[ CAS No. 152305-23-2 ] {[proInfo.proName]}

Name: 152305-23-2|(S)-4-(4-Aminobenzyl)oxazolidin-2-one|97%
Brand: Ambeed
SKU: A387352
Price: 10.0 USD
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Quality Control of [ 152305-23-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 152305-23-2 ]

SDS Specification

Alternatived Products of [ 152305-23-2 ]

Product Details of [ 152305-23-2 ]

CAS No. :	152305-23-2	MDL No. :	MFCD03411476
Formula :	C₁₀H₁₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WNAVSKJKDPLWBD-VIFPVBQESA-N
M.W :	192.21	Pubchem ID :	7099156
Synonyms :

Calculated chemistry of [ 152305-23-2 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	56.51
TPSA :	64.35 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.36
Log Po/w (XLOGP3) :	1.06
Log Po/w (WLOGP) :	0.55
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	1.15
Consensus Log Po/w :	0.99

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.88
Solubility :	2.51 mg/ml ; 0.013 mol/l
Class :	Very soluble
Log S (Ali) :	-2.0
Solubility :	1.91 mg/ml ; 0.00994 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.73
Solubility :	0.36 mg/ml ; 0.00187 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.19

Safety of [ 152305-23-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 152305-23-2 ]

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

Upstream synthesis route of [ 152305-23-2 ]
Downstream synthetic route of [ 152305-23-2 ]

[ 152305-23-2 ] Synthesis Path-Upstream 1~8

1
[ 139264-55-4 ]
[ 152305-23-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2347 - 2362
[2] Bioorganic Chemistry, 2002, vol. 30, # 5, p. 315 - 331
[3] Patent: WO2008/18090, 2008, A2, . Location in patent: Page/Page column 10

2
[ 726134-79-8 ]
[ 105-58-8 ]
[ 152305-23-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	at 115 - 135℃; for 2.5 h;	Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINO PHENYL) PROPANOL-7. 6Kg 2. Diethyl carbonate-13.5 Kg 3. Potassium carbonate-0. 633 Kg 4. METHANOL-35. 0 Kg 5. isopropanol-9. 5Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINO PHENYL)-PROPANOL obtained by the process explained in step (A), diethyl carbonate and potassium carbonate at 135°C. Distill off ethanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off the filtered methanol completely under vacuum and charge isopropanol to the residue. Filter through filter aid and wash the product ( (S)-4- (4- aminobenzyl)-2-oxazolidinone) with isopropanol. Dry at 50°C in vacuum (6.85 Kg, 76.7percent, mp 95-100OC). Analysis: CIOHI2N202, molecular weight: 192.0 IR spectrum: KBr, Lactone: 1759 cm-1 THNMR and 13CNMR were consistent with the proposed structure.; B) The preparation of (S)-4- (4-AMINOBENZYL)-2-OXAZOLIDINONE. H p '"NH2 Y'''''' (r Dimethyl carbonate J : y ; ZL" 0 H2N CH20H Potassium carbonate H2N+/ CGHI4N20 C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-6. 2 Kg 2. Dimethyl carbonate-8. 4 Kg 3. Potassium carbonate-0.520Kg 4. METHANOL-30. 0 Kg 5. Isopropanol-7. 5 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL prepared by the process explained in step (A), dimethyl carbonate and potassium carbonate at 115-120°C. DISTILL off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product [(S)-4- (4-aminobenzyl)-2- oxazolidinone] with isopropanol. Dry at 50°C In vacuum (5.5 Kg, 75.0percent, mp 95-100OC) Analysis: CLOH12N202, molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.; B) The preparation of (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL. H 0 H H 1°l /..,, NH2 ..,, NwC Dimethyl carbonate I I zozo H2N CH20H Potassium carbonate H2N C9H14N2O C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-5. 1 Kg 2. Dimethyl carbonate-9.1 Kg 3. Potassium carbonate-0.42 Kg 4. METHANOL-25. 0 Kg 5. Isopropanol-6. 5 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL obtained by the process explained in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature, charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product with isopropanol. Dry at 50°C under vacuum (4.5 Kg, 76.0percent, mp 95-100°C) Analysis : C, OHL2N202, MOLECULAR weight: 192.0 IR, THNMR and CNMR were consistent with the proposed structure.; B) The preparation of (S)-4- (4-AMINOBENZYL)-2-OXAZOLIDINONE. H 0 "rNH2 <"Ns ll Dimethyl carbonate. I I _ CH20H Potassium carbonate'10 C9H14N2O C10H12N2O2 M. W : 166.0 M. W : 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-7. 5 Kg 2. Dimethyl carbonate-13.3 Kg 3. Potassium carbonate-0.62 Kg 4. METHANOL-35. 0 Kg 5. Isopropanol-9. 4 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL obtained by the process described in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the PROD UCT [ (S)-4- (4-AMI NOBENZYL)-2- oxazolidinone.] with isopropanol. Dry at 50°C under vacuum (6.75 Kg, 76.7percent, mp 95-100°C) Analysis: CLOHL2N202 molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

Reference： [1] Patent: WO2004/63175, 2004, A1, . Location in patent: Page 9; 12; 14; 16-18

3
[ 949-99-5 ]
[ 152305-23-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2347 - 2362

4
[ 89288-22-2 ]
[ 152305-23-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2347 - 2362

5
[ 17193-40-7 ]
[ 152305-23-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2347 - 2362

6
[ 188404-34-4 ]
[ 152305-23-2 ]

Reference： [1] Patent: EP1227095, 2002, A2, . Location in patent: Example 1

7
[ 1116-77-4 ]
[ 152305-23-2 ]
[ 139264-17-8 ]

Reference： [1] Patent: WO2008/104134, 2008, A2, . Location in patent: Page/Page column title page; 5-7
[2] Patent: WO2010/73256, 2010, A2, . Location in patent: Page/Page column 4
[3] Patent: WO2008/7390, 2008, A2, . Location in patent: Page/Page column 6

8
[ 152305-23-2 ]
[ 139264-17-8 ]

Reference： [1] Patent: US2011/112157, 2011, A1,
[2] Patent: US2014/228582, 2014, A1,

[ 152305-23-2 ] Synthesis Path-Downstream 1~49

1
[ 152305-23-2 ]
4-((S)-2-Oxo-oxazolidin-4-ylmethyl)-benzenediazonium; chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In water; at -10 - 30℃; for 3h;	(S)-4-(4-Aminobenzyl)-l,3-oxazolidin-2-one (IX) (100 g) was charged in water (400 ml, 4.0 volumes) and cone. HCl (200 ml, 2.0 volumes) was added at 25-30°C. The solution was cooled to 5 to -10°C and a solution of sodium nitrite (54 g, 1.5 equivalents) in water (400 ml, 4.0 volumes) was added whilst maintaining the temperature below -5°C. After completion of the addition, the reaction mixture was stirred for 3 hours resulting in the formation of the diazonium chloride (XV) in solution.
		EXAMPLE 1 Ethyl-3-[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindoleyl)ethyl]-5-[(4S)-2-oxo-1,3-oxazolan-4-ylmethyl]-1H-2-indole carboxylate (VII) Part A: (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one of the formula (II) (200 g, 1.04 moles) was dissolved in methanol (600 ml) and water (900 ml) and cooled to 5-10° C., then concentrated HCl (272 ml) was added dropwise to avoid heat generation and stirring was continued for 10 minutes. To this mixture sodium nitrite (90 g, 1.25 moles) solution in water (600 ml) was added slowly at -5 to 0° C. After the addition, the solution was maintained under stirring at the same temperature for 30 minutes; EXAMPLE 9 Ethyl-3-[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindoleyl)ethyl]-5-[(4S)-2-oxo-1,3-oxazolan-4-ylmethyl]-1H-2-indole carboxylate (VII) Part A: (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one of the formula (II) (50 g, 0.26 moles) was dissolved in methanol (150 ml) and water (225 ml) and cooled to 5-10° C., then conc. HCl (100 ml) was added dropwise to avoid temperature rise, and the mixture was stirred for 10 minutes. To this mixture sodium nitrite (36 g, 0.52 moles) solution in water (150 ml) was added slowly at -5 to 0° C. After addition, the solution was maintained under stirring at the same temp for 30 minutes; EXAMPLE 10 Ethyl-3-[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindoleyl)ethyl]-5-[(4S)-2-oxo-1,3-oxazolan-4-ylmethyl]-1H-2-indole carboxylate (VII) Part A: (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one of the formula (II) (10 g, 0.052 moles) was dissolved in methanol (30 ml) and water (45 ml) and cooled to 5-10° C., then concentrated HCl (13.6 ml) was added dropwise to avoiding heating and the mixture was stirred for 10 minutes. To this mixture, sodium nitrite (4.5 g, 0.065 moles) solution in water (30 ml) was added slowly at -5 to 0° C. After the addition the solution was maintained under stirring at the same temperature for 30 minutes.
	With hydrogenchloride; sodium nitrite; In water; at -10 - 30℃;	EXAMPLES; Example 1; Preparation of Zolmitriptan (I)(S)-4-(4-Aminobenzyl)-1,3-oxazolidin-2-one (IX) (100 g) was charged in water (400 ml, 4.0 volumes) and conc. HCl (200 ml, 2.0 volumes) was added at 25-30° C. The solution was cooled to 5 to -10° C. and a solution of sodium nitrite (54 g, 1.5 equivalents) in water (400 ml, 4.0 volumes) was added whilst maintaining the temperature below -5° C. After completion of the addition, the reaction mixture was stirred for 3 hours resulting in the formation of the diazonium chloride (XV) in solution.

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362
[2]Patent: WO2009/44211,2009,A1 .Location in patent: Page/Page column 17; 21
[3]Patent: EP1227095,2002,A2 .Location in patent: Example 1
[4]Patent: US2005/245585,2005,A1 .Location in patent: Page/Page column 7; 10
[5]Patent: US2011/112157,2011,A1 .Location in patent: Page/Page column 10-11
[6]Journal of Heterocyclic Chemistry,2014,vol. 51,p. E332-E334

2
[ 139264-55-4 ]
[ 152305-23-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;nickel; In methanol; at 30℃; for 6 - 7h;	Example 7Preparation of (S)~4-(4-aminobcnzyl)-l,3-oxazoIidinc-2-one(S)-4-(4-Nitrobenzyl)-l,3-oxazolidine-2-one (65 g, 0.293 moles) was dissolved in methanol (0.65 It) followed by the addition of Raney nickel (13 c.c.) and hydrogenated in the presence of hydrogen at a pressure of 6.0 Kg at -3O0C for 6-7 hrs. The reaction mass was filtered through a hyflo bed and washed residue with methanol (195 ml). The filtrate <n="11"/>was concentrated under reduced pressure to distil off methanol. Ethyl acetate (130 ml) was added to residue and heated to 50-550C for lhr to obtain thick slurry. The reaction mixture was cooled to 1O0C and maintained. The solid was filtered and the precipitates washed with chilled ethyl acetate (65 ml) to get the desired compound.

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362
[2]Bioorganic Chemistry,2002,vol. 30,p. 315 - 331
[3]Patent: WO2008/18090,2008,A2 .Location in patent: Page/Page column 10

3
[ 152305-23-2 ]
[ 179534-87-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With Iodine monochloride; calcium carbonate; In methanol; ethyl acetate;	2. (S)-4-(3-Iodo-4-aminobenzyl)-1.3-oxazolidin-2-one A solution of iodine monochloride (4.84 g, 29.8 mmol) in methanol (35 ml) was added dropwise to a stirred mixture of <strong>[152305-23-2](S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one</strong> (5.2 g, 27.0 mmol) and calcium carbonate (5.42 g, 54.2 mmol) in methanol (1 15 ml), at -40° C. The reaction was allowed to warm to room temperature and stir for 16 h. The solvent was removed under reduced pressure, the residue taken up into ethyl acetate (300 ml) and washed with 20percent aqueous sodium thiosulphate (100 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), dried (Na2 SO4) and evaporated. The crude product was chromatographed on silica gel eluding with CH2 Cl2 /MeOH/98:2 to give the title-iodoaniline (3.88, 45percent), delta(250 MHz, D6 -DMSO) 2.55-2.60 (2H, m, CH2), 3.90-3.99 (2H, m, CH2 O), 4.19-4.28 (1H, m, CHNH), 5.09 (2H, s, NH2), 6.69 (1H, d, J=8.2 Hz, Ar-H,), 6.95 (1H, dd, J=1.9 and 8.2 Hz, Ar-H), 7.44 (1H, d, J=1.9 Hz, Ar-H). 7.74 (1H, s, NH).

Reference： [1]Patent: US5854247,1998,A
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

4
[ 90719-32-7 ]
MeX [ No CAS ]
[ 152305-23-2 ]

Reference： [1]Bioorganic Chemistry,2002,vol. 30,p. 315 - 331

5
[ 152305-23-2 ]
[ 179636-99-8 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

6
[ 152305-23-2 ]
[ 179637-01-5 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

7
[ 152305-23-2 ]
(3S)-3-(N-benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

8
[ 152305-23-2 ]
(3S)-3-[N-(S)-α-methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

9
[ 152305-23-2 ]
[ 1026413-06-8 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690

10
[ 63-91-2 ]
PhMgHal [ No CAS ]
[ 152305-23-2 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

11
[ 949-99-5 ]
[ 152305-23-2 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

12
[ 89288-22-2 ]
[ 152305-23-2 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

13
[ 17193-40-7 ]
[ 152305-23-2 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

14
[ 152305-23-2 ]
5-(dimethylamino)-2-({4-[(2-oxo-1,3-oxazolidin-4-yl)methyl]phenyl}hydrazin-2-ylidene)pentanamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

15
[ 152305-23-2 ]
ethyl 5-(dimethylamino)-2-({4-[(2-oxo-1,3-oxazolidin-4-yl)methyl]phenyl}hydrazin-2-ylidene)pentanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

16
[ 152305-23-2 ]
3-(1-Methyl-piperidin-4-yl)-2-[4-((S)-2-oxo-oxazolidin-4-ylmethyl)-phenyl]-hydrazono}-propionic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

17
[ 152305-23-2 ]
(S)-2-{2-amido-5-[(2-oxo-1,3-oxazolidin-4-yl)methyl]-1H-indol-3-yl}dimethylethylamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

18
[ 152305-23-2 ]
[ 191864-24-1 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

19
[ 152305-23-2 ]
(S)-ethyl 3-(N-methylpiperidin-4-yl)-5-[(2-oxo-1,3-oxazilidin-4-yl)methyl]-1H-indole-2-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2347 - 2362

20
[ 188404-34-4 ]
[ 152305-23-2 ]

Reference： [1]Patent: EP1227095,2002,A2 .Location in patent: Example 1

21
[ 726134-79-8 ]
[ 105-58-8 ]
[ 152305-23-2 ]

Yield	Reaction Conditions	Operation in experiment
75 - 76.7%	potassium carbonate; at 115 - 135℃; for 2.5h;	Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINO PHENYL) PROPANOL-7. 6Kg 2. Diethyl carbonate-13.5 Kg 3. Potassium carbonate-0. 633 Kg 4. METHANOL-35. 0 Kg 5. isopropanol-9. 5Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINO PHENYL)-PROPANOL obtained by the process explained in step (A), diethyl carbonate and potassium carbonate at 135°C. Distill off ethanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off the filtered methanol completely under vacuum and charge isopropanol to the residue. Filter through filter aid and wash the product ( (S)-4- (4- aminobenzyl)-2-oxazolidinone) with isopropanol. Dry at 50°C in vacuum (6.85 Kg, 76.7percent, mp 95-100OC). Analysis: CIOHI2N202, molecular weight: 192.0 IR spectrum: KBr, Lactone: 1759 cm-1 THNMR and 13CNMR were consistent with the proposed structure.; B) The preparation of (S)-4- (4-AMINOBENZYL)-2-OXAZOLIDINONE. H p '"NH2 Y'''''' (r Dimethyl carbonate J : y ; ZL" 0 H2N CH20H Potassium carbonate H2N+/ CGHI4N20 C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-6. 2 Kg 2. Dimethyl carbonate-8. 4 Kg 3. Potassium carbonate-0.520Kg 4. METHANOL-30. 0 Kg 5. Isopropanol-7. 5 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL prepared by the process explained in step (A), dimethyl carbonate and potassium carbonate at 115-120°C. DISTILL off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product [(S)-4- (4-aminobenzyl)-2- oxazolidinone] with isopropanol. Dry at 50°C In vacuum (5.5 Kg, 75.0percent, mp 95-100OC) Analysis: CLOH12N202, molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.; B) The preparation of (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL. H 0 H H 1°l /..,, NH2 ..,, NwC Dimethyl carbonate I I zozo H2N CH20H Potassium carbonate H2N C9H14N2O C10H12N2O2 M. W: 166.0 M. W: 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-5. 1 Kg 2. Dimethyl carbonate-9.1 Kg 3. Potassium carbonate-0.42 Kg 4. METHANOL-25. 0 Kg 5. Isopropanol-6. 5 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL obtained by the process explained in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature, charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the product with isopropanol. Dry at 50°C under vacuum (4.5 Kg, 76.0percent, mp 95-100°C) Analysis : C, OHL2N202, MOLECULAR weight: 192.0 IR, THNMR and CNMR were consistent with the proposed structure.; B) The preparation of (S)-4- (4-AMINOBENZYL)-2-OXAZOLIDINONE. H 0 "rNH2 <"Ns ll Dimethyl carbonate. I I _ CH20H Potassium carbonate'10 C9H14N2O C10H12N2O2 M. W : 166.0 M. W : 192.0 Raw materials Qty 1. (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL-7. 5 Kg 2. Dimethyl carbonate-13.3 Kg 3. Potassium carbonate-0.62 Kg 4. METHANOL-35. 0 Kg 5. Isopropanol-9. 4 Kg Procedure Charge into reactor (S)-2-AMINO-3- (4-AMINOPHENYL) PROPANOL obtained by the process described in step (A), dimethyl carbonate and potassium carbonate at 135°C. Distill off methanol from the reaction mass over a period of 2.5 hours. After cooling the reaction mass to room temperature charge methanol and filter salts through filter aid and wash with methanol. Distill off filtered methanol completely under vacuum and charge isopropanol to the residue. Filter and wash the PROD UCT [ (S)-4- (4-AMI NOBENZYL)-2- oxazolidinone.] with isopropanol. Dry at 50°C under vacuum (6.75 Kg, 76.7percent, mp 95-100°C) Analysis: CLOHL2N202 molecular weight: 192.0 IR, 1HNMR and 13CNMR were consistent with the proposed structure.

Reference： [1]Patent: WO2004/63175,2004,A1 .Location in patent: Page 9; 12; 14; 16-18

Yield	Reaction Conditions	Operation in experiment
		Procedure Charge to the reactor the butanol solution of method (S)-N-butyloxycarbonyl-4-aminophenylalaninate from Stage 3, and dilute with n-butanol to the required volume. Cool the reactor contents to about 25° C. Under a nitrogen atmosphere add half the amount of sodium borchydride whilst maintaining a reaction temperature of about 25° C. Stir for 3 hours and then add the second half of sodium borohydride. Further stir the mixture for 5 hours and warm to 35° C. After this time stir the reaction mixture for about 12 hours and then slowly add aqueous hydrochloric acid, maintaining temperature at about 30° C., to decompose any excess sodium borohydride. Add water, warm to about 35° C. and add ammonia solution to adjust to approximately pH10. Separate the aqueous layer and whilst maintaining a temperature of about 35° C., wash the organic layer with water. Distil some of the butanol, whilst simultaneously azeotroping dry the solution. The dry butanol solution is used directly at the next stage. Stage 3: The preparation of (S)-4-(4-aminobenzyl)-2-oxazolidinone

23
[ 152305-23-2 ]
[ 187975-62-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example - J: Preparation of (S)-4-(4-methylphenyl hydrazine)-., 3-oxazolidin-2-one (S)-4-4-(amino benzyl)-l,3- oxazolidine-2-one (10 g, 0.052 moles) is suspended in water (20 ml) and cooled to -5°C. A solution of sodium Nitrite (4.2 g; 0.06 moles in 42.0 ml water) is slowly added to the above solution and stirred for 45 min. at -5 to 00C.The above reaction mixture is added lot- wise at 5°C to 10°C to a solution of Triphenyl phosphine (40.91 g; 0.155 moles) in methanol (120.0 ml) and diethyl ether (40.0 ml).The reaction mixture is stirred at room temperature for about 8hrs. After the reaction is completed the resulted dark brown oily layer is separated and evaporated under vacuum. The obtained residue is triturated with chloroform and methanol to get the desired product (35.0g).
		Example 1 Synthesis of (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one hydrochloride (IIIa) A mixture of <strong>[152305-23-2](S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one</strong> (100 gms) and concentrated hydrochloric acid (250 ml) in water (500 ml) was treated with an 50percent aqueous solution of sodium nitrite (46 gms) at ?5 to 10° C. Upon completion of the reaction, as monitored by TLC, the reaction mass was further treated with stannous chloride dihydrate (420 gms) dissolved in concentrated hydrochloric acid (500 ml ) and water (544 ml ) at ?15 to 10° C. When the reaction was complete, as monitored by HPLC, the pH of the reaction mass was adjusted in the range of 2.0 to 6.0 by adding aqueous sodium hydroxide solution. The reaction mass was cooled and filtered to separate the solid. The aqueous layer was extracted with dichloromethane and further made alkaline in the pH range of 6.0 to 10.0 with aqueous sodium hydroxide. The mixture was cooled and filtered to give solid (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (III), which was then suspended in isopropanol (420 ml) and converted to the hydrochloride salt by treatment with hydrogen chloride at reflux temperature to yield the hydrochloride salt of (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one (IIIa). Yield: 85 g Purity (HPLC)?99percent

Reference： [1]Patent: WO2007/83320,2007,A2 .Location in patent: Page/Page column 6
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2009,vol. 48,p. 590 - 594
[3]Patent: US2011/112157,2011,A1
[4]Patent: US2014/228582,2014,A1 .Location in patent: Page/Page column 0030

24
[ 1116-77-4 ]
[ 152305-23-2 ]
[ 139264-17-8 ]

Yield	Reaction Conditions	Operation in experiment
		2.4 litres of concentrated HCl are added to 7.0 litres of water in a duplicator. In such diluted HCl 1.75 kg of (<S)-4-(4-aminobenzyl)-l,3-oxazolidine-2-one of formula (I) is stirred up and the mixture is cooled down to 0°C under stirring. During the cooling an aqueous solution ofNaNO2 (0.64 kg NaNO2 / 1.4 litres of water) is prepared for diazotation. At the temperature of ca. O0C a solution OfNaNO2 / H2O is slowly added to the solution of the starting substance (I) on intensive stirring and cooling. After adding of all the nitrite the mixture is further stirred at ca. O0C for ca. 30 min. Example 2 - Reduction of the diazonium saltWeighed 0.28 kg of NaOH is dissolved in 7.0 litres of water and of 2.66 kg of sodium disulphite are added under stirring. After dissolution the mixture is cooled to ca. 20C. The diazonium salt solution is slowly added to the cooled disulphite solution under intensive stirring at the temperature of 2 - 5°C. The mixture is then stirred at ca. 5°C for additional 30 minutes. Then, it is heated up to ca. 25°C and stirred at this temperature for 45 minutes.Further it is heated under a reflux condenser to ca. 6O0C while being stirred. After heating 900 ml of concentrated HCl is added to the reaction mixture and the mixture is stirred under the reflux condenser for another 5 hours. Then the mixture is diluted with 14 litres of water. <n="7"/>Example 3 - Fischer indole reactionThe diluted reaction mixture is heated up to ca. 90°C. 1.75 kg of 4,4-diethoxy-N,N- dimethylbutylamine of formula II is weighed. The weighed acetal (II) is added to the reaction mixture, which is then brought to moderate reflux (at ca. 980C) and being stirred under the reflux condenser it is left to react for about 2.5 hours. After 2.5 hours from the start of the reflux the heating of the mixture is switched off and the reaction mixture is cooled to the laboratory temperature.Example 4 - Isolation of the raw toluene solvate of ZOLMITRIPTANAt the laboratory temperature and being stirred the cooled mixture is neutralized with a ca. 20percent aqueous solution of NaOH. About 4 litres of toluene is added and the mixture is stirred to make an emulsion. Then, an aqueous solution of NaOH is slowly added under stirring until pH of ca. 9.5 is achieved. After approx. 30 minutes of stirring the solid product is filtered off and washed with water. It is dried at temperatures of about 300C to the constant weight (about 10 hours).
		Sodium nitrite (16 gm) in water (120 ml) was added slowly for a period of 30 minutes at 0 deg C to a solution of (S)-4-(4-Aminobenzyl)-2-oxazolidinone (40 gm), concentrated hydrochloric acid (46 ml) and water (480 ml) in round bottomed flask, cooled to 0 deg C and stirred for 1 hour. The above diazotized solution was added for a period of 30 minutes at 0 deg C to sodium sulfite (78.3 gm) in water (200 ml) in another round bottomed flask, cooled to 0 deg C, slowly allowed to room temperature, heated to 55 deg C and stirred for 15 minutes at 60 deg C. Added concentrated hydrochloric acid (80 ml) to the reaction mass, stirred for 16 hours at 60 deg C, nitrogen gas was applied and heated to 90 deg C. Water (80 ml) was added to the reaction mass for 15 minutes at 90 deg C, added 4-(dimethylamino)-butyraldehyde diethylacetal for a period of 40 minutes, heated to reflux, stirred for 3 hours at reflux, cooled to 25 - 30 deg C and the pH was adjusted to 7 by adding sodium hydroxide solution(30percent, 230 ml). Extracted with ethyl acetate (7 X 200 ml), adjusted the pH of the aqueous layer to 10 by adding sodium hydroxide solution (30percent, 100 ml), heated to 50 deg C and again extracted with ethyl acetate (8 X 200 ml) at 50 deg C. Both the organic layers were combined, dried with sodium sulfate, given carbon treatment and the solvent was distilled off completely under vacuum at 50 - 55 deg C, ethyl acetate (80 ml) was added to the reaction mass at 25 deg C, stirred for 1 hour and cooled to 10 deg C. Stirred for 30 minutes at 10 deg C, filtered the material and washed with chilled ethylacetate(20 ml) under nitrogen atmosphere and dried at 45 -50 deg C to yield 40 gm of (4S)-4-[[3-[2-(Dimethylamino)ethyl]~ 1 H-indol-5-yl]methyl]-2-oxazolidinone.(4S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone (40 gm, Zolmitriptan) was dissolved in isopropanol (200 ml) at 25 deg C, heated to reflux, stirred for 40 minutes at reflux and slowly allowed to cool to 0 deg C. Stirred the reaction mass for 1 hour at 0 deg C, filtered the compound, washed with chilled isopropanol(40 ml) and dried at 40 - 45 deg C under vacuum to yield (4S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone isopropanol solvate (32 gm, Zolmitriptan isopropanol solvate; HPLC purity. 99.32percent). Zolmitriptan isopropanol solvate obtained above (32 gm) was dissolved in isopropyl acetate (2250 ml) at 25 deg C. Then the contents were heated to reflux and maintained for 30 minutes to form clear solution. The solution was cooled to 25 deg C during a period of 1 hour. The separated solid was filtered, washed with isopropyl acetate (160 ml) to obtain 32 gm of zolmitriptan isopropyl acetate solvate (HPLC purity: 99.8percent).
		Example - 1;The preparation of (SV4-[(3-[2-(DimethgammalaminokthyIl-lH-indol-5-gammal1methvn-2- oxazolidinone (I):Charge to the flask 300 ml of cone, hydrochloric acid, 3L of demineralised water and 250 gms of (S)-4-(4-arninobenzyl)-2-oxazolidinone. Cool the reactor contents to between 0-5 DEG C and add aqueous sodium nitrite solution (99 gms in 900ml water), maintaining the temperature below 5 DEG C. After stirring for about 30 minutes add the diazonium salt solution to a chilled aqueous solution of sodium sulphite (492 gms in 800 ml water) maintaining the temperature below 10 DEG C. After stirring for 15 minutes slowly heat the resulting mixture to about 55-60 DEG C, and then slowly add 50 ml of cone. hydrochloric acid. The solution is maintained at about 60 DEG C for about 18 hours. Dilute the reaction mixture with 5L of water and heat to about 90 DEG C. Under a nitrogen atmosphere slowly add 246 gms of 4,4-diethoxy-N, N-dimethylbutylamine and heat at reflux for about 3 hours. Cool, and adjust the mixture to about pH7 using sodium hydroxide solution. Extract with chloroform and then adjust the aqueous layer to about pHIO, again using sodium hydroxide solution. Extract the product using chloroform. Treat the combined chloroform extracts (containing the product) with decolorizing charcoal, and filter through filter aid. Distil off most of the solvent and chill the suspension to about 0 DEG C. Centrifuge the crude product, wash with chloroform and vacuum dry at 50 DEG C. (150 gms, pale yellow powder, 99.4percent HPLC purity)

Reference： [1]Patent: WO2008/104134,2008,A2 .Location in patent: Page/Page column title page; 5-7
[2]Patent: WO2010/73256,2010,A2 .Location in patent: Page/Page column 4
[3]Patent: WO2008/7390,2008,A2 .Location in patent: Page/Page column 6

25
[ 152305-23-2 ]
[ 139264-17-8 ]

Reference： [1]Patent: US2011/112157,2011,A1
[2]Patent: US2014/228582,2014,A1

26
[ 55747-45-0 ]
[ 152305-23-2 ]
[ 868622-21-3 ]

Yield	Reaction Conditions	Operation in experiment
78%		Concentrated hydrochloric acid (34.0L, 325.5 mol) was slowly added to a stirred solution of <strong>[152305-23-2]4-(S)-(4-aminobenzyl)-1,3-oxazolidin-2-one</strong> 2 (25.0 kg, 130.2mol) in a mixture of methanol (75.0 L) and water (112.5L) at 5?10 ?C. After stirring for 10 min, a solution of sodium nitrite (11.2 kg, 162.7 mol) in water (75 L) was added slowly to the reaction mixture at 5 to 0?C and the solution was maintained under stirring at the same temperature for 30 min. Meanwhile, in a separate vessel, sodium acetate(42.7 kg, 520.8 mol) was added to a stirred solution of ethyl 2-acetyl-5-(1,3-dioxo-1,3-dihydro-2-isoindolyl) pentanoate (4) (43.3 kg, 136.6 mol) in methanol (437.5 L). After stirring for 1 h at 25?30 ?C the solution was cooled to 0?5 ?C, and the previously prepared diazotized solution was slowly added to this cooled reaction mixture and stirredfor 3 h at room temperature. After the completion of reaction (monitored by thin-layer chromatography, TLC, using ethyl acetate as mobile phase), the reactionmass was extracted three times with dichloromethane (3250 L). The combined dichloromethane layer was washed twice with water (2125 L) and once with brine(125 L). The organic layer was separated and concentrated. The crude residue (containing the hydrazone intermediate) was cyclized to form the indole moiety. Methanol (50 L) and methanolic HCl (15.0percent, 150 mL) were added to the residue. and the solution was refluxed for 6 h. The reaction mass was then cooled to room temperature (25 ?C) and the obtained solid was filtered, washed with methanol (25 L), and dried to furnish the title compound 7. Yield 46.8 kg (78percent); mp 215?220 ?C; 1H NMR: (DMSO-d6, 200 MHz): delta 11.55 (s, 1H), 7.78 (s, 4H), 7.4 (s, 1H), 7.35 (d, 1H, J=8.4 Hz), 7.1 (d, 1H, J=8.4 Hz), 4.25 (q, 2H, J=7.2 Hz), 4.08 (m, 1H), 3.9?3.8 (m, 4H), 3.4?3.3 (m, 2H), 2.9?2.6 (m, 2H), 1.35 (t, 3H, J=7.2 Hz); 13C NMR: (DMSO-d6, 50 MHz): delta 14.2, 23.4, 38.4, 40.9, 51.5, 53.2, 60.4, 68.2, 112.7, 118.9, 119.1, 119.9, 122.9, 123.8, 124.1, 126.7, 127.6, 127.7, 131.6, 134.3, 135.3, 158.7, 161.7, 162.1, 167.7; IR numax cm-1(KBr): 3357 (br), 2940 (br), 1759 (br), 1707, 1544, 1466, 1440, 1396, 1248, 1026 cm-1; MS: m/z 462 (100percent, M1; Et ester).

Reference： [1]Synthetic Communications,2013,vol. 43,p. 3294 - 3306

27
[ 152305-23-2 ]
(S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/228582,2014,A1

28
[ 403-43-0 ]
[ 152305-23-2 ]
(S)-4-fluoro-N-(4-((2-oxooxazolidin-4-yl)methyl)phenyl)-benzamide [ No CAS ]