[ CAS No. 300543-56-0 ] {[proInfo.proName]}

Name: 300543-56-0|(R)-1-((4-Chlorophenyl)(phenyl)methyl)piperazine|95%
Brand: Ambeed
SKU: A416464
Price: 11.0 USD
Availability: InStock
Rating: 96 (35 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 300543-56-0 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 300543-56-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 300543-56-0 ]

SDS Specification

Alternatived Products of [ 300543-56-0 ]

Product Details of [ 300543-56-0 ]

CAS No. :	300543-56-0	MDL No. :	MFCD11519277
Formula :	C₁₇H₁₉ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UZKBSZSTDQSMDR-QGZVFWFLSA-N
M.W :	286.80	Pubchem ID :	668697
Synonyms :

Calculated chemistry of [ 300543-56-0 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.29
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	91.55
TPSA :	15.27 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.61 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.19
Log Po/w (XLOGP3) :	3.43
Log Po/w (WLOGP) :	2.25
Log Po/w (MLOGP) :	3.28
Log Po/w (SILICOS-IT) :	3.84
Consensus Log Po/w :	3.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.03
Solubility :	0.0271 mg/ml ; 0.0000944 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.43
Solubility :	0.106 mg/ml ; 0.000371 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.07
Solubility :	0.000244 mg/ml ; 0.000000851 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.43

Safety of [ 300543-56-0 ]

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

Application In Synthesis of [ 300543-56-0 ]

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

Downstream synthetic route of [ 300543-56-0 ]

[ 300543-56-0 ] Synthesis Path-Downstream 1~75

1
C₇H₈N₂O₄ [ No CAS ]
[ 300543-56-0 ]
C₂₄H₂₇ClN₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2265 - 2268

2
C₁₀H₁₀N₂O₄ [ No CAS ]
[ 300543-56-0 ]
C₂₇H₂₉ClN₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2265 - 2268

3
[ 708263-47-2 ]
[ 300543-56-0 ]
C₂₇H₂₉ClN₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2265 - 2268

4
tert-butyl-[4-(5-chloromethyl-tetrahydro-furan-2-yl)-but-3-ynyloxy]-dimethyl-silane [ No CAS ]
[ 300543-56-0 ]
1-{(2S,5S)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine [ No CAS ]
1-{(2S,5R)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2265 - 2268

5
tert-butyl-[4-(5-chloromethyl-tetrahydro-furan-2-yl)-but-3-ynyloxy]-dimethyl-silane [ No CAS ]
[ 300543-56-0 ]
1-{(2R,5S)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine [ No CAS ]
1-{(2R,5R)-5-[4-(tert-Butyl-dimethyl-silanyloxy)-but-1-ynyl]-tetrahydro-furan-2-ylmethyl}-4-[(R)-(4-chloro-phenyl)-phenyl-methyl]-piperazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2265 - 2268

6
[ 300543-56-0 ]
[ 299461-25-9 ]
[ 299461-26-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5591 - 5594

7
[ 300543-56-0 ]
[ 802982-14-5 ]
[ 299461-37-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5591 - 5594

8
[ 300543-56-0 ]
[ 299461-39-5 ]
4-[4-(4-{4-[(R)-(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-butoxy)-phenyl]-but-3-yn-1-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5591 - 5594

9
[ 821-48-7 ]
[ 163837-57-8 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		(-) -1- [ (4-chlorophenyl)phenylmethyl] -4-piperazineCharge 300 mL of N-ethyldiisopropylamine, 30 g of -(-)-4- chlorobenzhydryamine (Clemo, J. Chem. Soc. (1939) 1958-1969; Ingold, J. Chem. Soc. (1933) 1493-1505) and 42 g of bis (2- chloroethyl) amine hydrochloride in a reaction vessel, stir and heat to reflux for 3 hours. Cool to 60 0C, add 24 mL of dieth- ylamine, then heat the mixture again reflux temperature for another 5 hours. After reaction is completed evaporate the solvent in vacuum, add a mixture of water and ethyl acetate (1:1), adjust aqueous phase pH value to 10-11 with 30% sodium hydroxide solution. Separate organic phase and extract aqueous phase with ethyl acetate. Wash combined organic phase with purified water, decolorize organic phase with activated carbon, and evaporate the filtrate in vacuum. Separate impurities by of silica gel chromatography by eluting with ethyl ace- tate/ethanol (7:1) and/or then with ethyl ace- tate/ethanol/ammonia (7:1:0.25). Collect the eluate and evaporate the solvent in vacuum to obtain the oily residue which is further dissolved in hexane, treated with activated carbon heated and filtered. Cool the filtrate to 10 0C for 1 hour, collect a precipitate and dry at 40-450C in vacuum for 5-8 hours to afford a product. HPLC (area) 98-99 %.
		300 ml of N-ethyldiisopropylamine, 30 g of -(-)-4- chlorobenzhydryamine (Clemo, J. Chem. Soc. (1939) 1958-1969; Ingold, J. Chem. Soc. (1933) 1493-1505) and 42 g of bis (2- chloroethyl) amine hydrochloride were charged in a reaction vessel, stirred and heated to reflux for 3 hours. It was cooled to 600C, 24 ml of diethylamine were added, then the mixture was heated again to reflux temperature for another 5 hours. After the reaction was completed the solvent was evaporated in vacuum, a mixture of water and ethyl acetate (1:1) was added, the pH value of the aqueous phase was adjusted to 10-11 with 30% sodium hydroxide solution. The organic phase and extract aqueous phase were separated with ethyl acetate. The combined organic phases were washed with purified water, the organic phase was decolorized with activated carbon, and the filtrate was evaporated in vacuum. The impurities were separated by use of silica gel chromatography by eluting with ethyl acetate/ethanol (7:1) and/or then with ethyl ace- tate/ethanol/ammonia (7:1:0.25) . The eluate was collected and the solvent was evaporated in vacuum to obtain the oily residue which was further dissolved in hexane, treated with activated carbon, heated and filtered. The filtrate was cooled to 100C for 1 hour, a precipitate was collected and dried at 40- 45 C in vacuum for 5-8 hours to afford a product. HPLC (area) 98-99 %.

Reference： [1]Patent: WO2008/110586,2008,A2 .Location in patent: Page/Page column 11; 20
[2]Patent: WO2009/150147,2009,A1 .Location in patent: Page/Page column 18

10
[ 31250-08-5 ]
[ 300543-56-0 ]
[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinil]ethoxy]-acetonitrile dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 2a) [2- [4- [ (4-chlorophenyl)phenylmethyl] -1-piperazinil] ethoxy] - acetonitrile dihydrochlorideCharge 2400 mL of acetonitrile to the reaction vessel, add 400 g of (-) -1- [ (4-chlorophenyl) phenylmethyl ] -4-piperazine, 300 g Na2CO3, 20 g KI and 300 g of 2- (2-chloroethoxy) acetonitrile in turn under stirring.Stir and gradually raise the temperature to 110-115 0C. Keep the temperature for 20 hours, after the reaction is completed, cool the mixture to 80-90 0C and add 25 g of activated carbon and stir for 20 minutes. Filter off carbon and wash cake with appropriate amount of acetonitrile. Into combined filtrate in¬ troduce dry HCl gas until pH value reaches 0.5-1. Continue to stir the slurry for 20 minutes and filter. Wash the cake with appropriate amount of ethanol and dry at 50-550C for 10 hours to obtain 520 g of the title product.The yield 95%, HPLC (area) 95 %. The obtained [2- [4- [(4- chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile dihydrochloride has in the X-ray powder diffractogram the peaks at about: 8.5; 18.5; 19.1; 22.7; 24.9; 25.7; 25.9 in 28.7 +/- 0.2 2Theta.b) Maceration of a crude [2- [4- [ (4-chlorophenyl)phenylmethyl] - 1-piperazinyl] ethoxy] -acetonitrile dihydrochloride10 g of [2- [4- [ (4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile dihydrochloride were suspended in 30 mL of methanol. The suspension was heated to the boiling tempera¬ ture and stirred at this temperature for at least 20 minutes. Thereafter the suspension was cooled to 0 0C and stirred at <n="23"/>this temperature for one hour. The precipitate was filtered, washed with cold methanol and dried. HPLC (area) 98 %.

Reference： [1]Patent: WO2008/110586,2008,A2 .Location in patent: Page/Page column 14; 21-22

11
[ 4480-83-5 ]
[ 300543-56-0 ]
[ 1058165-14-2 ]

Yield	Reaction Conditions	Operation in experiment
		Alternative A2 g of R-I- ( (4-chlorophenyl) (phenyl) methyl) piperazine and 0.88 g of diglycolic acid anhydride was dissolved in 107 mL of acetonitrile . The reaction mixture was refluxed for 12 h. After the reaction was completed the solvent was evaporated and the obtained residue dissolved in 20 mL water with addition of 2mL of IM NaOH and then 10 mL of dichloromethane was added. The suspension was stirred for 20 minutes and the organic phase was separated. To the aqueous phase another portion of 10 mL of dichloromethane was added, pH of suspension is adjusted at 4.5 to 5. Aqueous phase was extracted twice again with 2xl0mL of dichloromethane. Organic phases were collected, dried over anhydrous sodium sulfate, filtrated and evaporated. The obtained crude product could be used in the next step without further purification.
		Alternative B2 g of R-I- ( (4-chlorophenyl) (phenyl) methyl) piperazine and 0.88 g of diglycolic acid anhydride was dissolved in 10 ml of dimethylsulfoxide . To the solution 20 ml of tetrabutylammmo- nium bromide was added. The solution was stirred for another 10 hours until the reaction was completed. The solution was diluted with 67 ml of water and 15 ml of isopropyl acetate was added. The phases were separated and water layer was reex- tracted with isopropyl acetate. Organic layer was mixed with demineralised water (40 ml) and pH of suspension was adjusted to 10 with 2M NaOH. The layers were separated and to the water phase 40 ml of isopropyl acetate was added. pH of suspension <n="25"/>was adjusted to 3.5. The layers were separated and water phase was reextracted twice with isopropylacetate . Organic phase was rinsed with water and evaporated to dryness. 2.5 g of product(HPLC (area) is 98.5 %)) was crystallised. The product was dried at vacuum at 50 0C.
	With tetrabutylammomium bromide; In dimethyl sulfoxide; for 10h;Product distribution / selectivity;	2 g of R-I- ( (4-chlorophenyl) (phenyl) methyl) piperazine and 0.88 g of diglycolic acid anhydride were dissolved in 10 ml of dimethylsulphoxide . To the solution 20 ml of tetrabutylammo- nium bromide were added. The solution was stirred for another 10 hours until the reaction was completed. The solution was diluted with 67 ml of water and 15 ml of isopropyl acetate were added. The phases were separated and the water layer was reextracted with isopropyl acetate. The organic layer was mixed with demineralised water (40 ml) and the pH of the suspension was adjusted to 10 with 2 M NaOH. The layers were separated and to the water phase 40 ml of isopropyl acetate <n="22"/>were added. The pH of the suspension was adjusted to 3.5. The layers were separated and the water phase was reextracted twice with isopropylacetate . The organic phase was rinsed with water and evaporated to dryness. 2.5 g of product (HPLC (area) was 98.5 %) ) was crystallised. The product was dried at vacuum at 500C.

Reference： [1]Patent: WO2008/110586,2008,A2 .Location in patent: Page/Page column 23
[2]Patent: WO2008/110586,2008,A2 .Location in patent: Page/Page column 23-24
[3]Patent: WO2009/150147,2009,A1 .Location in patent: Page/Page column 19-20

12
[ 107-07-3 ]
[ 300543-56-0 ]
[ 705289-61-8 ]

Yield	Reaction Conditions	Operation in experiment
90.49%	With triethylamine; at 80 - 105℃; for 5.5 - 6h;Industry scale;	A mixture of 2-chloroethanol (7.95 kg), (-)-1 -[(4-chlorophenyl)phenylmethyl]- piperazine (23 kg) and triethylamine (9.58 kg) are charged in a clean and dry reactor and heated to about 80-85 0C for about 45-60 minutes. The reaction mass is further heated to about 90-95 0C and stirred at the same temperature for about 45-60 minutes. The reaction mass is further heated to about 96-105 0C for about 4 hours. After completion of the reaction, the reaction mass is cooled to about 65-75 0C and water (144 L) is charged and stirred for about 15 minutes. The reaction mass is then extracted with toluene (68 L), subsequently washed with toluene (223 L), and the combined organic layer is washed with water (368 L). The solvent is distilled off completely under vacuum at below 100 0C and cooled to 50-55 0C to afford 24 kg oily residue of the title compound. Yield: 90.49%, Purity by HPLC: 97.83%.
	With sodium carbonate; potassium iodide; In toluene; for 24h;Reflux;	Step-III: Levorotatory (-)-[2-[4-[(4-Chlorophenyl)-phenylmethyl]-1-piperazinyl]ethanolLevorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]piperazine (50 gm), 2-chloroethanol (31.4 gm), potassium iodide (1.3 gm) and sodium carbonate (40.8 gm) are taken in toluene (446 ml) and refluxed for 24 hours. The reaction mixture is cooled to 25-35 C., washed with water (285 ml) followed by two times with water (each time 185 ml). The layers are separated. Toluene is evaporated from organic layer under reduced pressure to yield 58 gm of levorotatory (-)-[2-[4-[(4-Chlorophenyl)-phenylmethyl]-1-piperazinyl]ethanol.

Reference： [1]Patent: WO2009/62036,2009,A2 .Location in patent: Page/Page column 22
[2]Patent: US2009/281318,2009,A1 .Location in patent: Page/Page column 3

13
[ 942283-97-8 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
84.8%		370 g (0.839 mol) of levorotatory (-)-1 -[(4-chlorophenyl)phenylmethyl]-4-[(4- methylphenyl)sulfonyl]piperazine (prepared in accordance with Example 3.A1 of U.S. Patent No. 5478941 ) and 405 g of 4-hydroxybenzoic acid are added to 1 liter of a 30% solution of hydrobromic acid in acetic acid. The suspension is stirred for 17 hours at 25 0C. 2 liters of water are then added thereto and the suspension is cooled in an ice bath. The precipitate which forms is filtered and washed with 750 mL of water. 2 liters of toluene and 0.9 liters of a 50 % aqueous solution of sodium hydroxide are then added to the filtrate. The organic phase is decanted off and washed with 100 mL of water and then once again with 1 liter of a saturated aqueous solution of sodium chloride. The organic phase is dried over <n="26"/>sodium sulfate, filtered and the solvent evaporated off under reduced pressure.The residue is recrystallized from 600 ml_ of boiling hexane. The solution is filtered while hot, so as to remove any slightly insoluble material and the filtrate is then allowed to crystallize, first at ambient temperature, and then for 24 hours in an ice bath. The crystals are filtered off, washed with hexane and dried under vacuum at 400C to afford 204.15 g of levorotatory (-)-1-[(4chlorophenyl) phenylmethyl]piperazine.M. P.: 90.5 0C. Yield: 84.8%[alpha]D25: 90.5 (c=1 , methanol).Optical purity: >99.8%.Analysis for Ci7H19CIN2 in %:CaIc: C 71.19, H 6.68, N 9.77, Cl 12.36Found: C 71.19, H 6.84, N 9.55, Cl 11.48

Reference： [1]Patent: WO2009/62036,2009,A2 .Location in patent: Page/Page column 24-25

14
[ 943987-59-5 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
92.7%		(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methoxyphenyl)sulfonyl] piperazine (22.0 kg) is slowly added to a solution of hydrobromic acid in glacial acetic acid (91.0 kg) in a clean and dry reactor, and the contents are heated to about 70-75 0C and maintained at the same temperature for about 3 hours. After completion of the reaction, the reaction mass is cooled to about 25-35 0C. Water (115 L) is slowly charged into the reactor at a temperature of about 25 0C to about 30 0C and stirred for about 10-15 minutes. The reaction mass is washed with toluene (2chi45 L) at room temperature followed by cooling of the aqueous layer to 0-5 0C <n="23"/>and then the pH of the aqueous layer is adjusted to about 12.0 to about 14.0 at below 35 0C using 40 % sodium hydroxide (67 L). The reaction mass is then extracted with toluene (370 L) at about 40 0C to about 45 0C. The combined organic layer is washed with water (225 L) and distilled off completely. To the residue so obtained, water (115 L) is charged at about 25 0C to about 35 0C and stirred at the same temperature for about 2-4 hours. The separated solid is then centrifuged and the wet material in the centrifuge is washed with water (25 L). The material is spin-dried for about 30 to about 60 minutes. The cake is further dried at about 30 0C to about 35 0C for about 10 hours to afford 12.8 kg of the title compound. Yield: 92.7%, Purity by HPLC: 98.9%, Chiral purity by HPLC: 99.87

Reference： [1]Patent: WO2009/62036,2009,A2 .Location in patent: Page/Page column 21-22

15
[ 144-62-7 ]
[ 300543-56-0 ]
C₂H₂O₄*C₁₇H₁₉ClN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.2 - 53%	In ethanol; at 5 - 20℃;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (1.05 g, 4.8 mmol), N,N-bis(2-chloroethyl) p-tolyl carbamate (1.39 g, 5 mmol) potassium iodide (0.42 g, 2.5 mmol) and diisopropyl ethylamine (2.6 ml) was stirred at 120 C. (oil bath 135 C.) for 5 hours. While cooling down 7 ml ethyl acetate was added. The mixture was stirred at ambient temperature overnight. The solid was filtered off and washed with ethyl acetate (5 ml) and concentrated to give an oily material (2.64 g).Above crude material was dissolved in a solution containing 1.3 g NaOH in 2.5 ml H2O and 10 ml 2-propanol. The mixture was refluxed for 1 hour 30 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 30 min. The solid was filtered off and layers were separated. 10 ml HCl (2M) was added to the toluene layer and stirred for 20 min. The separated toluene layer was extracted again with 10 ml HCl (1M). The acidic layers were combined, washed with 10 ml toluene and basified. The mixture was extracted with toluene (15 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product (840 mg oil).To the crude product ethyl acetate (25 ml) was added, followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. Solid obtained was filtered off and dried at 30 C. under vacuum to give a white solid material (1 g, 53% yield, 98.96% ee purity)..EXAMPLE 12Compound (4) Oxalate-R-EnantiomerA mixture containing (4-chlorophenyl)phenyl methylamine free base (1.05 g, 4.8 mmol), N,N-bis(2-chloroethyl) 4-methoxy phenyl carbamate (1.49 g, 5 mmol) potassium iodide (0.42 g, 2.5 mmol) and diisopropyl ethylamine (2.6 ml) was stirred at 120 C. (oil bath: 135 C.) for 5 hours.While cooling down, 7 ml ethyl acetate was added. Mixture was stirred at ambient temperature overnight. The solid was filtered off and washed with ethyl acetate (5 ml) and concentrated to give an oily material (2.734 g).Above crude material was dissolved in a solution containing 1.3 g NaOH in 2.5 ml H2O and 10 ml 2-propanol. The mixture was refluxed for 2 hour 45 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 30 min. The solid was filtered off and layers were separated. 10 ml HCl (2M) was added to the toluene layer and was stirred for 20 min. Separated toluene layer was extracted again with 10 ml HCl (1M). Acidic layers were combined, washed with 10 ml toluene and basified. The mixture was extracted with toluene (15 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product (800 mg oil). To the crude product ethyl acetate (25 ml) was added followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. The solid obtained was filtered off and dried at 40 C. under vacuum to give a solid material (0.86 g, 45.7% yield, 98.77% ee purity).EXAMPLE 16Compound (4) Oxalate-R-EnantiomerA mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl) 2,2,2-Trichloroethyl carbamate (6.59 g, 20 mmol), potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10 ml) was stirred at 140 C. (oil bath) for 4 hours 20 min.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 35 ml HCl (1M) was added to the dichloromethane. The organic layer was separated washed with NaCl (10 ml) dried and concentrated to give an oily material (11.1 g).Above crude material was dissolved in a solution containing 5.3 g NaOH in 10 ml H2O and 45 ml 2-propanol. The mixture was heated til 50 C. for 4 h.The temperature was increased til 70 C. and was stirred for 2 hours, then overnight at ambient temperature, 2 h at 70 C., 2 h at 100 C. Then, 2.5 g NaOH were added and was stirred 2 h more at 100 C. and overnight at ambient temperature. The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 40 ml toluene and 20 ml H2O. The mixture was stirred for 15 min, the solid was filtered off and layers were separated. 25 ml HCl (2M) was added to the toluene layer and stirred for 20 min. Separated toluene layer was extracted again with 25 ml HCl (2M). Acidic layers were combined, washed with 20 ml toluene and basified. The mixture was extracted with toluene (80 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product. To the crude product ethyl acetate (25 ml) was added followed by addition of 1.7 g oxalic acid dissolved in 2 ml EtOH. Suspension was stirred 4 h at ambient temperature and overnight at 5 C. Solid obtained was filtered off and dried at air to give a solid material (1.2 g, 16.2% yiel...
	In ethanol; ethyl acetate; at 5 - 20℃;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl) 4-nitrophenyl carbamate (6.4 g, 20.8 mmol) potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10.2 ml) was stirred at 140 C. (oil bath) for 4 hours.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 30 ml HCl (1M) was added to the dichloromethane. The organic layer was separated washed with NaCl (5 ml) dried and concentrated to give an oily material (13.6 g).Above crude material was dissolved in a solution containing 5.3 g NaOH in 10 ml H2O and 42 ml 2-propanol. The mixture was heated til 50 C. for 3 h 30 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 40 ml toluene and 20 ml H2O. The mixture was stirred for 30 min, the solid was filtered off and layers were separated. 40 ml HCl (2M) was added to the toluene layer and stirred for 20 min. Separated toluene layer was extracted again with 40 ml HCl (1M). Acidic layers were combined, washed with 40 ml toluene and basified. The mixture was extracted with toluene (80 ml). The separated organic layer was washed with H2O (10 ml), NaCl (10 ml) dried and concentrated in vacuo to give the desired product (1.2 g oil). To the crude product ethyl acetate (25 ml) was added, followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. Suspension was stirred 4 h at ambient temperature and overweekend at 5 C. Solid obtained was filtered off and dried at air to give a solid material (1.3 g, 17.6% yield). 98.56% ee purity.
	In ethanol; ethyl acetate; at 5 - 20℃;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl)benzyl carbamate (7 g, 26.7 mmol) potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10 ml) was stirred at 135 C. (oil bath), for 4 hours.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 35 ml HCl (1M) was added to the dichloromethane. The organic layer was separated, washed with NaCl (10 ml) dried and concentrated to give an oily material (10 g). The impure material was purified with AcOEt/heptane column (3?50%).0.5 grams of above pure material was dissolved in a solution containing 1.3 g NaOH in 1.2 ml H2O and 5 ml 2-propanol. The mixture was heated til 100 C. for 5 h. The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 20 min and layers were separated. The organic layer was dried over Na2SO4 and concentrated. To the crude product ethyl acetate (10 ml) was added, followed by addition of 0.2 g oxalic acid dissolved in 1 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. The solid obtained was filtered off and dried at air to give a solid material (0.3 g, 38.5% yield). 98.86% ee purity.

In isopropyl alcohol; at 80 - 85℃; for 0.5h;

Example 3; Preparation of oxalate salt of Compound (III); A solution of compound (III, obtained above) in IPA (508 ml) was heated to 40-45C. To this, oxalic acid (78.13 g) was added. The reaction mixture was allowed to reflux to 80-85C for 30 min and then cooled at 20-30C and stirred for 5h. The solid thus obtained was filtered and washed with IPA (124 ml). The title compound was then dried under vacuum at 50-55 C for 12h. The title compound (1 15.0 g) was obtained with 71.65% yield.

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 7-8
[2]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 7-8
[3]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 8-9
[4]Patent: WO2012/101475,2012,A1 .Location in patent: Page/Page column 15

16
[ 941576-99-4 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; at 20 - 100℃;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl) 2,2,2-Trichloroethyl carbamate (6.59 g, 20 mmol), potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10 ml) was stirred at 140 C. (oil bath) for 4 hours 20 min.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 35 ml HCl (1M) was added to the dichloromethane. The organic layer was separated washed with NaCl (10 ml) dried and concentrated to give an oily material (11.1 g).Above crude material was dissolved in a solution containing 5.3 g NaOH in 10 ml H2O and 45 ml 2-propanol. The mixture was heated til 50 C. for 4 h.The temperature was increased til 70 C. and was stirred for 2 hours, then overnight at ambient temperature, 2 h at 70 C., 2 h at 100 C. Then, 2.5 g NaOH were added and was stirred 2 h more at 100 C. and overnight at ambient temperature. The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 40 ml toluene and 20 ml H2O. The mixture was stirred for 15 min, the solid was filtered off and layers were separated. 25 ml HCl (2M) was added to the toluene layer and stirred for 20 min. Separated toluene layer was extracted again with 25 ml HCl (2M). Acidic layers were combined, washed with 20 ml toluene and basified. The mixture was extracted with toluene (80 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product. To the crude product ethyl acetate (25 ml) was added followed by addition of 1.7 g oxalic acid dissolved in 2 ml EtOH. Suspension was stirred 4 h at ambient temperature and overnight at 5 C. Solid obtained was filtered off and dried at air to give a solid material (1.2 g, 16.2% yield). 98.64% ee purity

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 8

17
[ 1136010-90-6 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; for 3 - 3.5h;Heating / reflux;Product distribution / selectivity;	Above crude material was dissolved in a solution containing 4 g NaOH in 10 ml H2O and 40 ml 2-propanol. With stirring, mixture was refluxed for 3 hours.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 50 ml ethyl acetate and 20 ml H2O. The mixture was stirred for 20 min, and layers were separated. 20 ml HCl (2M) was added to the ethyl acetate layer and stirred for 20 min. Separated ethyl acetate layer was extracted again with 10 ml HCl (1M). Acidic layers were combined and basified. The mixture was extracted with ethyl acetate (2×50 ml). Combined ethyl acetate layer was washed with H2O (10 ml), brine (10 ml), dried and concentrated in vacuo to give the desired product (2.7 g), which was solidified while seeded. Optical purity 99%. Step 2Above crude material was mixed with 100 ml 2-propanol, 25 ml water and 13.5 g sodium hydroxide. The mixture was refluxed for 3.5 hours. It was concentrated in vacuo to get rid of 2-propanol and re-dissolved in a mixture of 100 ml toluene and 40 ml water. The mixture was stirred for 45 min. The solid was filtered off. The organic layer was separated and washed with 10 ml water, and extracted twice with 50 ml HCl (2M). After washing the aqueous layer with 25 ml toluene, the mixture was basified to pH 8-9, extracted with 100 ml toluene. The organic layer was washed with 10 ml water, dried and concentrated in vacuo to give the desired product (8 g, 60% yield). Stirring the crude product in 20 ml of toluene for 20 minutes, followed by filtrating and drying at 40 C. (vacuum oven) overnight, gave 4.5 g of the purified product.

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 6

18
[ 1155402-57-5 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; for 1.5h;Heating / reflux;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (1.05 g, 4.8 mmol), N,N-bis(2-chloroethyl) p-tolyl carbamate (1.39 g, 5 mmol) potassium iodide (0.42 g, 2.5 mmol) and diisopropyl ethylamine (2.6 ml) was stirred at 120 C. (oil bath 135 C.) for 5 hours. While cooling down 7 ml ethyl acetate was added. The mixture was stirred at ambient temperature overnight. The solid was filtered off and washed with ethyl acetate (5 ml) and concentrated to give an oily material (2.64 g).Above crude material was dissolved in a solution containing 1.3 g NaOH in 2.5 ml H2O and 10 ml 2-propanol. The mixture was refluxed for 1 hour 30 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 30 min. The solid was filtered off and layers were separated. 10 ml HCl (2M) was added to the toluene layer and stirred for 20 min. The separated toluene layer was extracted again with 10 ml HCl (1M). The acidic layers were combined, washed with 10 ml toluene and basified. The mixture was extracted with toluene (15 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product (840 mg oil).To the crude product ethyl acetate (25 ml) was added, followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. Solid obtained was filtered off and dried at 30 C. under vacuum to give a white solid material (1 g, 53% yield, 98.96% ee purity).

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 7

19
[ 1155402-66-6 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; for 2.75h;Heating / reflux;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (1.05 g, 4.8 mmol), N,N-bis(2-chloroethyl) 4-methoxy phenyl carbamate (1.49 g, 5 mmol) potassium iodide (0.42 g, 2.5 mmol) and diisopropyl ethylamine (2.6 ml) was stirred at 120 C. (oil bath: 135 C.) for 5 hours.While cooling down, 7 ml ethyl acetate was added. Mixture was stirred at ambient temperature overnight. The solid was filtered off and washed with ethyl acetate (5 ml) and concentrated to give an oily material (2.734 g).Above crude material was dissolved in a solution containing 1.3 g NaOH in 2.5 ml H2O and 10 ml 2-propanol. The mixture was refluxed for 2 hour 45 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 30 min. The solid was filtered off and layers were separated. 10 ml HCl (2M) was added to the toluene layer and was stirred for 20 min. Separated toluene layer was extracted again with 10 ml HCl (1M). Acidic layers were combined, washed with 10 ml toluene and basified. The mixture was extracted with toluene (15 ml). The separated organic layer was washed with H2O (10 ml), dried and concentrated in vacuo to give the desired product (800 mg oil). To the crude product ethyl acetate (25 ml) was added followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. The solid obtained was filtered off and dried at 40 C. under vacuum to give a solid material (0.86 g, 45.7% yield, 98.77% ee purity).

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 7

20
[ 1155402-68-8 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; at 50℃; for 3.5h;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl) 4-nitrophenyl carbamate (6.4 g, 20.8 mmol) potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10.2 ml) was stirred at 140 C. (oil bath) for 4 hours.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 30 ml HCl (1M) was added to the dichloromethane. The organic layer was separated washed with NaCl (5 ml) dried and concentrated to give an oily material (13.6 g).Above crude material was dissolved in a solution containing 5.3 g NaOH in 10 ml H2O and 42 ml 2-propanol. The mixture was heated til 50 C. for 3 h 30 min.The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 40 ml toluene and 20 ml H2O. The mixture was stirred for 30 min, the solid was filtered off and layers were separated. 40 ml HCl (2M) was added to the toluene layer and stirred for 20 min. Separated toluene layer was extracted again with 40 ml HCl (1M). Acidic layers were combined, washed with 40 ml toluene and basified. The mixture was extracted with toluene (80 ml). The separated organic layer was washed with H2O (10 ml), NaCl (10 ml) dried and concentrated in vacuo to give the desired product (1.2 g oil). To the crude product ethyl acetate (25 ml) was added, followed by addition of 0.9 g oxalic acid dissolved in 2 ml EtOH. Suspension was stirred 4 h at ambient temperature and overweekend at 5 C. Solid obtained was filtered off and dried at air to give a solid material (1.3 g, 17.6% yield). 98.56% ee purity.

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 7

21
[ 1136010-92-8 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water; In isopropyl alcohol; at 100℃; for 5h;Product distribution / selectivity;	A mixture containing (4-chlorophenyl)phenyl methylamine free base (4.1 g, 18.8 mmol), N,N-bis(2-chloroethyl)benzyl carbamate (7 g, 26.7 mmol) potassium iodide (1.7 g, 10 mmol) and diisopropyl ethylamine (10 ml) was stirred at 135 C. (oil bath), for 4 hours.While cooling down, 60 ml dichloromethane was added. The mixture was stirred at ambient temperature for 20 min. 35 ml HCl (1M) was added to the dichloromethane. The organic layer was separated, washed with NaCl (10 ml) dried and concentrated to give an oily material (10 g). The impure material was purified with AcOEt/heptane column (3?50%).0.5 grams of above pure material was dissolved in a solution containing 1.3 g NaOH in 1.2 ml H2O and 5 ml 2-propanol. The mixture was heated til 100 C. for 5 h. The mixture was concentrated in vacuo to get rid of 2-propanol and redissolved in 10 ml toluene and 5 ml H2O. The mixture was stirred for 20 min and layers were separated. The organic layer was dried over Na2SO4 and concentrated. To the crude product ethyl acetate (10 ml) was added, followed by addition of 0.2 g oxalic acid dissolved in 1 ml EtOH. The suspension was stirred 4 h at ambient temperature and overnight at 5 C. The solid obtained was filtered off and dried at air to give a solid material (0.3 g, 38.5% yield). 98.86% ee purity.

Reference： [1]Patent: US2009/143582,2009,A1 .Location in patent: Page/Page column 8-9

22
[ 1161573-31-4 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; water; at 20℃; for 12.5h;Product distribution / selectivity;	Step (2): Preparation of (R)-(-)-l-[(4- chlorophenyl)phenylmethyl]piperazine of formula (I); Example 7; 20 g of the (R)-(-)-l-[(4-chlorophenyl)phenyhnethyl]piperazine N- acetyl-L-phenylalanine salt obtained in Example Ib was suspended in 200 m£ <n="10"/>of water, and 3.2 g of sodium hydroxide dissolved in 50 ml of water was slowly added thereto for 30 min, followed by stirring at room temperature for 12 hours. The recrystallized solid was filtered, washed with 25 ml of water, and dried at 40 C to obtain (R)-(-)-l-[(4-chlorophenyl)phenylmethyl]piperazine as a white crystalline powder (11.5 g, yield: 99%, optical purity: 99.5%). m.p.: 90-92 C .Specific rotation: [alpha]D25 = -21.2 (c=T.O, methanol).1H-NMR (CDCl3, ppm): d 7.4(m, 4H), 7.2(m, 5H), 4.2(s, IH), 2.9(m, 4H), 2.3(m, 4H). IR (EGBr, cm"1): 3304, 2952, 2907, 2792, 1486, 1452, 1124, 109O5 1014,998, 797, 755, 718, 692, 549, 506.
90%	With sodium hydroxide; water; In ethyl acetate;Product distribution / selectivity;	Example 8; 5 g of the (R)-(-)-l-[(4-chlorophenyl)phenylmethyl]piperazine N-acetyl- L-phenylalanine salt obtained in Example Ic was suspended in 50 mi of ethyl acetate and 30 m£ of water, and 0.75 g of sodium hydroxide dissolved in 10 ml of water was added thereto to neutralize it. The organic layer was isolated, washed with 20 ml of salt solution, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. 10 m£ of hexane was added to the concentrated residue to filtrate the produced crystal, and the crystal was dried at40 C to obtain (R)-(-)-l-[(4-chlorophenyl)phenylmethyl]piperazine as a white crystalline powder (2.6 g, yield: 90%, optical purity: 99.2%). m.p.: 91-92 C .Specific rotation: [alpha]D25 = -21.0 (c=1.0, methanol).

Reference： [1]Patent: WO2009/78627,2009,A2 .Location in patent: Page/Page column 8-9
[2]Patent: WO2009/78627,2009,A2 .Location in patent: Page/Page column 9

23
[ 1092460-01-9 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step-II: Levorotatory (-)-1-[(4-Chloro phenyl)phenylmethyl]piperazineLevorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine (100 gm) is added to 30% hydrobromic acid in acetic acid (271 ml). The suspension is stirred at 25-30 C. for 1 hour, heated to 60 C. and maintained for 4 hours. Water (1000 ml) is added to reaction mass and cooled to 25-30 C. The precipitate formed is filtered off and washed with water (250 ml). Toluene (500 ml) is added to the aqueous layer and basified with 50% aqueous solution of sodium hydroxide. Toluene layer is separated, distilled under reduced pressure and the residue left is recrystallised from boiling hexane (160 ml). The solution is filtered and allowed to recrystallise first at ambient temperature, and then in an ice bath. The product is filtered off, washed with hexane and dried to obtain 55 gm of levorotatory (-)-1-[(4-chloro phenyl)phenylmethyl]piperazine [M.R: 89-93 C.; [alpha]D25=-15.6 (c=1, methanol); Chiral Purity by HPLC: 99.7%].

Reference： [1]Patent: US2009/281318,2009,A1 .Location in patent: Page/Page column 3

24
[ 1228582-98-6 ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 7 Hydrolysis of the Carbamate 2.5 g carbamate salt was suspended in 5 ml isopropanol. With stirring at room temperature, 2 ml sulfuric acid was added dropwise. Formed solution was stirred at 90 C. (heating temp.) for 5 hours.After cooling down to room temperature, 20 ml isopropyl ether and 20 ml water were added. Mixture was stirred for 20 minutes. Separated aquous layer was neutrallized to pH 8, by addition of a 2 N NaOH solution. Mixture was extracted with ethyl acetate (2×20 ml). Combined ethyl acetate layer was washed with H2O, brine, dried and concentrated to give an oily material. The oil was re-dissolved in 10 ml dried toluene. After partly evaporated on rotorvapor, solid was precipitated. The solid was filtered off.960 mg of a solid product was obtained after drying at 40 C. in vacuo over night.

Reference： [1]Patent: US2010/145049,2010,A1 .Location in patent: Page/Page column 8-9

25
C₂₈H₃₇ClN₂O₂*(x)H₂O₄S [ No CAS ]
[ 300543-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 7: (hydrolysis of the carbamate) Z* is (lS)-(-)-menthyl2.5 g carbamate salt was suspended in 5 ml isopropanol. With stirring at room temperature, 2 ml sulphuric acid was added dropwise. Formed solution was stirred at 9O0C (heating temp.) for 5 hours.After cooling down to room temperature, 20 ml isopropyl ether and 20 ml water were added. Mixture was stirred for 20 minutes. Separated aquous layer was neutrallized to pHr8, by addition of a 2 N NaOH solution. Mixture was extracted with ethyl acetate (2x20 ml). Combined ethyl acetate layer was washed with H2O, brine, dried and concentrated to give an oily material. The oil was re-dissolved in 10 ml dried toluene. After partly evaporated on rotorvapor, solid was precipitated. The solid was filtered off.960 mg of a solid product was obtained after drying at 400C in vacuo over night.

Reference： [1]Patent: WO2010/57515,2010,A1 .Location in patent: Page/Page column 22-23

26
[ 107-04-0 ]
[ 300543-56-0 ]
C₁₉H₂₂Cl₂N₂ [ No CAS ]