Patent Application: US-201514821595-A

Abstract:
the invention describes methods and systems for making particular organic compounds from unsaturated fatty acids derived from biological materials . particular embodiments describe synthesizing civetone and olefins from a mixture of palmitoleic and oleic unsaturated fatty acid esters . the inventive methods use reaction steps such as metathesis , cyclization , hydrolysis , and / or decarboxylation .

Description:
in some preferred embodiments , a mixture comprising palmitoleic acid ( c16 : 1 ) and oleic acid ( c18 : 1 ) is used as a precursor for synthesis of civetone . preferably , the mixture of palmitoleic acid and oleic acid is obtained by transesterification of an omega - 7 rich oil followed by molecular distillation and is termed “ the omega - 7 rich fraction ”. a fraction of fatty acids that can be obtained from biomaterials such as algae or plants is a mixture of ethyl esters palmitoleic acid ( c16 : 1 ) and oleic acid ( c18 : 1 ). the metathesis of this composition will produce a unique mixture of products , not available through prior art methods . referring to fig6 , the omega 7 fraction self - metathesis of the palmitoleic acid ester ( a ) will yield olefin ( d ), and diethyl ester ( f ) as products . the products will also include self - metathesis products of the oleic acid esters ( b ), which are olefin ( e ) and diethyl ester ( f ). the omega 7 fraction will also undergo a cross metathesis reaction between the palmitoleic acid ester ( a ) and the oleic acid ester ( b ) to give olefin ( c ), a product not available through prior art methods , and diethyl ester ( f ). the palmitoleic acid of the omega - 7 rich fraction is derived from sources such as sea buckthorn and macadamia oil , but not palm oil . therefore the olefin metathesis reaction of the omega - 7 rich oil will give unique products which are not obtainable by the prior art methods comprising olefin metathesis of ethyl oleate obtained from palm oil , as shown in fig7 . the diethyl ester ( product f in fig6 ) produced from the metathesis stage can be cyclized using dieckmann condensation or its variant . the cyclized compound can be hydrolyzed and decarboxylated to form civetone . ethenolysis comprises a cross - metathesis reaction involving ethene . according to some preferred embodiments of the invention , a mixture of ethyl esters of palmitoleic acid ( c16 : 1 ) and oleic acid ( c18 : 1 ) are subjected to conditions of ethenolysis to yield a mixture of α - olefins ( 1 - octene and 1 - decene ) and methyl 9 - decenoate . see fig8 . the 1 - octene is a product unique to ethenolysis of palmitoleic acid ( c16 : 1 ). in the inventive method , ethyl 9 - decenoate and 1 - decene will also form from the mixture of palmitoleic and oleic acid ethyl esters . prior art methods using oleic acid esters ( methyl oleate ) as the starting material only produce methyl 9 - decenoate and 1 - decene . the ethyl 9 - decanoate ( see above ) can be subjected to a claisen condensation . the product of the condensation stage can be subjected to an intramolecular metathesis reaction to produce ethane gas and a macrocyclic compound , such as 2 - ethoxycarbonyl - 9 - cycloheptadecenone . the ethene gas can be recycled to the ethenolysis step for use in the ethenolysis reaction . the macrocyclic beta - ketoester compound can be hydrolyzed and decarboxylated to form civetone . the 2 nd generation ruthenium catalyst ( imesh 2 )( pcy 3 )( cl ) 2 ru = chph where imesh 2 is 1 , 3 - dimesityl - 4 , 5 - di - hydroimidazol - 2 - ylidene with its bulky n - heterocyclic carbine ( nhc ) ligand ( dinger & amp ; mol , 2002 ) is known to perform with high turnover numbers and gives the product with high selectivity and can be an ideal catalyst for metathesis of omega - 7 fraction . the reaction will be carried out in inert atmosphere at about 55 ° c . the products diethyl 9 - octadecenedioate and mixture of olefins formed in this reaction will be purified by silica - gel chromatography . see fig1 . in oleochemistry , olefin metathesis is well known and it includes self - metathesis ( sm ), cross - metathesis ( cm ), ring closing metathesis ( rcm ), ring - opening metathesis ( rom ) and rom polymerization ( romp ) as well as acyclic diene metathesis polymerization ( admet ) reactions . a variety of catalytic systems can be utilized for metathesis of omega - 7 fraction to achieve selectivity and high turnover numbers , such as : wcl 6 / heterogeneous re 2 o 7 / a 12o3 heterogeneous re 2 o 7 / sio 2 . al 2 o 3 / snbu 4 w ( o - 2 , 6 - c 6 h 3 x 2 ) 2cl 4 ( x ═ cl , ph ) precatalysts promoted with me 4 sn b 2 o 3 . re 2 o 7 / al 2 o 3 . sio 2 / snbu 4 wcl 6 and wocl 4 , as primary catalysts and snme 4 , pbme 4 , cp 2 time 2 , and cp 2 zrme 2 , as cocatalysts , ruthenium based catalysts ( grubb &# 39 ; s catalyst first , second generation and hoveyda - grubbs catalyst ). table 1 illustrates examples of catalysts which can be used to perform metathesis of the omega - 7 fraction ( mol , 2002 ). ti - dieckmann ( intramolecular ti - claisen ) condensation ( hamasaki et al ., 2000 ; tanabe , makita , funakoshi , hamasaki , & amp ; kawakusu , 2002a ; “ u . s . pat . no . 6 , 861 , 551 . pdf ,” n . d .) ( ticl 4 / amine ) will be used to cyclize diethyl 9 - octadecenedioate . the reaction will be carried out at around 0 - 5 ° c . for about 1 hour to give the cyclized product 2 - ethoxycarbonyl - 9 - cycloheptadecenone which can be purified by silica - gel chromatography . the same macro cyclization ( dieckmann condensation ) can be carried out in different conditions : kh or nah ( metal hydrides ) under inert conditions . tio 2 doped with alkali or alkaline earth metal oxides ( na 2 o or k 2 o ) in gaseous phase reaction . zrcl 4 / bu 3 n similar to ti - dieckmann condensation . 2 - ethoxycarbonyl - 9 - cycloheptadecenone will be refluxed with about 10 % naoh in methanol for about 1 hour to give civetone . after completion of the reaction , the reaction mixture will be neutralized using about 10 % sulfuric acid . the product will be extracted using ether and can be purified using silica - gel chromatography . ethenolysis of the omega - 7 fraction will be carried out under inert atmosphere with ethylene under conditions of about 150 psi pressure and about 40 ° c . ( thomas et al ., 2011 ). n - aryl , n - alkyl n - heterocyclic carbene ( nhc ) ruthenium metathesis catalysts are highly selective toward the ethenolysis of methyl oleate . the catalysts shown in fig1 , ( a ) and ( b ), give more kinetic selectivity when catalyst loading was 2500 ppm due to their sterically demanding ligands . catalyst a - 88 % selectivity with 78 % yield while catalyst b with 88 % selectivity and 77 % yield . the products will be separated using silica gel chromatography . similar to the invention embodiment 1 example , a metathesis reaction can be performed by selecting a catalyst from a variety of metathesis catalysts ( table 1 ). ti - claisen condensation ( hamasaki et al ., 2000 ) will be performed by adding ticl4 to mixture of bu 3 n and ethyl decenoate at around 0 - 5 ° c . the reaction mixture will be stirred for approximately 1 hour and then will be quenched by the addition of water . the product β - ketoester will be extracted using ether and will be purified by silica - gel chromatography . the intramolecular metathesis reaction will be similar to the invention embodiment 1 example metathesis reaction of an omega - 7 fraction . the metathesis reaction can be carried out with a selected catalyst as described above . the hydrolysis and decarboxylation will be carried out as described above . potential products from invention methods of synthesizing civetone relevant to perfume industry ( macrocyclic ketone ): the invention methods disclosed above for synthesizing civetone will give geometrical isomers of the final product which are cis - civetone and trans - civetone . invention embodiment 1 cyclization mediated ti - dieckmann conditions ( tanabe , makita , funakoshi , hamasaki , & amp ; kawakusu , 2002a ) will predominately give z - isomer of civetone with approximately 50 % yield . invention embodiment 2 intramolecular metathesis will give a mixture of e : z ( 3 : 1 ) isomers of civetone with 90 % yield ( hamasaki et al ., 2000 ). ti - dieckmann cyclization conditions may lead to the formation of 34 - membered macrocyclic ketones , which have potential uses in the perfume industry . the 34 - membered macrocycle can be formed using ticl 4 - et 3 n , with approximately 14 % yield ( tanabe , makita , funakoshi , hamasaki , & amp ; kawakusu , 2002b ). dihydrocivetone ( cycloheptadecanone ) is another macrocyclic ketone with musk fragrance and can be synthesized by hydrogenation of the final product ( civetone ) or by hydrogenation of diethyl 9 - octadecenedioate followed by cyclization . in 2011 international flavors & amp ; fragrances inc . introduced a new class of chemical entities cyclopropanated macrocycles ( see u . s . pat . no . 7 , 943 , 560 ) as flavors and fragrances . civetone ( both geometrical isomers ) can undergo simmons - smith reaction using zncu and ch 2 i 2 to give cyclopropanated civetone . muscone ( 3 - methyl cyclopentadecanone ) is methylated macrocycle with musk fragrance . civetone macrocycle can be alkylated ( methylated ) to give 2 - methyl 9 - cycloheptadecen - 1 - one which can be potential product for perfume industry . alkylation reaction can be done using stork enamine conditions to substitute the macrocycles with different alkyl groups . see fig1 . macrocycles with potential melanin production inhibition activity which can be used in skin care products (“ melanin production inhibitors ,” n . d . ): diethyl 9 - octadecenedioate product from invention embodiment 1 can undergo acyloin condensation to give 2 - hydroxy macrocyclic ketones , which can inhibit melanin production , as shown in fig1 . civetone can be reduced to give product c , which is a potential melanin production inhibitor , and hydrogenation of product c gives civetol d . alamu , 0 . j ., waheed , m . a ., & amp ; jekayinfa , s . o . 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