[ CAS No. 393509-23-4 ] {[proInfo.proName]}

Name: 393509-23-4|2-(5-Bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid|95%
Brand: Ambeed
SKU: A199314
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Quality Control of [ 393509-23-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 393509-23-4 ]

SDS Specification

Alternatived Products of [ 393509-23-4 ]

Product Details of [ 393509-23-4 ]

CAS No. :	393509-23-4	MDL No. :	MFCD16250085
Formula :	C₁₃H₁₁BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UFDLKQSJWWUVOQ-UHFFFAOYSA-N
M.W :	312.13	Pubchem ID :	16109371
Synonyms :

Calculated chemistry of [ 393509-23-4 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.31
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	69.97
TPSA :	53.09 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	2.82
Log Po/w (WLOGP) :	3.99
Log Po/w (MLOGP) :	3.01
Log Po/w (SILICOS-IT) :	4.04
Consensus Log Po/w :	3.19

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.79
Solubility :	0.0506 mg/ml ; 0.000162 mol/l
Class :	Soluble
Log S (Ali) :	-3.59
Solubility :	0.0798 mg/ml ; 0.000256 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.78
Solubility :	0.00523 mg/ml ; 0.0000167 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.77

Safety of [ 393509-23-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 393509-23-4 ]

* 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 [ 393509-23-4 ]
Downstream synthetic route of [ 393509-23-4 ]

[ 393509-23-4 ] Synthesis Path-Upstream 1~8

1
[ 393509-22-3 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/89309, 2006, A2, . Location in patent: Page/Page column 43
[3] Patent: WO2006/26273, 2006, A2, . Location in patent: Page/Page column 26-27
[4] Patent: WO2006/57922, 2006, A2, . Location in patent: Page/Page column 76
[5] Patent: US2007/299122, 2007, A1, . Location in patent: Page/Page column 13
[6] Patent: WO2006/52555, 2006, A2, . Location in patent: Page/Page column 98-99
[7] Patent: WO2006/113150, 2006, A1, . Location in patent: Page/Page column 60
[8] Patent: WO2006/113150, 2006, A1,

2
[ 20826-94-2 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/113150, 2006, A1,
[3] Patent: WO2006/113150, 2006, A1,
[4] Patent: WO2006/113150, 2006, A1,
[5] Patent: WO2006/113150, 2006, A1,

3
[ 393509-22-3 ]
[ 393509-23-4 ]

Reference： [1] Patent: US2003/158246, 2003, A1,
[2] Patent: US2004/229844, 2004, A1,

4
[ 571170-84-8 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/113150, 2006, A1,
[3] Patent: WO2006/113150, 2006, A1,

5
[ 61272-76-2 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/113150, 2006, A1,
[3] Patent: WO2006/113150, 2006, A1,

6
[ 1003-98-1 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/113150, 2006, A1,
[3] Patent: WO2006/113150, 2006, A1,

7
[ 371-40-4 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806

8
[ 393509-21-2 ]
[ 393509-23-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 794 - 806
[2] Patent: WO2006/113150, 2006, A1,
[3] Patent: WO2006/113150, 2006, A1,

[ 393509-23-4 ] Synthesis Path-Downstream 1~28

1
(+/-)-(7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid dicyclohexylamine salt [ No CAS ]
[ 393509-23-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: (+/-)-('5-bromo-7-fluoro-l,2,3,4-tetrahydrocvclopentarb1mdol-3-yl)acetic acid A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 0C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0C and -15 0C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 0C. Acetic acid (3.04 eq.) was EPO <DP n="49"/>then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 0C and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 0C to -10 0C)). This operation was repeated with about 5 shots of zinc over about 30 rnin. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes.After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IP A/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 0C
		A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0C and -15 0C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 0C and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 0C to -10 C)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IP A/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 0C.
		Step 2: (+/-)-(5-bromo-7-fluoro-l,2,3,4-tetrahydrocvclopentarblindol-3-yl)acetic acidA slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 0C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0C and -15 C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 0C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 0C and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 0C to -10 0C)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IP A/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 0C.

		A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 C. and -15 C. (At about addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about ½ addition of bromine, the mixture became ?loose? again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 C. and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 C. to -10 C.)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IPA/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 C.
		A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 0C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0C and -15 0C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 0C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added EPO <DP n="103"/>at -15 0C and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 0C to -10 0C)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g py?dium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and ?nse with 30/70 IP A/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 0C.
	With pyridine; bromine; acetic acid; zinc; In dichloromethane; at -20 - 20℃; for 1h;Product distribution / selectivity;	Step 2: (r+/-)-('5-bromo-7-£luoro-l,2,3,4-tetrahvdrocvclopenta['b]indol-3-vDacetic acid A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 0C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 0C and -15 0C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 0C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 0C and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 0C to -10 0C)). This operation was repeated over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IP A/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 0C

Reference： [1]Tetrahedron Asymmetry,2005,vol. 16,p. 3094 - 3098
[2]Patent: WO2006/89309,2006,A2 .Location in patent: Page/Page column 46-47
[3]Patent: WO2006/26273,2006,A2 .Location in patent: Page/Page column 29-30
[4]Patent: WO2006/57922,2006,A2 .Location in patent: Page/Page column 79
[5]Patent: US2007/299122,2007,A1 .Location in patent: Page/Page column 14-15
[6]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 101-102
[7]Patent: WO2006/113150,2006,A1 .Location in patent: Page/Page column 63

2
[ 393509-23-4 ]
[ 104-83-6 ]
[4-(4-chlorobenzyl)-7-fluoro-5-bromo-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid [ No CAS ]
[ 393509-05-2 ]

Reference： [1]Tetrahedron Asymmetry,2005,vol. 16,p. 3094 - 3098

3
(3a,5,8b-tribromo-7-fluoro-1,2,3,3a,4,8b-hexahydro-cyclopenta[b]indol-3-yl)-acetic acid [ No CAS ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

4
[ 393509-23-4 ]
[ 67-56-1 ]
[ 571170-85-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

5
[ 393509-22-3 ]
[ 393509-23-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: (+/-)-(5-bromo-7-fluoro-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acidTo a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -400C. The suspension was stirred for 10 min at 00C and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 00C. The suspension was stirred for 15 min at 15C and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of IN HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta 10.77 (br s, IH), 9.84 (br s, IH), 7.09 (m, 2H), 3.60 (m, IH), 2.95-2.65 (m, 4H), 2.56 (dd, IH), 2.19 (m, IH).
		To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -400C. The suspension was stirred for 10 min at 00C and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 00C. The suspension was stirred for 15 min at 15C and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of IN HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta 10.77 (br s, IH), 9.84 (br s, IH), 7.09 (m, 2H), 3.60 (m, IH), 2.95-2.65 (m, 4H), 2.56 (dd, IH), 2.19 (m, IH).
		(+/-)-(5-bromo-7-fluoro-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -400C. The suspension was stirred for 10 min at 0C and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 00C. The suspension was stirred for 15 min at 150C and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of IN HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step.1H NMR (acetone-d6) delta 10.77 (br s, IH), 9.84 (br s, IH), 7.09 (m, 2H), 3.60 (m, IH), 2.95-2.65 (m, 4H),2.56 (dd, IH), 2.19 (m, IH).

		To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -40 C. The suspension was stirred for 10 min at 0 C. and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 0 C. The suspension was stirred for 15 min at 15 C. and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta 10.77 (br s, 1H), 9.84 (br s, 1H), 7.09 (m, 2H), 3.60 (m, 1H), 2.95-2.65 (m, 4H), 2.56 (dd, 1H), 2.19 (m, 1H).
		To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -400C. The suspension was stirred for 10 min at 00C and warmed to room temperature for 30 min Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 00C. The suspension was stirred for 15 min at 15C and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separately funnel containing b?ne/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta 10.77 (br s, 1H), 9.84 (br s, 1H), 7.09 (m, 2H), 3.60 (m, 1H), 2.95-2.65 (m, 4H), 2.56 (dd, 1H), 2.19 (m, 1H).
		Step 3: (+/-)-(5-bromo-7-fluoro-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acidTo a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -400C. The suspension was stirred for 10 min at 00C and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 00C. The suspension was stirred for 15 min at 150C and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of IN HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SC"4 and concentrated. This material was used without further purification in the next step.1H NMR (acetone-d6) delta 10.77 (br s, IH), 9.84 (br s, IH), 7.09 (m, 2H), 3.60 (m, IH), 2.95-2.65 (m, 4H), 2.56 (dd, IH), 2.19 (m, IH).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/89309,2006,A2 .Location in patent: Page/Page column 43
[3]Patent: WO2006/26273,2006,A2 .Location in patent: Page/Page column 26-27
[4]Patent: WO2006/57922,2006,A2 .Location in patent: Page/Page column 76
[5]Patent: US2007/299122,2007,A1 .Location in patent: Page/Page column 13
[6]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 98-99
[7]Patent: WO2006/113150,2006,A1 .Location in patent: Page/Page column 60
[8]Patent: WO2006/113150,2006,A1

6
[ 393509-23-4 ]
[ 393509-05-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1

7
[ 393509-23-4 ]
[ 571170-89-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1

8
[ 393509-23-4 ]
[5-bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diazomethane; In tetrahydrofuran; diethyl ether;	To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78 C. The suspension was stirred for 10 min at 0 C., cooled again to -78 C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0 C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. 1H NMR (acetone-d6) delta 10.70 (br s, 1H), 7.31 (d, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H), 5.74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2.65 (dd, 1H), 2.39 (dd, 1H), 2.26 (m, 1H), MS (-APCI) m/z 436.3, 434.5 (M-H)-.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: US2007/299122,2007,A1 .Location in patent: Page/Page column 13

9
[ 393509-23-4 ]
[ 393509-04-1 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

10
[ 393509-23-4 ]
[ 936337-07-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

11
[ 393509-23-4 ]
[ 794535-36-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

12
[ 393509-23-4 ]
[ 571170-92-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1

13
[ 393509-23-4 ]
[ 571170-77-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Tetrahedron Asymmetry,2005,vol. 16,p. 3094 - 3098

14
[ 571170-84-8 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1
[3]Patent: WO2006/113150,2006,A1

15
[2-(4-fluoro-2-iodo-phenylimino)-cyclopentyl]-acetic acid ethyl ester [ No CAS ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

16
[ 20826-94-2 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1
[3]Patent: WO2006/113150,2006,A1
[4]Patent: WO2006/113150,2006,A1
[5]Patent: WO2006/113150,2006,A1

17
[ 61272-76-2 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1
[3]Patent: WO2006/113150,2006,A1

18
[ 1003-98-1 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1
[3]Patent: WO2006/113150,2006,A1

19
[ 371-40-4 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806

20
[ 393509-21-2 ]
[ 393509-23-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 794 - 806
[2]Patent: WO2006/113150,2006,A1
[3]Patent: WO2006/113150,2006,A1

21
[ 393509-23-4 ]
[ 186581-53-3 ]
[5-bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; diethyl ether;	Step 4: (+/-)-r5-bromo-4-("4-chlorobenzyl)-7-fluoro-L2.3,4-tefrahydrocvclopentarb1indol-3-yll- acetic acid To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78C. The suspension was stirred for 10 min at 00C, cooled again to -78C and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 00C and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory EPO <DP n="78"/>funnel containing IN HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. 1H NMR (acetone-d6) delta 10.70 (br s, IH), 7.31 (d, 2H), 7.18 (d, IH), 7.06 (d, IH), 6.92 (d, 2H), 5.90 (d,IH), 5.74 (d, IH), 3.61 (m, IH), 3.00-2.70 (m, 3H), 2.65 (dd, IH), 2.39 (dd, IH), 2.26 (m, IH). MS (- APCI) m/z 436.3, 434.5 (M-H)".

Reference： [1]Patent: WO2006/57922,2006,A2 .Location in patent: Page/Page column 76-77

22
[ 393509-23-4 ]
[ 104-83-6 ]
[ 393509-04-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: (+/-)- [5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,314-tetrahvdrocyclopenta[b]indol-3-vll- acetic acidThe bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion A- chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 0C for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0C). The reaction was aged at 50 0C for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (DPAc, 2 volumes) and cooled to +15 0C. The solution was acidified with 5N HCl to pH~2. Layers were separated and the organic layer was washed with water (2x2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 0C for 24 hours
		The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4- chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 0C for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0C). The reaction was aged at 50 0C for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 0C. The solution was acidified with 5N HCl to pH~2. Layers were separated and the organic layer was washed with water (2x2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 0C for 24 hours.
		Step 3: (+/-)- r5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2.3,4-tetrahvdrocvclopentaP3lindol-3-yll- acet'c acid EPO <DP n="81"/>The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4- chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 0C for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0C). The reaction was aged at 50 0C for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 0C. The solution was acidified with 5N HCl to pH~2. Layers were separated and the organic layer was washed with water (2x2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 0C for 24 hours.

		The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4-chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 C. for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 C.). The reaction was aged at 50 C. for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 C. The solution was acidified with 5N HCl to pH2. Layers were separated and the organic layer was washed with water (2×2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 C. for 24 hours.
		The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4- chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 0C for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0C). The reaction was aged at 50 0C for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 0C. The solution was acidified with 5N HCl to pH~2. Layers were separated and the organic layer was washed with water (2x2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 0C for 24 hours.
		Step 3: (+/-)- [5-bromo-4-(4-chlorobenzylV7-fluoro-l,2,3,4-tetrahvdrocyclopentarblindol-3-yll- acetic acidThe bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4- chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 0C for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 0C). The reaction was aged at 50 0C for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 0C. The solution was acidified with 5N HCl to pH~2. Layers were separated and the organic layer was washed with water (2x2 volumes). DPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 0C for 24 hours. EPO <DP n="65"/>DP

Reference： [1]Patent: WO2006/89309,2006,A2 .Location in patent: Page/Page column 47
[2]Patent: WO2006/26273,2006,A2 .Location in patent: Page/Page column 30
[3]Patent: WO2006/57922,2006,A2 .Location in patent: Page/Page column 79-80
[4]Patent: US2007/299122,2007,A1 .Location in patent: Page/Page column 15
[5]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 102
[6]Patent: WO2006/113150,2006,A1 .Location in patent: Page/Page column 63

Yield	Reaction Conditions	Operation in experiment
		Step 2 (+-)-(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 C. and -15 C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -5 C. and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 C. to -10 C.)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation takes around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with 30/70 IPA/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 C.
		Step 3 (+/-)-2-(5-Bromo-7-fluoro-1,2,3-trihydrocyclopenta[2,3-b]indol-3-yl)acetic acid Using the method described in example 1, step 4, starting with 2.2 g of the acid of Step 2 (>90% purity), 2.13 g of the title compound was obtained as a crude and unstable brown solid. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta10.77 (1H, br s), 9.84 (1H, br s), 7.09 (2H, m), 3.60 (1H, m), 2.95-2.65 (4H, m), 2.56 (1H, dd), 2.19 (1H, m).
		Step 2: (+-)-(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to -20 to -15 C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between -20 C. and -15 C. (At about 1/3 addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about 1/2 addition of bromine, the mixture became "loose" again.) After completion of the addition, the reaction mixture was aged for one additional hour at -15 C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at -15 C. and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about -15 C. to -10 C.)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation took around 30 to 45 minutes. After completion of the addition, the batch was warmed to room temperature, aged 1 hour and concentrated. The reaction mixture was switched to methyl t-butyl ether (MTBE, 0.8 volume) and a 10% aqueous acetic acid solution (0.8 volume) was added. The mixture (crystallization of salts, e.g pyridium) was aged at room temperature for 1 hour and filtered through solka-floc. The pad of solka-floc was rinsed with MTBE (ca. 0.2 volume) and the filtrate (biphasic, MTBE/aqueous) was transferred into an extractor. The organic phase was washed with water (0.8 volume). The MTBE extract was concentrated and switched to isopropyl alcohol (IPA, 0.25 volume) to crystallize the compound. Water (0.25 volumes) was added and the batch was aged for 1 hour. Additional water (0.33 volumes) was added over 1 hour. After completion of the water addition, the batch was aged for one additional hour, filtered, and rinse with {fraction (30/70)} IPA/Water (0.15 volumes). Crystallized bromoacid was dried in the oven at +45 C.

24
[ 393509-23-4 ]
[ 186581-53-3 ]
[ 14804-61-6 ]
[ 7787-70-4 ]
[ 794535-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; caesium carbonate; acetic acid; In tetrahydrofuran; methanol; hexane; ethyl acetate; acetonitrile;	EXAMPLE 2 (+-)-{4-[1-(4-chlorophenyl)ethyl]-7-fluoro-5-methanesulfonyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl}acetic acid To a solution of 1.5 g of the methyl ester of the acid of Example 1, Step 3 (which was prepared by esterification of the corresponding acid with diazomethane in tetrahydrofuran), 2.03 g of 1-(1-bromoethyl)-4-chlorobenzene in 50 mL of acetonitrile and 6.01 g of cesium carbonate was added. The resulting mixture was heated to reflux with rigorous stirring for 3 hr. Then the reaction mixture was cooled to room temperature, diluted with 50 mL of ethyl acetate, filtered, and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 4% EtOAc/hexane) to afford 1.41 g of desired N-benzylation product as an approximate 1:1 mixture of diastereomers according to 1H NMR analysis. To the above ester (1.2 g) dissolved in 80 mL of NMP, 2.63 g of methanesulfinic acid sodium salt and 3.7 g of Cu(I)Br was added successively. The resulting suspension was degassed under a flow of N2, heated to 140 C. and stirred rigorously for 8 h. Then the reaction mixture was cooled to room temperature and diluted with 500 ml of ethyl acetate and 500 ml of hexane. The resulting mixture was filtered through a pad of silica gel, further eluted with EtOAc. The filtrate was concentrated to about 300 mL of volume and washed with water and brine. The organic phase was separated and dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was further purified by flash chromatography over silica gel eluding with 30% EtOAc/hexane to provide 1.0 g of the sulfonated material. It was hydrolyzed to its corresponding acid using 10 mL of 2 N NaOH in a solvent mixture composed of 10 mL of THF and 10 mL of MeOH at rt for 3 h. The reaction mixture was neutralized with 1 M HCl aqueous solution and extracted with EtOAc. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to afford the crude acid. The two diastereomers were separated by using preparative HPLC (Zobax, 30% EtOAC/hexane with 0.2% AcOH) to afford 300 mg of diastereomer A (shorter retention time) and 210 mg of diastereomer B (longer retention time). Diastereomer B: 1H NMR (acetone-d6) delta10.70 (br s, 1H), 7.66 (dd, 1H), 7.56 (dd, 1H), 7.32 (d, 2H), 6.95 (d, 2H), 6.91 (q, 1H), 3.39 (s, 3H), 3.05-3.00 (m, 1H), 2.90-2.75 (m, 2 H), 2.70 (dd, 1H), 2.44 (dd, 1H), 2.43-2.34 (m, 1H), 2.21 (dd, 1H), 2.11 (d, 3H). MS (-APCI) m/z 448.0(M-H)-.

Reference： [1]Patent: US2003/158246,2003,A1

25
[ 393509-23-4 ]
[ 186581-53-3 ]
[ 622-95-7 ]
[ 393509-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; acetic acid; In tetrahydrofuran; N,N-dimethyl-formamide;	Step 4 (+-)-[5-bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]-indol-3-yl]acetic acid To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78 C. The suspension was stirred for 10 min at 0 C., cooled again to -78 C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0 C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to yield 2.35 g of the title compound as a pale brown solid. 1H NMR (acetone-d6) delta10.70 (br s, 1H), 7.31 (d, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H), 5.74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2.65 (dd, 1H), 2.39 (dd, 1H), 2.26 (m, 1H). MS (-APCI) m/z 436.3, 434.5 (M-H)-.
	With hydrogenchloride; acetic acid; In tetrahydrofuran; N,N-dimethyl-formamide;	Step 4: (+-)-[5-bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78 C. The suspension was stirred for 10 min at 0 C., cooled again to -78 C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0 C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. 1H NMR (acetone-d6) delta 10.70 (br s, 1H), 7.31 (d, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H), 5.74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2.65 (dd, 1H), 2.39 (dd, 1H), 2.26 (m, 1H). MS (-APCI) m/z 436.3, 434.5 (M-H)-.

Reference： [1]Patent: US2003/158246,2003,A1
[2]Patent: US2004/229844,2004,A1

26
[ 393509-22-3 ]
pyridinium tribromide [ No CAS ]
[ 393509-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In pyridine; acetic acid;	Step 3 (+-)-(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -40 C. The suspension was stirred for 10 min at 0 C. and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 0 C. The suspension was stirred for 15 min at 15 C. and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta10.77 (br s, 1H), 9.84 (br s, 1H), 7.09 (m, 2H), 3.60 (m, 1H), 2.95-2.65 (m, 4H), 2.56 (dd, 1H), 2.19 (m, 1H).
	With hydrogenchloride; In pyridine; acetic acid;	Step 3: (+-)-(5-bromo-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at -40 C. The suspension was stirred for 10 min at 0 C. and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 0 C. The suspension was stirred for 15 min at 15 C. and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step. 1H NMR (acetone-d6) delta 10.77 (br s, 1H), 9.84 (br s, 1H), 7.09 (m, 2H), 3.60 (m, 1H), 2.95-2.65 (m, 4H), 2.56 (dd, 1H), 2.19 (m, 1H).

Reference： [1]Patent: US2003/158246,2003,A1
[2]Patent: US2004/229844,2004,A1

27
[ 393509-23-4 ]
bromoacid [ No CAS ]
[ 393509-04-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydroxide; caesium carbonate; In ISOPROPYLAMIDE; water; 1-Chloro-4-(chloromethyl)benzene;	Step 3 (+-)-[5-bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]-indol-3-yl]acetic acid The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4-chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 C. for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rises to +40 C.). The reaction was aged at 50 C. for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (EPAc, 2 volumes) and cooled to +15 C. The solution was acidified with 5N HCl to pH~2. Layers are separated and the organic layer was washed with water (2*2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound in 88% isolated yield. The batch can be dried in the oven at +40 C. for 24 hours.
	With sodium hydroxide; caesium carbonate; In ISOPROPYLAMIDE; water; 1-Chloro-4-(chloromethyl)benzene;	Step 3: (+-)-[5-bromo-4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid The bromoacid of Step 2 was dissolved in dimethylacetamide (0.416 M solution) and cesium carbonate (2.5 eq.) was added in one portion. To the slurry was added in one portion 4-chlorobenzyl chloride (2.5 eq.) and the batch was heated to 50 C. for 20 h. The batch was cooled to r.t. and sodium hydroxide 5N (4.00 eq.) was added over 5 minutes (temperature rose to +40 C.). The reaction was aged at 50 C. for ca. 3 hours, cooled to room temperature and transferred into an L extractor. The solution was diluted with isopropylacetate (IPAc, 2 volumes) and cooled to +15 C. The solution was acidified with 5N HCl to pH-2. Layers were separated and the organic layer was washed with water (2*2 volumes). IPAc solution was concentrated and switched to IPA (0.8 volumes) to crystallize the product. Water (8 L) was added over 2 hours and the batch was filtered to give the title compound. The batch can be dried in the oven at +40 C. for 24 hours.

Reference： [1]Patent: US2003/158246,2003,A1
[2]Patent: US2004/229844,2004,A1

28
[ 393509-23-4 ]
[ 186581-53-3 ]
[ 571170-85-9 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; diethyl ether;	Step 4: (+/-)-["5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,3,4-tetrahvdrocyclopentarb]indol-3-vn- acetic acidTo a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazoraethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78C. The suspension was stirred for 10 min at O0C, cooled again, to -78C and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 00C and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing IN HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. 1H NMR (acetone-d6) delta 10.70 (br s, IH), 7.31 (d, 2H), 7.18 (d, IH), 7.06 (d, IH), 6.92 (d, 2H), 5.90 (d,IH), 5.74 (d, IH), 3.61 (m, IH), 3.00-2.70 (m, 3H), 2.65 (dd, IH), 2.39 (dd, IH), 2.26 (m, IH). MS (- APCI) m/z 436.3, 434.5 (M-H)".
	In tetrahydrofuran; diethyl ether;	To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78C. The suspension was stirred for 10 min at O0C, cooled again to -78C and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to O0C and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing IN HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. 1H NMR (acetone-d6) delta 10.70 (br s, IH), 7.31 (d, 2H), 7.18 (d, IH), 7.06 (d, IH), 6.92 (d, 2H), 5.90 (d, IH), 5.74 (d, IH), 3.61 (m, IH), 3.00-2.70 (m, 3H), 2.65 (dd, IH), 2.39 (dd, IH), 2.26 (m, IH). MS (-APCI) m/z 436.3, 434.5 (M-H)".
	In tetrahydrofuran;	To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed m 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78C. The suspension was stirred for 10 min at 00C, cooled again to -78C and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 00C and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound.1H NMR (acetone-d6) delta 10.70 (br s, 1H), 7.31 (d, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 5.90 (d, 1H), 5 74 (d, 1H), 3.61 (m, 1H), 3.00-2.70 (m, 3H), 2 65 (dd, 1H), 2.39 (dd, 1H), 2 26 (m, 1H). MS (-APCI) m/z 436.3, 434 5 (M-H)-

In tetrahydrofuran; diethyl ether;

Step 4: (+/-)-r5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,3,4-tetrahvdrocvclopentarblindol-3-yl1- acetic acidTo a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at -78C. The suspension was stirred for 10 min at 00C, cooled again to -78C and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 00C and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing IN HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to provide the title compound. EPO <DP n="62"/>1H NMR (acetone-d6) delta 10.70 (br s, IH), 7.31 (d, 2H), 7.18 (d, IH), 7.06 (d, IH), 6.92 (d, 2H), 5.90 (d, IH), 5.74 (d, IH)5 3.61 (m, IH), 3.00-2.70 (m, 3H), 2.65 (dd, IH), 2.39 (dd, IH), 2.26 (m, IH). MS (-APCI) m/z 436.3, 434.5 (M-H)".

Reference： [1]Patent: WO2006/89309,2006,A2 .Location in patent: Page/Page column 44
[2]Patent: WO2006/26273,2006,A2 .Location in patent: Page/Page column 27
[3]Patent: WO2006/52555,2006,A2 .Location in patent: Page/Page column 99
[4]Patent: WO2006/113150,2006,A1 .Location in patent: Page/Page column 60-61

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[ 393509-23-4 ] Synthesis Path-Upstream 1~8

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Fluorinated Building Blocks

Bromides

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