀N₂O₄ [ No CAS ]

Reference： [1]Patent: WO2004/101540,2004,A2 .Location in patent: Page/Page column 14-15

56
[ 799255-56-4 ]
[ 99469-99-5 ]
[ 807319-44-4 ]

Reference： [1]Patent: WO2004/101540,2004,A2 .Location in patent: Page/Page column 15

57
α-(4-methyl-phenyl)-2-piperidino-benzylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{α-(4-methyl-phenyl)-2-piperidinobenzyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		(v) Ethyl 2-ethoxy-4-[N-{alpha-(4-methyl-phenyl)-2-piperidinobenzyl}-aminocarbonylmethyl]-benzoate Prepared from alpha-(4-methyl-phenyl)-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 34% of theory. M.p. 150-152 C. Calculated: C--74.68%; H--7.44%; N--5.44%. Found: C--74.71%; H--7.51%; N--5.29%.
34%		(v) Ethyl 2-ethoxy-4-[N-{alpha-(4-methyl-phenyl)-2-piperidinobenzyl}-aminocarbonylmethyl]-benzoate Prepared from alpha-(4-methyl-phenyl)-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 34% of theory. M.p. 150-152 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

58
[ 808133-90-6 ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(6-methyl-α-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		(u) Ethyl 2-ethoxy-4-[N-(6-methyl-alpha-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate Prepared from 6-methyl-alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 39% of theory. M.p. <20 C. Calculated: C--74.68%; H--7.44%; N--5.44%. Found: C--74.81%; H--7.56%; N--5.32%.
39%		(u) Ethyl 2-ethoxy-4-[N-(6-methyl-alpha-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate Prepared from 6-methyl-alpha-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 39% of theory. M.p. <20 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

59
[ 1270459-90-9 ]
[ 99469-99-5 ]
Ethyl 2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		(g) Ethyl 2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-pyrrolidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 50% of theory. M.p. 85-87 C. Calculated: C--71.65%; H--8.02%; N--6.19%. Found: C--71.90%; H--8.37%; N--6.34%.
50%		(g) Ethyl 2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-pyrrolidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 50% of theory. M.p. 85-87 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

60
1-[2-(4-methyl-piperidino)-phenyl]-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		(h) Ethyl 2-ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-[2-(4-methyl-piperidino)-phenyl]-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 44% of theory. M.p. 127-128 C. Calculated: C--72.47%; H--8.39%; N--5.83%. Found: C--72.20%; H--8.23%; N--5.69%.
44%		(h) Ethyl 2-ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-[2-(4-methyl-piperidino)-phenyl]-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 44% of theory. M.p. 127-128 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

61
1-(2-hexamethyleneimino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		(i) Ethyl 2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-hexamethyleneimino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 44% of theory. M.p. 97-100 C. Calculated: C--72.47%; H--8.39%; N--5.83%. Found: C--72.41%; H--8.50%; N--5.66%.
44%		(i) Ethyl 2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(2-hexamethyleneimino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 44% of theory. M.p. 97-100 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

62
1-(4-methyl-2-piperidino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
Ethyl 2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		(k) Ethyl 2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methyl-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 68% of theory. M.p. 113-114 C. Calculated C--72.47%; H--8.39%; N--5.83%. Found: C--72.36%; H--8.31%; N--5.91%.
68%		(k) Ethyl 2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methyl-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 68% of theory. M.p. 113-114 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

63
1-(6-methyl-2-piperidino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		(l) Ethyl 2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(6-methyl-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 62% of theory. M.p. <20 C. Calculated: C--72.47%; H--8.39%; N--5.83%. Found: C--72.30%; H--8.50%; N--5.72%.
62%		(l) Ethyl 2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(6-methyl-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 62% of theory. M.p. <20 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

64
1-(6-chloro-2-piperidino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(6-chloro-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		(m) Ethyl 2-ethoxy-4-[N-{1-(6-chloro-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(6-chloro-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 85% of theory. M.p. <20 C. Calculated: C--67.12%; H--7.44%; N--5.50%; Cl--7.08%. Found: C--67.60%; H--7.77%; N--5.92%; Cl--7.24%.
85%		(m) Ethyl 2-ethoxy-4-[N-{1-(6-chloro-2-piperidino -phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(6-chloro-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 85% of theory. M.p. <20 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

65
1-(4-methoxy-2-piperidino-phenyl)-1-butylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		(n) Ethyl 2-ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methoxy-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 65% of theory. M.p. 109-110 C. Calculated: Mol peak m/e=496 Found: Mol. peak m/e=496.
65%		(n) Ethyl 2-ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from 1-(4-methoxy-2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 65% of theory. M.p. 109-110 C. Calculated: Mol. peak m/e=496 Found: Mol. peak m/e=496

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

66
[ 765255-42-3 ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		(s) Ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate Prepared from 5-chloro-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 65% of theory. M.p. 106-108 C. Calculated: C--65.41%; H--6.81%; N--6.10%; Cl-7.73%. Found: C--65.81%; H--6.89%; N--6.11%; Cl--7.62%.
65%		(s) Ethyl 2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate Prepared from 5-chloro-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 65% of theory. M.p. 106-108 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

67
α-phenyl-2-pyrrolidino-benzylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(α-phenyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		(w) Ethyl 2-ethoxy-4-[N-(alpha-phenyl-2-pyrrolidino-benzyl)aminocarbonylmethyl]-benzoate Prepared from alpha-phenyl-2-pyrrolidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 45% of theory. M.p. 85-87 C. Calculated: C--74.05%; H--7.04%; N--5.76%. Found: C--73.95%; H--7.07%; N--5.70%.
45%		(w) Ethyl 2-ethoxy-4-[N-(alpha-phenyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared from alpha-phenyl-2-pyrrolidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 45% of theory. M.p. 85-87 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

68
[2-(azepan-1-yl)phenyl](phenyl)methanamine [ No CAS ]
[ 99469-99-5 ]
Ethyl 2-ethoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		(y) Ethyl 2-ethoxy-4-[N-(2-hexamethyleneimino-alpha-phenyl-benzyl)aminocarbonylmethyl]-benzoate Prepared from 2-hexamethyleneiminoalpha-phenyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 41% of theory. M.p. 140-141 C. Calculated: C--74.68%; H--7.44%; N--5.44%. Found: C--74.46%; H--7.62%; N--5.45%.
41%		(y) Ethyl 2-ethoxy-4-[N-(2-hexamethyleneimino-alpha-phenyl-benzyl)aminocarbonylmethyl]-benzoate Prepared from 2hexamethyleneimino-alpha-phenyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Yield: 41% of theory. M.p. 140-141 C.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

69
2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzylamine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 86 Ethyl 2-ethoxy-4-[N-(2-piperidino-alpha-(tetrahydrofuran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from 2-piperidino-alpha-(tetrahydrofuran-2-yl-methyl)-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 111-113 C. Calculated: C 70.84; H 7.93; N 5.51. Found: C 70.76; H 7.73; N 5.51.

Reference： [1]Patent: US5216167,1993,A

70
α-cycloheptylmethyl-benzylamine [ No CAS ]
[ 99469-99-5 ]
[ 219922-30-2 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 88 Ethyl 2-ethoxy-4-[N-(alpha-cycloheptylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from alpha-cycloheptylmethyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 96-98 C. Calculated: C 74.12; H 8.67; N 5.24. Found: C 74.40; H 8.87; N 5.39.
		EXAMPLE 88 Ethyl 2-ethoxy-4-[N-(alpha-cycloheptylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from alpha-cycloheptylmethyl-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 96-98 C. Calculated: C 74.12; H 8.67; N 5.24. Found C 74.40; H 8.87; N 5.39.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

71
1-(2-piperidino-phenyl)-3-buten-1-yl-amine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 92 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-3-buten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 110-112 C. Calculated: C 72.39; H 7.81; N 6.03. Found: C 72.10; H 7.66; N 5.94.
		EXAMPLE 92 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-3-buten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 110-112 C. Calculated: C 72.39; H 7.81; N 6.03. Found: C 72.10; H 7.66; N 5.94.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

72
1-(2-piperidino-phenyl)-3-butyn-1-yl-amine [ No CAS ]
[ 99469-99-5 ]
ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 98 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-3-butyn-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 86-90 C. Calculated: C 72.70; H 7.41; N 6.06. Found: C 72.60; H 7.40; N 6.04.
		EXAMPLE 98 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)-aminocarbonylmethyl]-benzoate Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-3-butyn-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid. Melting point: 86-90 C. Calculated: C 72.70; H 7.41; N 6.06. Found: C 72.60; H 7.40; N 6.04.

Reference： [1]Patent: US5216167,1993,A
[2]Patent: US5312924,1994,A

73
3-methyl-1-(2-piperidino-phenyl)-2-buten-1-yl-amine [ No CAS ]
[ 99469-99-5 ]
[ 108157-52-4 ]
Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-2-buten-1-yl)-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 96 Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-2-buten-1-yl)-aminocarbonylmethyl]-benzoate [with 25% of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate] Prepared analogously to Example 19 from 3-methyl-1-(2-piperidino-phenyl)-2-buten-1-yl-amine [containing 25% of 3-methyl-1-(2-piperidino-phenyl)-1-butylamine] and 3-ethoxy--4-ethoxycarbonylphenylacetic acid. Melting point: 141-142 C. Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.60; H 7.77; N 5.73.

Reference： [1]Patent: US5312924,1994,A

74
[ 99469-99-5 ]
[ 147769-96-8 ]
ethyl 2ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE F Ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl]-benzoate Prepared from isobutyl-(2-piperidino-phenyl)-ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example B. Purification by column chromatography on silica gel(toluene/acetone=10/1), eluding first the (E)-form and then the (Z)-form.

Reference： [1]Patent: US5312924,1994,A

75
ethyl 2ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate [ No CAS ]
[ 99469-99-5 ]
[ 147769-96-8 ]
[ 108175-51-5 ]

Yield	Reaction Conditions	Operation in experiment
51%		EXAMPLE 17 Ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoate Prepared from ethyl 2ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate, melting point 125-126 C., which in turn was prepared from (2-piperidino-phenyl)-isobutyl-ketimine and 3-ethoxy-4-ethoxy-carbonyl-phenyl-acetic acid analogous to Example 1. Yield: 51% of theory. M.p. 139-141 C.

Reference： [1]Patent: US5312924,1994,A

76
[ 124-38-9 ]
[ 88709-17-5 ]
[ 99469-99-5 ]

Yield	Reaction Conditions	Operation in experiment
72.7%		Under an atmosphere of nitrogen, n-butyllithium (25 ml, 15% w/w solution in hexane) was added to a solution of diisopropylamine (3.6 g) in tetrahydrofuran (30 ml) at -30 C. The mixture was stirred at -30 C. for 30 minutes, cooled to -75 C., and hexamethylphosphoramide (HMPA, 10 g) was added slowly. A solution of <strong>[88709-17-5]ethyl 2-ethoxy-4-methylbenzoate</strong> (5 g) in tetrahydrofuran (10 ml) was then added at -75 C. and the mixture was stirred for two hours. Carbon dioxide gas was then purged into the reaction mixture at -75 C. till complete decolorization. The reaction mixture was then stirred at -75 to -70 C. for 30 minutes and then brought to 10 C., diluted with water (50 ml), and extracted with ether. The aqueous layer was acidified with 10% aqueous sulphuric acid to pH 2 and extracted with dichloromethane. The combined dichloromethane layer was washed with water and concentrated in vacuo. The oily product so obtained was re-dissolved in ether (50 ml) and washed with water. The ethereal layer was then concentrated in vacuo to afford a thick oil which solidified on keeping at room temperature to afford 3-ethoxy-4-(ethoxycarbonyl)phenyl acetic acid 4.4 g (72.7%).
59.5%		Under an atmosphere of nitrogen, n-butyllithium (50 ml, 15% w/w solution in hexane) was added to a solution of diisopropylamine (7.25 g) in tetrahydrofuran (90 ml) at -30 C. The mixture was stirred at -30 C. for 30 minutes, cooled to -75 C., and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 30 ml), was added slowly. A solution of <strong>[88709-17-5]ethyl 2-ethoxy-4-methylbenzoate</strong> (10 g) in tetrahydrofuran (10 ml) was then added at -75 C. and the mixture was stirred for two hours. Carbon dioxide gas was then purged into the reaction mixture at -75 C. till complete decolorization. The reaction mixture was then brought to room temperature, diluted with water (100 ml), and extracted with dichloromethane (100 ml). The aqueous layer was acidified with 10% aqueous sulphuric acid to pH 1.95 and extracted with toluene. The combined toluene layer was washed with water and concentrated in vacuo. Crystallisation with ethyl acetate/petroleum ether afforded (3-ethoxy-4-ethoxycarbonyl)-phenyl acetic acid 7.2 g (59.5%).
23%		To a solution of diisopropylamine (1 .46 g, 14.4 mmol) in anhydrous THF (20 mL) at -30 C was added n-BuLi (2.4M in hexane, 5.8 mL, 14.4 mmol) slowly under a nitrogen atmosphere. The mixture was stirred at -30 C for 30 minutes then cooled to -78 C and HMPA (4.0 g) was added. A solution of <strong>[88709-17-5]ethyl 2-ethoxy-4-methylbenzoate</strong> I76 (2.0 g, 9.6 mmol) in anhydrous THF (5 mL) was then added dropwise and the resulting mixture stirred at -78 C for 2 hours. CO? (g) was bubbled through the mixture until the colour of the anion discharged then for a further 30 minutes. The reaction was allowed to warm to 10 C, then diluted with water (20 mL) and extracted with diethyl ether (2 x 20 mL). The aqueous layer was acidified to pH 2 by addition of 10% aqueous H2S04 and extracted with DCM (2 x 20 mL). The combined DCM layers were washed with water and brine, dried ( a2SC) and concentrated to give the title compound (550 mg, 23%) as yellow oil. LCMS-C: RT 2.36 min; m/z (0798) 253.1 [M+H]+

Reference： [1]Patent: US6686497,2004,B1 .Location in patent: Page column 4
[2]Organic Process Research and Development,2002,vol. 6,p. 184 - 186
[3]Patent: US6686497,2004,B1 .Location in patent: Page column 4
[4]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 103-104

77
[ 799255-55-3 ]
[ 99469-99-5 ]
[ 147770-06-7 ]

Reference： [1]Patent: WO2004/101540,2004,A2 .Location in patent: Page/Page column 13-14

78
[ 799255-59-7 ]
[ 99469-99-5 ]
[ 147770-06-7 ]

Reference： [1]Patent: WO2004/101540,2004,A2 .Location in patent: Page/Page column 15-16

79
[ 99469-99-5 ]
[ 1091599-82-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2.0 g of [3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid in 40 ml of THF was added 1.54 g of CDI at room temperature, followed by stirring overnight. 360 mg of sodium borohydride and 20 ml of water were added thereto under ice-cooling, followed by further stirring at room temperature overnight. To the reaction liquid were added water and ethyl acetate to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2.0 g of colorless oily ethyl 2-ethoxy-4-(2-hydroxyethyl)benzoate.

Reference： [1]Patent: EP2154130,2010,A1 .Location in patent: Page/Page column 23

80
[ 99469-99-5 ]
[ 219922-02-8 ]
(S)(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-1-butyl]aminocarbonyl-methyl]-benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.85 g (51.2%)		Comparative Example 1 (according to EP 0 147 850, Example 2) (S)(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-1-butyl]aminocarbonyl-methyl]-benzoic acid ethyl ester 0.90 g (3.57 mmol) 2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid together with 0.61 g (3.73 mmol) N,N'-carbonyldiimidazole in 9 ml THF were heated to reflux for 5h. Thereafter, a solution of 0.85 g (3.67 mmol) (S)-1-(2-(piperidin-1-yl)phenyl)butan-1-amine (e.e. = 94.2) in 9 ml THF was added and heated to reflux for 3h. The solvent was evaporated in vacuo and the residue was distributed in chloroform and water. The organic phase was dried, filtered and evaporated in vacuo. The crude residue was then purified by column chromatography (SiO2) to give a yield of 0.85 g (51.2%).

Reference： [1]Patent: EP2177221,2010,A1 .Location in patent: Page/Page column 14

81
[ 99469-99-5 ]
[ 147769-93-5 ]
[ 1098066-88-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	With phenylboronic acid; In toluene;Reflux;	Example 2Preparation of 2-ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide (Dimer Impurity)In a round bottom flask fitted with a Dean Stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (2.0 g, 0.00813 mol) was dissolved in toluene (50 ml), which was followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (0.91 g, 0.00406 mol) and phenylboronic acid (0.099 g, 0.000813 mol). The reaction mixture was refluxed for 16-18 hours. The reaction mixture was cooled to 25-30 C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution. This was followed by complete distillation of toluene. Hexane (20 ml) was added to the resulting residue in order to precipitate the solid and stirred for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The crude product was purified by column chromatography to produce 2-ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide (Dimer impurity) with 30% yield.1H NMR (500 MHz, DMSO-d6) d (ppm): 0.89-0.97 (d, 4×3H), 1.3-1.7 (m, 20H), 1.38-1.41 (t, 3H), 2.58-2.6 (m, 2H), 3.08-3.1 (m, 4H), 3.48 (s, 2H), 4.07-4.12 (q, 2H), 5.37-5.38 (m, 1H), 5.5-5.57 (m, 1H), 6.8-7.6 (m, 8H), 6.8-7.6 (d, 3H), 8.32-8.34 (d, 1H), 8.41-8.44 (d, 1H); and MS: m/z: 681.

Reference： [1]Patent: US2010/197732,2010,A1 .Location in patent: Page/Page column 12

82
(S)-2-phenyl-1-[2-(piperidin-1-yl)phenyl]ethylamine [ No CAS ]
[ 99469-99-5 ]
(S)-2-ethoxy-4-[2-({2-phenyl-1-[2-(piperidin-1-yl)phenyl]ethyl}amino)-2-oxoethyl]benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.2%		To a suspension of 7 (3.0 g, 11.9 mmol) in toluene (20 mL), oxalyl chloride (1.8 g., 14.2 mmol) was added at 25-30 C. The reaction mixture was stirred for 3 h at 25-30 C and distilled under vacuum to remove the traces of oxalyl chloride. The residue was dissolved in toluene (20 mL) at 25-30 C. This acid chloride solution was added over a mixture of 6 (4.0g, 14.3 mmol) in toluene (20 mL) contains triethylamine (1.5 g, 14.8 mmol) at 25-30 C. The reaction mixture was stirred for 2 h and diluted with water (20 mL). The mixture was stirred for 15 min and the organic layer was separated. The solvent was removed under reduced pressure to get an oily mass, which on crystallization with diisopropyl ether yields 12 as a white solid. Yield 6.4 g (87.2%).

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2092 - 2098

83
[ 99469-99-5 ]
[ 220438-80-2 ]

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2092 - 2098

84
[ 99469-99-5 ]
2-ethoxy-[4-(ethoxycarbonyl)methyl]benzoic acid [ No CAS ]
[ 332347-69-0 ]

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2092 - 2098

85
[ 99469-99-5 ]
C₂₉H₄₀N₂O₄ [ No CAS ]

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2092 - 2098

86
[ 99469-99-5 ]
C₂₇H₃₆N₂O₄ [ No CAS ]

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2092 - 2098

87
3-oxa-8-azabicyclo[3.2.1]octane hydrochloride [ No CAS ]
[ 99469-99-5 ]
ethyl 4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	A mixture of <strong>[99469-99-5]2-(3-ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid</strong> 177 (550 mg, 2.2 mmol), 3- oxa-8 -azabicyclo[3.2.1] octane hydrochloride salt (320 mg, 2.1 mmol), EDCI (500 mg, 2.6 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (710 mg, 5.5 mmol) in DCM (10 mL) was stirred at room temperature overnight. Water (20 mL) was added and the reaction mixture extracted with DCM (3 x 10 mL), the organic layers were combined and washed with saturated aqueous NaHCOa, water and brine, dried ( a2S04) and concentrated to give the title product (710 mg, 93%) as a yellow oil. LCMS-C: RT 2.38 min; m/z 348.2 [M+H]

Reference： [1]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 104

88
[ 99469-99-5 ]
4-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl)-2-ethoxybenzoic acid [ No CAS ]

Reference： [1]Patent: WO2016/34673,2016,A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	99469-99-5	MDL No. :	MFCD08704233
Formula :	C₁₃H₁₆O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OTGSESBEJUHCES-UHFFFAOYSA-N
M.W :	252.26	Pubchem ID :	10131212
Synonyms :		Chemical Name :	2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)acetic acid

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.38
Num. rotatable bonds :	7
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	65.37
TPSA :	72.83 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.46 cm/s

Log Po/w (iLOGP) :	2.41
Log Po/w (XLOGP3) :	1.94
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	1.83
Log Po/w (SILICOS-IT) :	2.31
Consensus Log Po/w :	2.08

[ CAS No. 99469-99-5 ] {[proInfo.proName]}

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[ 99469-99-5 ] Synthesis Path-Downstream 1~88

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

Log S (ESOL) :	-2.41
Solubility :	0.979 mg/ml ; 0.00388 mol/l
Class :	Soluble
Log S (Ali) :	-3.09
Solubility :	0.203 mg/ml ; 0.000806 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.19
Solubility :	0.161 mg/ml ; 0.000638 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.24

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

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling