Butyne diol derivatives

Bolli etaU US Patent 6,720,322 (April 13, 2004) Assignee Actelion Pharmaceuticals Ltd. 

Utility Endothelin Receptor Antagonists in Treating Hypertension 

4-t-Butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl] benzene sulfonamide 

To a solution of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (6g) dissolved in 100 ml THF was added 4-t-butyl benzene sulfonamide potassium salt at ambient temperature and the mixture stirred overnight. The reaction mixture was then poured into 150 ml of water and diethyl ether and the pH adjusted to 5 by the addition of HO Ac. Thereupon a precipitate formed and the product isolated by filtration as a beige crystal. MS data supplied. 

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The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

Ethynylation. Condensation of acetylene with a reagent such as aldehyde to yield an acetylenic derivative. The best example is the union of formaldehyde and acetylene to produce butyne-diol, H0-CH2.C C.CH2.0H Ref CondChemDict (1961), 478-R 8th edit (1971), 375-R... 

Butyne-l,4-diol derivatives undergo dicarbonylation of different types. A simple synthetic method of bis(methylene)succinate 78 is the carbonylation of the dicarbonate of but-2-yne-l,4-diol (77) at 50°C [20]. 

Alkyne derivatives such as 1,4-butyne diol denoted as golpanol (Fig. 15) and its ethoxylated derivatives were introduced as an alternative polar ligand... 

Prepared by heating ammonium mucate, or from butyne-l,4-diol and ammonia in the presence of an alumina catalyst. The pyrrole molecule is aromatic in character. It is not basic and the imino-hydrogen atom can be replaced by potassium. Many pyrrole derivatives occur naturally, e.g. proline, indican, haem and chlorophyll. 

The carbonylation of 2-methyl-3-butyn-2-oI (50) in benzene gives teraconic anhydride (51). Fulgide (53) (a dimethylenesuccinic anhydride derivative), which is a photochromic compound, can be prepared by the carbonylation of 2,5-dimethyl-3-hexyne-2,5-diol (52)[21], The reaction proceeds under milder conditions when PdlOAc) is used as a catalyst in the presence of iodine [23],... 

The principal chemicals based on Reppe chemistry today are propargyl alcohol and butyn-l,4-diol and derivatives such as 2-pyrrohdinone, Ai-vinyl-2-pyrrohdinone, polyvinylpyrroHdinone, vinyl ethers, and tetrahydrofuran (33). 

Ethynylation. Base-catalyzed addition of acetylene to carbonyl compounds to form -yn-ols and -yn-glycols (see Acetylene-DERIVED chemicals) is a general and versatile reaction for the production of many commercially useful products. Finely divided KOH can be used in organic solvents or Hquid ammonia. The latter system is widely used for the production of pharmaceuticals and perfumes. The primary commercial appHcation of ethynylation is in the production of 2-butyne-l,4-diol from acetylene and formaldehyde using supported copper acetyHde as catalyst in an aqueous Hquid-fiHed system. 

Acetylene is condensed with carbonyl compounds to give a wide variety of products, some of which are the substrates for the preparation of families of derivatives. The most commercially significant reaction is the condensation of acetylene with formaldehyde. The reaction does not proceed well with base catalysis which works well with other carbonyl compounds and it was discovered by Reppe (33) that acetylene under pressure (304 kPa (3 atm), or above) reacts smoothly with formaldehyde at 100°C in the presence of a copper acetyUde complex catalyst. The reaction can be controlled to give either propargyl alcohol or butynediol (see Acetylene-DERIVED chemicals). 2-Butyne-l,4-diol, its hydroxyethyl ethers, and propargyl alcohol are used as corrosion inhibitors. 2,3-Dibromo-2-butene-l,4-diol is used as a flame retardant in polyurethane and other polymer systems (see Bromine compounds Elame retardants). 

Diol Components. Ethylene glycol (ethane 1,2-diol) is made from ethylene by direct air oxidation to ethylene oxide and ring opening with water to give 1,2-diol (40) (see Glycols). Butane-1,4-diol is stiU made by the Reppe process acetylene reacts with formaldehyde in the presence of catalyst to give 2-butyne-l,4-diol which is hydrogenated to butanediol (see Acetylene-DERIVED chemicals). The ethynylation step depends on a special cuprous... 

In contrast, synthesis of 3,4-diphosphorylthiophenes requires more elaboration because of low reactivity of 3,4-positions of thiophene and unavailability of 3,4-dihalo or dimetallated thiophenes. Minami et al. synthesized 3,4-diphosphoryl thiophenes 16 as shown in Scheme 24 [46], Bis(phosphoryl)butadiene 17 was synthesized from 2-butyne-l,4-diol. Double addition of sodium sulfide to 17 gave tetrahydrothiophene 18. Oxidation of 18 to the corresponding sulfoxide 19 followed by dehydration gave dihydrothiophene 20. Final oxidation of 20 afforded 3,4-diphosphorylthiophene 16. 3,4-Diphosphorylthiophene derivative 21 was also synthesized by Pd catalyzed phosphorylation of 2,5-disubstituted-3,4-dihalothiophene and converted to diphosphine ligand for Rh catalysts for asymmetric hydrogenation (Scheme 25) [47],... 

Methyl 4-chloro-2-butynoate has been prepared in 54% yield by treatment of 4-chloro-2-butynoic acid with 10% sulfuric acid in methanol. 4-Chloro-2-butynoic (chlorotetrolic) acid has been prepared in 40% yield by chromic acid oxidation of 4-chloro-2-butyn-l-ol (the latter obtained 1n 45% yield by the reaction of 2-butyne-l, 4-diol with thlonyl chloride) or in 85% yield by treatment of the lithium derivative of propargyl chloride with carbon... 

In the reaction of dienol silyl ether derived from butyn-l,4-diol, conjugated dienol silyl ether 22 was obtained as a 1 1 mixture of (Z,Z) and (Z, ) stereo isomers. The... 

Derivation Reaction of 2-butyne-l,4-diol with water, followed by reduction. 

Reppe process. Any of several processes involving reaction of acetylene (1) with formaldehyde to produce 2-butyne-l,4-diol which can be converted to butadiene (2) with formaldehyde under different conditions to produce propargyl alcohol and, from this, allyl alcohol (3) with hydrogen cyanide to yield acrylonitrile (4) with alcohols to give vinyl ethers (5) with amines or phenols to give vinyl derivatives (6) with carbon monoxide and alcohols to give esters of acrylic acid (7) by polymerization to produce cyclooctatetraene and (8) with phenols to make resins. The use of catalysts, pressures up to 30 atm, and special techniques to avoid or contain explosions are important factors in these processes. 

Three important processes have evolved from Reppe s work. Vinylation, the formation of vinyl derivatives by reaction of such compounds as acids, glycols, and alcohols with acetylene, produces the important vinyl esters and vinyl ethers. Ethinylation is defined as the reaction of acetylene with the carbon atom of a reactant without loss of the triple bond. A major application of the ethinylation reaction is to aldehydes and ketones to give alkynols and alkyndiols—e.g., the reaction of acetylene with formaldehyde to give propargyl alcohol and butyn-2-diol-l,4. Carboxylation (also referred to as carbonylation), the reaction of acetylene with carbon monoxide in the presence of metal carbonyls, has been applied to the production of acrylic acid, acrylates, and hydroquinone. 

The reagent has also been used for the synthesis of acetylenic diols.4 Thus 3-methyl-l-butyne-3-ol (6) is heated with two moles of the reagent to form the dilithio derivative. Cyclohexanone is added and the diol (7) is obtained in 60% yield. The reaction can also be carried out with acetylene and two different ketones. 

The titanium reagents add to aldehydes to give anti vicinal diols. For example, the allenyltitanium reagent generated from 1-alkyl-1-butyne derivatives gives anti 3-alkynic alcohols with high dia-stereoselectivities (Scheme 31). This method has been applied in a stereocontrolled synthesis of ( )-asperlin and related compounds (Scheme 32). °... 

Aerial oxidation of acetylene derivatives to diacetylenes in the presence of copper salts is a method that is also often used. As an example, passing air for 6.5 h through an aqueous-alcoholic solution of 3-butyn-2-ol containing copper(i) chloride, ammonium chloride, and hydrogen chloride gives a very good yield of the mixed stereoisomers of 3,5-octadiyne-2,7-diol 296... 

The compounds are generally not active. The most active polymer is derived from 2-butyne-l,4-diol, whose synthesis was recently reported. It forms fibers on mechanical agitation so might be a candidate as a combination fiber-bacterialcide for use in composites. 

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