333963-40-9

Basic information

• Product Name: lubiprostone
• Synonyms: (2R,4aR,5R,7aR)-2-(1,1-Difluoropentyl)-2-hydroxy-6-oxo-3,4,4a,5,7,7a-hexahydrocyclopenta[b]pyran-5-heptanoic acid;Lubiprostone;Prostan-1-oic acid, 11,15-epoxy-16,16-difluoro-15-hydroxy-9-oxo-, (11alpha,15R)-;Spi 0211;Unii-7662kg2R6k;(2R,4aR,5R,7aR)-2-(1,1-Difluoropentyl)-2-hydroxy-6-oxo-3,4,4a,5,7,7a-hexahydrocyclopenta[b]pyran-5-h;7-((1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-3-hydroxy-5-oxocyclopentyl)heptanoic acid;AMitiza Lubiprostone
• CAS NO: 333963-40-9
• Molecular Formula: C₂₀H₃₂F₂O₅
• Molecular Weight: 390.46
• EINECS: 1312995-182-4
• Product Categories: API
• Mol File: 333963-40-9.mol
• Article Data: 16

Chemical Properties

• Boiling Point: 532.3 °C at 760 mmHg
• Flash Point: 275.7 °C
• Appearance: /
• Density: 1.175
• Vapor Pressure: 1.49E-13mmHg at 25°C
• Refractive Index: 1.486
• Storage Temp.: -20°C Freezer
• PKA: 4.77±0.10(Predicted)
• CAS DataBase Reference: lubiprostone(CAS DataBase Reference)
• NIST Chemistry Reference: lubiprostone(333963-40-9)
• EPA Substance Registry System: lubiprostone(333963-40-9)

Safety Data

• Hazardous Substances Data: 333963-40-9(Hazardous Substances Data)

Usage

Description

Lubiprostone is a bicyclic fatty acid with a unique mechanism of action that activates intestinal chloride ion channels, increasing intestinal water secretion and intestinal fluid chloride ion concentration. It is used for the treatment of chronic constipation and constipation associated with irritable bowel syndrome (IBS-C). Marketed as Amitiza by Sucampo Pharmaceuticals, Inc. and Takeda Pharmaceuticals America, Inc., it is recommended to be taken orally at a dosage of 24 μg twice a day with food. Precautions and side effects are similar to those for other prostaglandin-derived products.

Uses

Used in Pharmaceutical Industry:
Lubiprostone is used as a treatment for chronic idiopathic constipation in adults, addressing the need for novel agents to combat this condition that affects 4-5 million Americans and is often refractory to traditional therapy.
Lubiprostone is used as a treatment for constipation associated with irritable bowel syndrome (IBS-C), providing relief for patients suffering from this condition by increasing intestinal water secretion and chloride ion concentration, which helps to alleviate constipation symptoms.

Originator

Sucampo (US)

Synthesis

Synthesis of lupiprostone started with the tetrahydropyran (THP) protected (-)Corey lactone 30. Desilylation of 30 with TBAF in THF gave free carbinol in 82% yield which was oxidized with oxalyl chloride and DMSO to give corresponding crude aldehyde 31. Aldehyde 31 was condensed with dimethyl 3,3,-difluoro-2-oxoheptylphosphonate (32) in the presence of thallium ethoxide to give unsaturated difluoroketone 33 which was hydrogenated with H2 over Pd/C in ethyl acetate and the resulting ketone was subsequently reduced with sodium borohydride in methanol to give lactone 34 in excellent yield. The lactone 34 was reduced to lactol 35 with DIBAL at -78°C in toluene and the crude lactol 35 was condensed with 4-carboxybutyl triphenylphosphonium bromide (36) in the presence of t-BuOK in THF to yield compound 37. Crude 37 was reacted with benzyl bromide and DBU in dichloromethane (DCM) to give the benzyl ester in 96% yield. Oxidation of the alcohol with Collins reagent and removal of the THP protecting group under acidic conditions gave corresponding prostaglandin E2 benzyl ester 38. Finally, compound 38 was submitted to simultaneous benzyl ester group cleavage and double bond hydrogenation with H2 over Pd/C in ethyl acetate to give lubiprostone (V) in 94% yield.

InChI:InChI=1/C20H32F2O5/c1-2-3-11-19(21,22)20(26)12-10-15-14(16(23)13-17(15)27-20)8-6-4-5-7-9-18(24)25/h14-15,17,26H,2-13H2,1H3,(H,24,25)/t14-,15+,17+,20+/m0/s1

Upstream product

• 945651-35-4 benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)octahydro-2-hydroxy-6-oxocyclopenta[b]pyran-5-yl]heptanoate 
• 136790-79-9 (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-3-hydroxy-5-oxocyclopentyl]heptanoic acid-5-enbenzyl ester 
• 54996-33-7 7-(3R-hydroxy-5-oxo-cyclopent-1-enyl)heptanoic acid 
• 74106-81-3 ethyl 2,2-difluorohexanoate 

Downstream Products

• 1372609-11-4 7-((2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxo-octahydrocyclopenta[b]pyran-5-yl)heptanoate guanidinium 
• 511229-76-8 N₁-ethyl-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxoperhydrocyclopenta[b]pyran-5-yl]heptanamide 

Relevant articles and documents

METHOD OF PRODUCING LUBIPROSTONE

PROBLEM TO BE SOLVED: To provide a method allowing efficient production of lubiprostone. SOLUTION: The invention provides a compound represented by the general formula (I) in the figure, where n represents an integer from 0 to 5, and R1 are identical or different and each represent an alkyl group, aralkyl group, aryl group, halogen atom, hydroxy group, alkoxy group, trifluoromethyl group, nitro group, or amino group. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT

Process for the preparation of Lubiprostone and intermediates thereof

The present invention relates to a novel process for preparing Lubiprostone and novel intermediates prepared from the process. The process of the present invention does not generate hydrogenated by-products that are difficult to be removed, and thus enables the production of Lubiprostone in an efficient and economical way.

A process for the preparation of intermediates useful in the ruby's forefront, preparation method thereof and through its preparation ruby's forefront method

The invention relates to an intermediate for preparing lubiprostone, a preparation method of the intermediate and a method for preparing the lubiprostone through the intermediate, in particular to a compound as shown in a formula V for preparing the lubiprostone (as shown in a formula I), a preparation method of the compound and a method for preparing the lubiprostone through the compound. The method comprises the following steps: performing reduction treatment on the compound as shown in the formula V, performing selective deprotection and hydroxyl oxidation to obtain a compound as shown in a formula II, and performing hydroxyl deprotection on the compound as shown in the formula II to prepare the lubiprostone as shown in the formula I. The method is easy and convenient to operate, high in synthetic yield and suitable for large-scale production.