116649-85-5

Basic information

• Product Name: Ramatroban
• Synonyms: BAY-U3405;3R-[[(4-FLUOROPHENYL)SULFONYL]AMINO]-1,2,3,4-TETRAHYDRO-9H-CARBAZOLE-9-PROPANOIC ACID;RAMATROBAN;9H-Carbazole-9-propanoic acid, 3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-, (3R)- (9CI);9H-Carbazole-9-propanoic acid, 3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-, (R)-;Baynas;3R-[[(4-Fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-;Ramatroban for research
• CAS NO: 116649-85-5
• Molecular Formula: C₂₁H₂₁FN₂O₄S
• Molecular Weight: 416.47
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors
• Mol File: 116649-85-5.mol
• Article Data: 2

Chemical Properties

• Melting Point: 134-135°
• Boiling Point: 654.7 °C at 760 mmHg
• Flash Point: 349.7 °C
• Appearance: white/
• Density: 1.43 g/cm³
• Vapor Pressure: 4.94E-18mmHg at 25°C
• Refractive Index: 1.664
• Storage Temp.: Desiccate at -20°C
• Solubility: DMSO: ≥40mg/mL
• PKA: 4.60±0.10(Predicted)
• CAS DataBase Reference: Ramatroban(CAS DataBase Reference)
• NIST Chemistry Reference: Ramatroban(116649-85-5)
• EPA Substance Registry System: Ramatroban(116649-85-5)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36/37/39-45
• WGK Germany: 1
• Hazardous Substances Data: 116649-85-5(Hazardous Substances Data)

Usage

Description

Ramatroban, originally developed for the treatment of cardiovascular pathologies as thromboembolism, was finally introduced in Japan for the treatment of allergic rhinitis. It is a (3R)-enantiomer that can be synthesized in 5 steps from 3-oxo-1,2,3,4- tetrahydrocarbazole by stereoselective reductive amination, using S-phenethylamine as the chiral source, followed by hydrogenolysis, sulfonylation and finally 2-step Ncarboxyethylation. Ramatroban is a potent antagonist of prostaglandin receptors (PGD2, PGH2) and thromboxane receptors (TxA2); accordingly, it blocks the contractions induced by thromboxane or TxA2-mimetics in animal and human airway smooth muscle. It also prevents, when administered i.v., p.o. or by aerosol, bronchoconstriction induced by PGD2 or antigen. In animal models of nasal allergy, ramatroban inhibits antigen-induced neutrophil infiltration into nasal mucosa and also inhibits nasal symptoms. In several species including humans, it is well-absorbed, extensively protein-bound (>95%) and eliminated mainly as a glucuro-conjugate; in man, its terminal half-life is 2 to 3 hours.

Chemical Properties

WHite to Off-White Solid

Originator

Bayer (Germany)

Uses

A thromboxane receptor antagonist for use in the treatment of coronary artery disease.

Brand name

Baynas

Biological Activity

Potent dual antagonist of TP/DP 2 (CRTH2) prostanoid receptors (K i values are 4.3, 4.5 and > 10000 nM for hDP 2 , hTP and hDP 1 receptors respectively). Suppresses PGD 2 -induced migration of human eosinophils (IC 50 = 170 nM).

in vitro

bay u3405 showed significant inhibitory effects on the binding of 3h-labeled pgd2 to crth2, albeit with much lower potency. bay u3405 and indomethacin also inhibited pgd2-induced ca2+ mobilization in crth2 transfectants to almost the same extent. however, indomethacin but not bay u3405 was confirmed as an agonist of ca2+ mobilization at concentrations greater than 10 nm [1].

in vivo

for rat with splanchnic artery occlusion shock, administration of bay u3405 at 30 mg/kg i.v. could significantly increase the survival time and survival rate, improve mean arterial blood pressure, reduce the plasma levels of myocardial depressant factor, partially restore macrophage phagocytosis and lower mpo activity in both the ileum and the lung [2].

IC 50

100-170 nm

references

[1] sugimoto, h. ,shichijo, m.,iino, t., et al. an orally bioavailable small molecule antagonist of crth2, ramatroban (bay u3405), inhibits prostaglandin d2-induced eosinophil migration in vitro. journal of pharmacology and experimental therapeutics 305, 347-352 (2003).[2] canale p, squadrito f, altavilla d, ioculano m, campo gm, squadrito g, urna g, sardella a, caputi ap. beneficial effects of bay u3405, a novel thromboxane a2 receptor antagonist, in splanchnic artery occlusion shock. pharmacology. 1994 dec;49(6):376-85.[3] aizawa h, shigyo m, nogami h, hirose t, hara n. bay u3405, a thromboxane a2 antagonist, reduces bronchial hyperresponsiveness in asthmatics. chest. 1996 feb;109(2):338-42.

InChI:InChI=1/C21H21FN2O4S/c22-14-5-8-16(9-6-14)29(27,28)23-15-7-10-20-18(13-15)17-3-1-2-4-19(17)24(20)12-11-21(25)26/h1-6,8-9,15,23H,7,10-13H2,(H,25,26)/t15-/m1/s1

Synthetic route

(R)-N-[9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide (118699-38-0) → ramatroban (116649-85-5)

Conditions	Yield
Stage #1: (R)-N-[9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide With water; sodium hydroxide In isopropyl alcohol at 100℃; for 24h; Stage #2: With hydrogenchloride In water	79%

acrylonitrile (107-13-1) + (R)-4-fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)benzenesulfonamide (116650-36-3) → ramatroban (116649-85-5)

Conditions	Yield
With potassium hydroxide; sodium hydride 1.) dimethylformamide, 2 h, room temperature, 2.) isopropanol, reflux, 16 h; Yield given. Multistep reaction;

1,2,3,4-tetrahydrocarbazol-3-one (51145-61-0) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2.) tetrabutylammonium borohydride, 3.) 2N sulfuric acid / 1.) benzene, reflux, 1 h, 2.) CH2Cl2, -50 deg C to room temperature, 3.) methanol, room temperature, 1 h 2: 1.) 2N NaOH, conc. HCl, 2.) ammonium formiate / 2.) 10percent Pd/C / 1.) methanol, ethyl acetate, 2.) dimethylformamide, reflux, 20 min 3: 84 percent / triethylamine / CH2Cl2 / 1 h / Ambient temperature 4: 1.) 80percent sodium hydride (in mineral oil), 2.) 10percent potassium hydroxide / 1.) dimethylformamide, 2 h, room temperature, 2.) isopropanol, reflux, 16 h View Scheme
Multi-step reaction with 6 steps 1.1: D-glucose / water / 24 h / 30 °C / Enzymatic reaction 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 2.2: 10 h / -25 - -15 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 2.1: Candida antarctica Lipase A / tetrahydrofuran / 5 h / 30 °C / Enzymatic reaction 3.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 3.2: 10 h / -25 - -15 °C 4.1: water; triphenylphosphine / 15 h / 65 °C 5.1: triethylamine / dichloromethane / 1 h / 20 °C 6.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 6.2: 1 h / 20 °C 7.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(3R)-3-(1S-phenylethylamino)-1,2,3,4-tetrahydrocarbazole hydrogensulfate → ramatroban (116649-85-5)

Conditions

Yield

Multi-step reaction with 3 steps 1: 1.) 2N NaOH, conc. HCl, 2.) ammonium formiate / 2.) 10percent Pd/C / 1.) methanol, ethyl acetate, 2.) dimethylformamide, reflux, 20 min 2: 84 percent / triethylamine / CH2Cl2 / 1 h / Ambient temperature 3: 1.) 80percent sodium hydride (in mineral oil), 2.) 10percent potassium hydroxide / 1.) dimethylformamide, 2 h, room temperature, 2.) isopropanol, reflux, 16 h View Scheme

(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (116650-33-0) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / triethylamine / CH2Cl2 / 1 h / Ambient temperature 2: 1.) 80percent sodium hydride (in mineral oil), 2.) 10percent potassium hydroxide / 1.) dimethylformamide, 2 h, room temperature, 2.) isopropanol, reflux, 16 h View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 1 h / 20 °C 3.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

cyclohexanedione monoethylene ketal (4746-97-8) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Candida antarctica Lipase A / tetrahydrofuran / 5 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Pseudomonas cepacia lipase / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Candida antarctica lipase B / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(S)-2,3,4,9-tetrahydro-1H-carbazol-3-yl methanesulfonate (1374648-17-5) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium azide / dimethyl sulfoxide / 24 h / 20 °C 2.1: water; triphenylphosphine / 15 h / 65 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h / 20 °C 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 2.1: water; triphenylphosphine / 15 h / 65 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h / 20 °C 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(R)-3-azido-2,3,4,9-tetrahydro-1H-carbazole (1374648-18-6) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: water; triphenylphosphine / 15 h / 65 °C 2.1: triethylamine / dichloromethane / 1 h / 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 3.2: 1 h / 20 °C 4.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

4-fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)benzenesulfonamide (116650-12-5) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 20 °C 1.2: 20 °C 2.1: chiralpak IC / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 3.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: chiralpak IC / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 2.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 1 h / 20 °C 3.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

N-[9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: chiralpak IC / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 2: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

2,3,4,9-tetrahydro-1H-carbazol-3-yl methanesulfonate → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium azide / 24 h 2.1: chiralcel OD / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium azide / 24 h 2.1: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 20 °C 4.2: 20 °C 5.1: chiralpak IC / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium azide / 24 h 2.1: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 3.1: triethylamine / dichloromethane / 20 °C 4.1: chiralpak IC / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: chiralcel OD / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 2.1: sodium azide / dimethyl sulfoxide / 24 h / 20 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: chiralcel OD / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 2.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(S)-(-)-2,3,4,9-tetrahydro-1H-carbazol-3-ol (1374648-14-2) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 1.2: 10 h / -25 - -15 °C 2.1: water; triphenylphosphine / 15 h / 65 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h / 20 °C 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2.1: sodium azide / dimethyl sulfoxide / 24 h / 20 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(+/-)-2,3,4,9-tetrahydro-1H-carbazol-3-ol (128432-38-2, 14384-34-0) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: Candida antarctica Lipase A / tetrahydrofuran / 5 h / 30 °C / Enzymatic reaction 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 2.2: 10 h / -25 - -15 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: Candida antarctica lipase B / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 2.2: 10 h / -25 - -15 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 6 steps 1.1: Pseudomonas cepacia lipase / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 2.2: 10 h / -25 - -15 °C 3.1: water; triphenylphosphine / 15 h / 65 °C 4.1: triethylamine / dichloromethane / 1 h / 20 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 1 h / 20 °C 6.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

4-Fluorobenzenesulfonyl chloride (349-88-2) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 1 h / 20 °C 3.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

3-azido-2,3,4,9-tetrahydro-1H-carbazole → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 2.1: triethylamine / dichloromethane / 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 20 °C 3.2: 20 °C 4.1: chiralpak IC / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 5 steps 1.1: palladium on activated charcoal; hydrogen / methanol / 2 h / 20 °C 2.1: triethylamine / dichloromethane / 20 °C 3.1: chiralpak IC / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h / 20 °C 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 5 steps 1.1: chiralcel OD / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 2.1: water; triphenylphosphine / 15 h / 65 °C 3.1: triethylamine / dichloromethane / 1 h / 20 °C 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h / 20 °C 5.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

2,3,4,9-tetrahydro-1H-carbazol-3-yl-amine (61894-99-3, 116650-33-0, 116650-34-1, 134525-54-5) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 20 °C 2.2: 20 °C 3.1: chiralpak IC / hexane; isopropyl alcohol / 40 °C / Resolution of racemate 4.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 20 °C 2.1: chiralpak IC / hexane; isopropyl alcohol / 30 °C / Resolution of racemate 3.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 3.2: 1 h / 20 °C 4.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

phenylhydrazine (100-63-0) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Candida antarctica Lipase A / tetrahydrofuran / 5 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Pseudomonas cepacia lipase / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 10 steps 1.1: magnesium sulfate / dichloromethane / 2 h / 20 °C 1.2: 4 h / 110 °C 2.1: trifluoroacetic acid / acetone / 24 h / 65 °C 3.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 4.1: Candida antarctica lipase B / tetrahydrofuran / 8 h / 30 °C / Enzymatic reaction 5.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 6.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 7.1: water; triphenylphosphine / 15 h / 65 °C 8.1: triethylamine / dichloromethane / 1 h / 20 °C 9.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 9.2: 1 h / 20 °C 10.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

(R)-4-fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)benzenesulfonamide (116650-36-3) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 1.2: 1 h / 20 °C 2.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

1,2,4,9-tetrahydrospiro[3H-carbazole-3,2*-[1,3]doxolane] (54621-12-4) → ramatroban (116649-85-5)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: trifluoroacetic acid / acetone / 24 h / 65 °C 2.1: D-glucose / water / 24 h / 30 °C / Enzymatic reaction 3.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 3.2: 10 h / -25 - -15 °C 4.1: water; triphenylphosphine / 15 h / 65 °C 5.1: triethylamine / dichloromethane / 1 h / 20 °C 6.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 6.2: 1 h / 20 °C 7.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 8 steps 1.1: trifluoroacetic acid / acetone / 24 h / 65 °C 2.1: D-glucose / water / 24 h / 30 °C / Enzymatic reaction 3.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 4.1: sodium azide / N,N-dimethyl-formamide / 24 h / 70 °C 5.1: water; triphenylphosphine / 15 h / 65 °C 6.1: triethylamine / dichloromethane / 1 h / 20 °C 7.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 7.2: 1 h / 20 °C 8.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme
Multi-step reaction with 8 steps 1.1: trifluoroacetic acid / acetone / 24 h / 65 °C 2.1: sodium tetrahydroborate / methanol / 1.5 h / 0 - 20 °C / Inert atmosphere 3.1: Candida antarctica Lipase A / tetrahydrofuran / 5 h / 30 °C / Enzymatic reaction 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 4.2: 10 h / -25 - -15 °C 5.1: water; triphenylphosphine / 15 h / 65 °C 6.1: triethylamine / dichloromethane / 1 h / 20 °C 7.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 7.2: 1 h / 20 °C 8.1: water; sodium hydroxide / isopropyl alcohol / 24 h / 100 °C View Scheme

methanol (67-56-1) + ramatroban (116649-85-5) → (R)-methyl 3-[3-(4-fluorophenylsulfonamido)-3,4-dihydro-1H-carbazol-9(2H)-yl]propanoate (141307-19-9)

Conditions	Yield
With sulfuric acid In water at 65℃; for 15h;	60%

ramatroban (116649-85-5) → (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-terahydro-9-carbazolepropanoic acid sodium salt

Conditions	Yield
With sodium hydroxide

Upstream product

• 54621-12-4 1,2,4,9-tetrahydrospiro[3H-carbazole-3,2*-[1,3]doxolane] 
• 116650-36-3 (R)-4-fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)benzenesulfonamide 
• 100-63-0 phenylhydrazine 
• 61894-99-3 2,3,4,9-tetrahydro-1H-carbazol-3-yl-amine 
• 349-88-2 4-Fluorobenzenesulfonyl chloride 
• 128432-38-2 (+/-)-2,3,4,9-tetrahydro-1H-carbazol-3-ol 
• 1374648-14-2 (S)-(-)-2,3,4,9-tetrahydro-1H-carbazol-3-ol 
• 118699-38-0 (R)-N-[9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide 
• 116650-12-5 4-fluoro-N-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)benzenesulfonamide 
• 1374648-18-6 (R)-3-azido-2,3,4,9-tetrahydro-1H-carbazole 
• 1374648-17-5 (S)-2,3,4,9-tetrahydro-1H-carbazol-3-yl methanesulfonate 
• 4746-97-8 cyclohexanedione monoethylene ketal 
• 116650-33-0 (3R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine 
• 107-13-1 acrylonitrile 

Downstream Products

• 141307-19-9 (R)-methyl 3-[3-(4-fluorophenylsulfonamido)-3,4-dihydro-1H-carbazol-9(2H)-yl]propanoate 

Relevant articles and documents

Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.