101692-02-8

Basic information

• Product Name: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol
• Synonyms: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol;(1R,2R,3aS,9aS)-1-((S)-3-Hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol;(1R,2R,3aS,9aS)-1-((S,E)-3-hydroxyoct-1-en-1-yl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol;Treprostinil Intermediates
• CAS NO: 101692-02-8
• Molecular Formula: C₂₁H₃₂O₃
• Molecular Weight: 332.47698
• Mol File: 101692-02-8.mol
• Article Data: 11

Chemical Properties

• Melting Point: 113-115 °C
• Boiling Point: 506.1±50.0 °C(Predicted)
• Appearance: /
• Density: 1.106±0.06 g/cm3(Predicted)
• PKA: 10.34±0.60(Predicted)
• CAS DataBase Reference: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol(CAS DataBase Reference)
• NIST Chemistry Reference: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol(101692-02-8)
• EPA Substance Registry System: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol(101692-02-8)

Safety Data

• Hazardous Substances Data: 101692-02-8(Hazardous Substances Data)

Usage

Description

(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol is a complex organic compound with a unique molecular structure. It is characterized by its hexahydro-1H-benz[f]indene core, which is adorned with various hydroxyl and octyl groups. This molecule exhibits specific stereochemistry, with the R and S configurations at different carbon positions, which may influence its biological activity and interactions.

Uses

Used in Pharmaceutical Industry:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol is used as an active pharmaceutical ingredient for the treatment of pulmonary arterial hypertension (PAH). It serves as a synthetic analog of Prostacyclin, a naturally occurring compound with potent vasodilatory and antihypertensive properties. The compound is marketed under the trade name Remodulin, providing a therapeutic option for patients suffering from PAH.
Used in Chemical Synthesis:
In the field of chemical synthesis, (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol can be utilized as a key intermediate or building block for the development of novel compounds with potential applications in various industries, such as pharmaceuticals, agrochemicals, and materials science. Its unique structural features may offer new opportunities for the design of innovative molecules with improved properties and functionalities.
Used in Research and Development:
As a complex organic molecule with specific stereochemistry, (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol can be employed in research and development efforts to study its biological activities, interactions with biological targets, and potential applications in drug discovery. Understanding its properties and behavior can contribute to the advancement of scientific knowledge and the development of new therapeutic strategies.
Used in Drug Delivery Systems:
Similar to gallotannin, (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]indene-2,5-diol may also benefit from novel drug delivery systems to enhance its bioavailability, delivery, and therapeutic outcomes. The development of carriers, such as organic and metallic nanoparticles, could improve the compound's efficacy and applicability in various medical conditions, including pulmonary arterial hypertension and other potential indications.

Synthetic route

(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol (101692-01-7) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With aluminum (III) chloride; 1-dodecylthiol In dichloromethane at 0 - 20℃; Inert atmosphere;	95%
With n-butyllithium; diphenylphosphane In tetrahydrofuran; hexane for 20h; Heating;	80%
With n-butyllithium; diphenylphosphane In tetrahydrofuran; hexane for 19h; Reflux;	8.3 g

(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate (1425937-56-9) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 1h;	85%
With methanol; sodium hydroxide at 20℃; for 1h;	85%

(1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-ol (1613271-23-0) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20 - 50℃; for 25.5h; Reagent/catalyst; Temperature; Inert atmosphere;	77%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20 - 50℃; for 25.5h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	77%

(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((3S,1E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate (1425937-55-8) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 28h;	73%
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 28h;	73%
Multi-step reaction with 2 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 5 h / 20 °C 2: sodium hydroxide / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 5 h / 20 °C 2: sodium hydroxide; methanol / 1 h / 20 °C View Scheme

(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-((3S,1E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalene-2,5-diol (1257983-83-7) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; potassium hydroxide In methanol at 20℃;	72%
With 5%-palladium/activated carbon; hydrogen; potassium hydroxide In methanol at 20℃;	72%

C21H29ClO3 → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; triethylamine In methanol for 15h;	65%

3-methoxybenzyl alcohol (6971-51-3) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 13 steps 1: 94 percent / imidazole / CH2Cl2 2: n-BuLi / hexane / 24 h / 0 - 20 °C 3: 4695 g / TBAF / tetrahydrofuran / 20 °C 4: (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - 20 °C 5: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 6: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 7: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 8: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 9: CH2Cl2 / 2 h / 20 °C 10: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 11: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 12: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 13: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(2-allyl-3-methoxyphenyl)methanol (136911-16-5) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 10 steps 1: (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - 20 °C 2: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 3: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 4: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 5: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 6: CH2Cl2 / 2 h / 20 °C 7: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 8: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 9: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 10: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

3-methoxy-O-tert-butyldimethylsilylbenzyl alcohol (153974-48-2) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 12 steps 1: n-BuLi / hexane / 24 h / 0 - 20 °C 2: 4695 g / TBAF / tetrahydrofuran / 20 °C 3: (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - 20 °C 4: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 5: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 6: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 7: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 8: CH2Cl2 / 2 h / 20 °C 9: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 10: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 11: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 12: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(S)-1-chloroheptane-2-ol (81007-64-9) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 12 steps 1: TsOH*pyridine / CH2Cl2 / 15 h / 20 °C 2: BuLi / tetrahydrofuran; hexane / 15 h / 0 - 20 °C 3: NaOH / ethanol / 20 h / 20 °C 4: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 5: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 6: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 7: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 8: CH2Cl2 / 2 h / 20 °C 9: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 10: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 11: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 12: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

2-allyl-3-methoxybenzaldehyde (94956-98-6) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 9 steps 1: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 2: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 3: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 4: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 5: CH2Cl2 / 2 h / 20 °C 6: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 7: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 8: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 9: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

2-allyl-3-methoxy-O-tert-butyldimethylsilylbenzyl alcohol (223734-55-2) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 11 steps 1: 4695 g / TBAF / tetrahydrofuran / 20 °C 2: (COCl)2; DMSO; Et3N / CH2Cl2 / -78 - 20 °C 3: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 4: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 5: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 6: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 7: CH2Cl2 / 2 h / 20 °C 8: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 9: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 10: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 11: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(S)-1-chloro-O-tetrahydropyran-2-yl-heptan-2-ol (678992-51-3) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 11 steps 1: BuLi / tetrahydrofuran; hexane / 15 h / 0 - 20 °C 2: NaOH / ethanol / 20 h / 20 °C 3: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 4: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 5: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 6: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 7: CH2Cl2 / 2 h / 20 °C 8: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 9: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 10: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 11: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

2-[[(1S)-1-(3-butynyl)hexyl]oxy]tetrahydro-2H-pyran (223734-62-1) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 9 steps 1: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 2: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 3: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 4: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 5: CH2Cl2 / 2 h / 20 °C 6: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 7: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 8: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 9: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

1-(trimethylsilyl)-O-tetrahydropyran-2-yl-1-decyn-5-(S)-ol (678992-52-4) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 10 steps 1: NaOH / ethanol / 20 h / 20 °C 2: 92 percent / EtMgBr / tetrahydrofuran; diethyl ether / 0 - 20 °C 3: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 4: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 5: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 6: CH2Cl2 / 2 h / 20 °C 7: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 8: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 9: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 10: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(6S)-1-[3-methoxy-2-(2-propenyl)phenyl]-6-[(tetrahydro-2H-pyran-2-yl)oxy]-2-undecyn-1-one (223734-57-4) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 7 steps 1: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 2: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 3: CH2Cl2 / 2 h / 20 °C 4: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 5: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 6: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 7: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

3-methoxy-2-(2-propenyl)-α-[(5S)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-decynyl]benzenemethanol (223734-56-3) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 8 steps 1: 75 percent / PCC / CH2Cl2 / 15 h / 0 - 20 °C 2: BH3; Me2S; (R)-methyloxazaborolidine / toluene; tetrahydrofuran / 1 h / -30 °C 3: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 4: CH2Cl2 / 2 h / 20 °C 5: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 6: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 7: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 8: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(αS)-3-methoxy-2-(2-propenyl)-α-[(5S)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-decynyl]benzenemethanol (223734-58-5) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 92 percent / imidazole; 4-(dimethylamino)pyridine / dimethylformamide; CH2Cl2 / 15 h / 20 °C 2: CH2Cl2 / 2 h / 20 °C 3: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 4: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 5: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 6: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

1,3,3a,4,9,9a-hexahydro-5-methoxy-1-[(3S)-3-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-benz[f]inden-2-one (223734-61-0) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 2: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 3: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-5-methoxy-1-[(3S)-3-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-1H-benz[f]inden-2-ol (101758-87-6) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 2: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(1,1-dimethylethyl)[[(1S,6S)-1-[3-methoxy-2-(2-propenyl)phenyl]-6-[(tetrahydro-2H-pyran-2-yl)oxy]-2-undecynyl]oxy]dimethylsilane (223734-59-6) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: CH2Cl2 / 2 h / 20 °C 2: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 3: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 4: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 5: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

(3aS,9aS)-9-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3a,4,9-tetrahydro-5-methoxy-1-[(3S)-3-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-benz[f]inden-2-one (223734-60-9) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2; K2CO3 / Pd/C / ethanol / 20 °C / 4654.33 Torr 2: NaBH4; aq. NaOH / ethanol / 6 h / -10 °C 3: 2162 g / TsOH / methanol / 15 h / 0 - 20 °C 4: 80 percent / Ph2PH; n-BuLi / tetrahydrofuran; hexane / 20 h / Heating View Scheme

3-allyloxy-benzaldehyde (40359-32-8) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 10 steps 1: decalin / 7 h / 217 °C / Inert atmosphere 2: potassium carbonate; sodium iodide / acetone / 4 h / Reflux 3: n-butyllithium / hexane; tetrahydrofuran / Cooling 4: pyridinium chlorochromate / dichloromethane / 20 °C 5: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene; tetrahydrofuran / -30 - -25 °C 6: 1H-imidazole / dichloromethane / 20 °C 7: dichloromethane / 20 °C / Inert atmosphere 8: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 9: sodium hydroxide; water; sodium tetrahydroborate / ethanol 10: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme
Multi-step reaction with 8 steps 1: decalin / 7 h / 217 °C / Inert atmosphere 2: sodium iodide; potassium carbonate / acetone / 4 h / Reflux 3: n-butyllithium / hexane; tetrahydrofuran 4: 1H-imidazole / dichloromethane / 20 °C 5: dicobalt octacarbonyl / dichloromethane; acetonitrile / 20 °C / Inert atmosphere 6: palladium 10% on activated carbon; potassium carbonate; hydrogen / ethanol / 20 °C 7: water; sodium tetrahydroborate; sodium hydroxide / ethanol 8: palladium 10% on activated carbon; hydrogen / acetic acid View Scheme

meta-hydroxybenzaldehyde (100-83-4) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 11 steps 1: potassium carbonate; sodium iodide / ethanol / 3 h / Reflux 2: decalin / 7 h / 217 °C / Inert atmosphere 3: potassium carbonate; sodium iodide / acetone / 4 h / Reflux 4: n-butyllithium / hexane; tetrahydrofuran / Cooling 5: pyridinium chlorochromate / dichloromethane / 20 °C 6: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene; tetrahydrofuran / -30 - -25 °C 7: 1H-imidazole / dichloromethane / 20 °C 8: dichloromethane / 20 °C / Inert atmosphere 9: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 10: sodium hydroxide; water; sodium tetrahydroborate / ethanol 11: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme
Multi-step reaction with 9 steps 1: sodium iodide; potassium carbonate / ethanol / 3 h / Reflux 2: decalin / 7 h / 217 °C / Inert atmosphere 3: sodium iodide; potassium carbonate / acetone / 4 h / Reflux 4: n-butyllithium / hexane; tetrahydrofuran 5: 1H-imidazole / dichloromethane / 20 °C 6: dicobalt octacarbonyl / dichloromethane; acetonitrile / 20 °C / Inert atmosphere 7: palladium 10% on activated carbon; potassium carbonate; hydrogen / ethanol / 20 °C 8: water; sodium tetrahydroborate; sodium hydroxide / ethanol 9: palladium 10% on activated carbon; hydrogen / acetic acid View Scheme

2-allyl-3-hydroxy-benzaldehyde (79950-42-8) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 9 steps 1: potassium carbonate; sodium iodide / acetone / 4 h / Reflux 2: n-butyllithium / hexane; tetrahydrofuran / Cooling 3: pyridinium chlorochromate / dichloromethane / 20 °C 4: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene; tetrahydrofuran / -30 - -25 °C 5: 1H-imidazole / dichloromethane / 20 °C 6: dichloromethane / 20 °C / Inert atmosphere 7: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 8: sodium hydroxide; water; sodium tetrahydroborate / ethanol 9: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme
Multi-step reaction with 7 steps 1: sodium iodide; potassium carbonate / acetone / 4 h / Reflux 2: n-butyllithium / hexane; tetrahydrofuran 3: 1H-imidazole / dichloromethane / 20 °C 4: dicobalt octacarbonyl / dichloromethane; acetonitrile / 20 °C / Inert atmosphere 5: palladium 10% on activated carbon; potassium carbonate; hydrogen / ethanol / 20 °C 6: water; sodium tetrahydroborate; sodium hydroxide / ethanol 7: palladium 10% on activated carbon; hydrogen / acetic acid View Scheme

(S)-1-[2-allyl-3-(4-methoxybenzyloxy)phenyl]-6-benzyloxyundec-2-yn-1-ol (1355990-13-4) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 7 steps 1: pyridinium chlorochromate / dichloromethane / 20 °C 2: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene; tetrahydrofuran / -30 - -25 °C 3: 1H-imidazole / dichloromethane / 20 °C 4: dichloromethane / 20 °C / Inert atmosphere 5: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 6: sodium hydroxide; water; sodium tetrahydroborate / ethanol 7: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme
Multi-step reaction with 5 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: dicobalt octacarbonyl / dichloromethane; acetonitrile / 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; potassium carbonate; hydrogen / ethanol / 20 °C 4: water; sodium tetrahydroborate; sodium hydroxide / ethanol 5: palladium 10% on activated carbon; hydrogen / acetic acid View Scheme

(S)-1-[2-allyl-3-(4-methoxybenzyloxy)phenyl]-6-benzyloxyundec-2-yn-1-one (1355990-15-6) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene; tetrahydrofuran / -30 - -25 °C 2: 1H-imidazole / dichloromethane / 20 °C 3: dichloromethane / 20 °C / Inert atmosphere 4: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 5: sodium hydroxide; water; sodium tetrahydroborate / ethanol 6: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme

(1R,6S)-1-[-2-allyl-3-(4-methoxybenzyloxy)phenyl]-6-benzyloxyundec-2-yn-1-ol (1355990-17-8) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1H-imidazole / dichloromethane / 20 °C 2: dichloromethane / 20 °C / Inert atmosphere 3: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 4: sodium hydroxide; water; sodium tetrahydroborate / ethanol 5: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme

{(1R,6S)-1-[-2-allyl-3-(4-methoxybenzyloxy)phenyl]-6-benzyloxyundec-2-ynyloxy}-tert-butyl-dimethyl-silane (1355990-19-0) → (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: dichloromethane / 20 °C / Inert atmosphere 2: potassium carbonate; hydrogen / palladium 10% on activated carbon / ethanol / 20 °C 3: sodium hydroxide; water; sodium tetrahydroborate / ethanol 4: hydrogen / palladium 10% on activated carbon / acetic acid View Scheme

chloroacetonitrile (107-14-2) + (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → 2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((3S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetonitrile (101692-03-9)

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In acetone for 8h; Heating;	100%
With tetrabutylammomium bromide; potassium carbonate In acetone at 70℃; for 14h; Inert atmosphere;	99%
With tetrabutylammomium bromide; potassium carbonate In acetone at 30℃;	82%

(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) + Benzyl bromoacetate (5437-45-6) → treprostinil benzyl ester

Conditions	Yield
With potassium carbonate In acetone at 20℃; for 72h; Inert atmosphere;	99%
With potassium carbonate In acetone at 20℃;	96.7%
With potassium carbonate In acetone at 20℃; for 32h; Large scale;	94.5%

ethyl bromoacetate (105-36-2) + (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → 2-((1R,2R,3aS,9aS)-2-hydroxy-1-(S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxylacetic acid ethyl ester (1355990-07-6)

Conditions	Yield
With potassium carbonate; potassium iodide In acetone for 16h; Inert atmosphere; Reflux;	96%
With potassium carbonate; potassium iodide In acetone for 16h; Inert atmosphere; Reflux;	96%
With potassium carbonate In acetone at 30 - 35℃;	95%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In ethanol at 20℃; Reflux;

2-bromoacetic acid-2-[2-(2-methoxyethoxy)ethoxy]ethyl ester (56521-80-3) + (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → C30H48O8

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone at 58℃; for 5h;	82%

bromoacetic acid methyl ester (96-32-2) + (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → 2-((1R,2R,3aS,9aS)-2-hydroxy-1-(S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxylacetic acid methyl ester (81845-98-9)

Conditions	Yield
With potassium carbonate In acetone at 50 - 60℃;	74.8%
With potassium carbonate In acetone at 50 - 60℃;	74.8%
With potassium carbonate In acetone for 6.5h; Reflux;
With potassium carbonate In acetone for 6.5h; Reflux;
With potassium carbonate In acetone for 6.5h; Reflux;

tetra-(n-butyl)ammonium iodide (311-28-4) + ethyl bromoacetate (105-36-2) + (1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → 2-((1R,2R,3aS,9aS)-2-hydroxy-1-(S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxylacetic acid ethyl ester (1355990-07-6)

Conditions	Yield
Stage #1: ethyl bromoacetate; (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalene-2,5-diol With potassium carbonate In ethanol at 20℃; Stage #2: tetra-(n-butyl)ammonium iodide In ethanol Reflux;	68%

(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) + N-(bromoacetyl)methanesulfonamide (59504-75-5) → C24H37NO6S

Conditions	Yield
Stage #1: (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalene-2,5-diol With sodium hydride In hexane; N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: N-(bromoacetyl)methanesulfonamide With sodium hydride In hexane; N,N-dimethyl-formamide; mineral oil	20%

(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol (101692-02-8) → treprostinil (81846-19-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / K2CO3; tetrabutylammonium bromide / acetone / 8 h / Heating 2: 83 percent / aq. KOH / methanol / 3 h / Heating View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate; tetra-(n-butyl)ammonium iodide / ethanol / 20 °C / Reflux 2: sodium hydroxide / ethanol; water View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 6.5 h / Reflux 2.1: potassium hydroxide; water / methanol / 2 h / Reflux 2.2: pH 1 - 2 View Scheme

Upstream product

• 101692-01-7 (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol 
• 6971-51-3 3-methoxybenzyl alcohol 
• 136911-16-5 (2-allyl-3-methoxyphenyl)methanol 
• 153974-48-2 3-methoxy-O-tert-butyldimethylsilylbenzyl alcohol 
• 81007-64-9 (S)-1-chloroheptane-2-ol 
• 94956-98-6 2-allyl-3-methoxybenzaldehyde 
• 223734-55-2 2-allyl-3-methoxy-O-tert-butyldimethylsilylbenzyl alcohol 
• 678992-51-3 (S)-1-chloro-O-tetrahydropyran-2-yl-heptan-2-ol 
• 223734-62-1 2-[[(1S)-1-(3-butynyl)hexyl]oxy]tetrahydro-2H-pyran 
• 678992-52-4 1-(trimethylsilyl)-O-tetrahydropyran-2-yl-1-decyn-5-(S)-ol 
• 223734-57-4 (6S)-1-[3-methoxy-2-(2-propenyl)phenyl]-6-[(tetrahydro-2H-pyran-2-yl)oxy]-2-undecyn-1-one 
• 223734-56-3 3-methoxy-2-(2-propenyl)-α-[(5S)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-decynyl]benzenemethanol 
• 223734-58-5 (αS)-3-methoxy-2-(2-propenyl)-α-[(5S)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-decynyl]benzenemethanol 
• 223734-61-0 1,3,3a,4,9,9a-hexahydro-5-methoxy-1-[(3S)-3-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-benz[f]inden-2-one 

Downstream Products

• 81846-19-7 treprostinil 
• 1355990-07-6 2-((1R,2R,3aS,9aS)-2-hydroxy-1-(S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxylacetic acid ethyl ester 
• 81845-98-9 2-((1R,2R,3aS,9aS)-2-hydroxy-1-(S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxylacetic acid methyl ester 
• 1422975-14-1 C₃₇H₅₇NO₇S 

Relevant articles and documents

Process for Preparing Treprostinil and Intermediate Therefor

The present invention relates to a synthesis method of high-purity treprostinil, and an intermediate for the same. According to the synthesis method of the present invention, high-purity treprostinil can be synthesized in an economical and efficient manner by using intramolecular Friedel-Crafts allylic alkylation. Accordingly, the synthesis method of the present invention may be effectively used for commercial mass-production of treprostinil.COPYRIGHT KIPO 2017

NOVEL INTERMEDIATE FOR SYNTHESIZING TREPROSTINIL DIETHANOLAMINE AND METHOD FOR PREPARING THE SAME

The present invention relates to a method for treprostinil diethanolamine synthesis. The present invention also relates to a novel intermediate used in the method for treprostinil diethanolamine synthesis. The novel intermediate is shown in the following formula (II): wherein R1 and R2 are described in the description.

AMINE SALTS OF A PROSTACYCLIN ANALOG

The present invention provides amine salts of the prostacyclin analogue of Formula I and processes for generating these amine salts.