Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/40—Succinic acid esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C391/00—Compounds containing selenium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
  • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/593—Dicarboxylic acid esters having only one carbon-to-carbon double bond
  • C07C69/60—Maleic acid esters; Fumaric acid esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/604—Polycarboxylic acid esters, the acid moiety containing more than two carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
  • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/32—Oxygen atoms
  • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to synthesis procedures of Ci and C3 cinnatrins and intermediates of said synthesis. It also refers to the use of said intermediates in the synthesis of cinnatrins Ci and C3.
• Cinatrins C 3 ((35 ', 45', 5i?) - 3,4-dihydroxy-3-dodecyl-4,5-dicarboxytetrahydro-2-furanone) and Ci ((35 ', 45', 5i?) - 3,4-dihydroxy-5-dodecyl-4,5-dicarboxytetrahydro-2-furanone) belong to the family of Cinnatrins.
• Cinnatrins Ci and C3 inhibit the action of Phospholipase A 2 enzyme (PLA 2 ), and therefore have anti-inflammatory activity (Farooqui, AA; Litski, ML; Farooqui, T .; Horrocks, L. Brain Res. BuIl. 1999, 49, 139-153; Pi ⁇ ón, P .; Kaski, JC Rev. Esp. Cardiol. 2006, 59, 247-258).
• Phospholipase A 2 Phospholipase A 2 enzyme
• Cinatrins C 3 and Ci. Evans, DA; Trotter, BW; Barrow, JC Tetrahedron 1997, 55, 8779-8794 describes the first synthesis of these compounds.
• the key step in said synthesis consists of the titanium-mediated stereoselective aldol reaction of a tartrate-derived acetal silylketene, generated from the di-tert-butyl ester of the acid (i?, I?) - tartaric acid, and an ⁇ -ketoester Aquiral, prepared from the myristic acid benzyl ester.
• This synthesis is convergent, comprises 5 stages and provides an overall yield of 24% for Cinatrin C 3 and 31% for Cinatrin C 1 .
• the materials used are expensive and use various types of protecting groups. Cuzzupe, AN; Di Florio, R .; White, JM; Rizzacasa, MA Org. Biomol
• Chem. 2003, 1, 3572-3577 describes the second synthesis described to date for Cinatrins C3 and C 1 .
• the key step comprises the chelation controlled addition of an organometallic reagent to an ⁇ -hydroxyketone in the presence of an ester, whereby the C4 quaternary stereogenic center of Cinatrine C3 is generated.
• the synthesis is linear, comprises 18 stages, and has an overall yield of 0.95%.
• a first aspect of the present invention relates to a process for the synthesis of a compound of formula (II), intermediate in the synthesis of the compounds of formula (Ia) and (Ib), which include the cinnatrins Ci and C 3 , its stereoisomers, or mixtures thereof, from a compound of formula (III).
• An additional aspect refers to the compounds of formula (III), intermediate synthesis of the compounds of formula (Ia) and (Ib), their stereoisomers, or mixtures thereof, and processes for obtaining it.
• Another additional aspect relates to a process for obtaining the compounds of formula (Ia) and (Ib) their stereoisomers, or mixtures thereof, from a compound of formula (III).
• Another additional aspect relates to a process for obtaining a compound of formula (Ia) its stereoisomers, or mixtures thereof, from a compound of formula (III).
• Another additional aspect is directed to a compound of formula (II) and its use in the synthesis of the compounds of formula (Ia) or (Ib) their stereoisomers, or mixtures thereof.
• An additional aspect refers to the use of at least one compound of formula
• the present invention is directed to a process for obtaining a compound of formula (II), immediate precursor to the cinnatrins Ci and C3,
• R 2 is a C10-C15 alkyl group
• R 3 and R 5 are independently selected from a substituted or unsubstituted C1-C20 alkyl group; its stereoisomers, or mixtures thereof; process comprising dihydroxylating the double bond of a compound of formula
• R 2 , R 3 and R 5 are as defined above; and R 1 is selected from a substituted or unsubstituted C1-C20 alkyl group. Therefore, the process of the invention for obtaining the compounds of formula (II) first comprises a dihydroxylation of the carbon-carbon double bond of the compound of formula (III), followed by an intramolecular cyclization which gives rise to the compound of formula ( II). The stereochemistry of dihydroxylation is directed by the C3 hydroxyl of the compound of formula (III), so that depending on the stereochemistry in this carbon ((R) or (S)) then different stereoisomers of the compounds of formula (Ia) and (Ib) can be obtained .
• the compound of formula (III) is in racemic form, it will be possible to obtain the compounds of formula (Ia) and (Ib) in racemic form, being able to be used as such or separated into each of its enantiomers according to the methods that are common general knowledge.
• the compound of formula (III) is a compound of formula (Illa), or its enantiomers
• the dihydroxylation reaction can be performed under conditions known to the skilled person, as described in Smith, MB; March, J. March 's Advanced Organic Chemistry; Jonh Wiley & Sons: New York, 2001. pp .: 1048-1051.
• dihydroxylation is carried out in the presence of osmium tetroxide / ⁇ / -oxide- ⁇ / -methylmorpholine or potassium permanganate.
• the preparation of the compound of formula (III) can be carried out by two alternative routes.
• the compound of formula (III) is prepared (a) by reacting a compound of formula (V)
• R 1 , R 2 and R 3 are as defined above; in the presence of a compound of formula (XII)
• R 5 is as defined above;
• R 1 , R 2 , R 3 and R 5 are as defined above; Y
• R 6 is selected from the group consisting of C1-C3 alkyl and phenyl.
• the compound of formula (XII), a stabilized ilide reacts with the compound of formula (V) to give the compound of formula (III).
• Said stabilized ilium can be prepared according to known methods (Villa, MJ; Warren, SJ Chem. Soc. P. T 1 1994, 12, 1569-1572) or acquired commercially.
• said ilium is [(methoxycarbonyl) methylene] triphenylphosphorane.
• the C3 hydroxyl of the compound of formula (III) is introduced according to conditions known in the state of the art, for example with a peroxide, preferably hydrogen peroxide, or with sodium permanganate.
• R 5 is as defined above and R 7 is a C1-C3 alkyl group.
• said base is selected from the group consisting of sodium hydride, lithium di- ⁇ -propylamine, l, 8-diazabicyclo [5.4.0] undec-7- ene (DBU) and l, 5-diazabicyclo [ 4.3.0] non-5-eno (DBN), preferably sodium hydride.
• the phosphonate of formula (XIV) used is methyl (dimethoxyphosphoryl) acetate.
• the compound of formula (XIII) is prepared by reacting in the presence of a base a compound of formula (VII) where
• R 1 , R 2 and R 3 are as defined above; with a compound of formula (XV) R 6 SeX
• R 6 is as defined above, and X is a halogen selected from Cl and Br.
• said base is selected from the group consisting of sodium hydride, a secondary amine such as morpholine, diethylamine, JV-phthalimide or bis (trimethylsilyl) amides of alkali metals such as lithium (LiHMDS), sodium (NaHMDS) or potassium (KHMDS), preferably sodium hydride or morpholine.
• phenylselanyl bromide (PhSeBr) is used as the compound of formula (XV).
• Said reaction can be carried out following methods known in the state of the art. For example, it is possible to add the compound of formula (XV) onto a solution of the sodium enolate generated from the compound of formula (VII) (see Smith, MB; March, J. March 's Advanced Organic Chemistry; John Wiley & Sons: New York, 2001. pp .: 548-556.). Alternatively, it is possible to prepare a solution comprising an amine, for example morpholine, and the compound of formula (XV), and then add the compound of formula (VII) onto said solution (see Boivin, S .; Outurquin, F .; Paulmier, C. Tetrahedron 1997, 55, 16767-16782.).
• the base used is a chiral secondary amine giving rise to a compound of formula (XIII) enantiomerically pure or enantiomerically enriched.
• known chiral secondary amines such as proline (see for example Vignola, N .; List, BJ Am. Chem. Soc. 2004, 126, 450-451), provide access to the two enantiomers of the compounds of formula ( XIII) or enantiomerically enriched mixtures thereof, and therefore access to compounds of formula (VI), (III) and (II), and the enantiomerically enriched or enantiomerically pure cinnatrins Ci and C3.
• the compounds of formula (VI) can be prepared following a synthetic route comprising (i) reacting a compound of formula (VII) with a compound of formula
• the compound of formula (V) is prepared by reacting a compound capable of generating fluoride ions with a compound of formula (XI)
• R 1 , R 2 and R 3 are as defined above, and
• R 4 is a trialkylsilyl group.
• the epoxide group in the compound of formula (XI) opens regioselectively to form a compound of formula (V).
• General methods of regioselective opening are known in the art, such as those described in Pujol, B .; Sabatier, R .; Driguez, P. A .; Doutheau, A. Tetrahedron Lett. 1992, 33, 1447-1450.
• This opening is done with a compound capable of generating fluoride ions.
• a compound capable of generating fluoride ions Preferably, the system hydrofluoric acid-pyridine, hydrofluoric acid in aqueous solution or a trihydrogen fluoride of formula NR 3 -3HF is used, wherein R is independently selected from the group consisting of hydrogen and Ci-Cs alkyl; more preferably, the compound used is trriethylamine tris hydrofluoride (Et 3 N SHF).
• Each of the two enantiomers of the compounds of formula (V) can be obtained by the regiospecific opening of the suitable enantiomer of the compound of formula (XI), when it is prepared by asymmetric epoxidation.
• the compound of formula (XI) is in its racemic form
• the compound of formula (V) will also be obtained in its racemic form, being able to be used as such or separated into each of its enantiomers according to the methods that are of common general knowledge.
• the compound of formula (XI) is obtained by reacting an epoxidant agent with a compound of formula (X)
• R 1 , R 2 , R 3 and R 4 are as defined above.
• Non-limiting examples of conditions under which this transformation can be carried out can be found in, for example, a) Pujol, B .; Sabatier, R .; Driguez, PA; Doutheau, A. Tetrahedron Lett. 1992, 33, 1447-1450; or b) Lowinger, TB; Chu, J .; Spence, PL Tetrahedron Lett. 1995, 36, 8383-8386. Also in the following references it is possible to find a general explanation about these reactions: (a) Smith, MB; March, J. March 's Advanced Organic Chemistry; John Wiley & Sons: New York, 2001, pp. 1051-1054; (b) Davis, FA; Sheppard, ACJ Org. Chem.
• said epoxidant agent is selected from the group consisting of m-CPBA, 2-sulfonyloxaziridines and the HOF-CHsCN complex; more preferably m-CPBA.
• the compound of formula (X) is prepared by reacting a compound of formula (VII)
• R 1 , R 2 and R 3 are as defined above; with a trialkylsilyl halide or with a trialkylsilyl triflate in the presence of a base.
• Non-limiting examples of conditions under which this transformation can be carried out can be found in, for example, Dalla, V .; Catteau, JP Tetrahedron 1999, 55, 6497-6510, and trialkylsilyl groups that can be used in this reaction, as well as reagents suitable for introduction, are known to the person skilled in the art (eg see Greene, TW; Wuts, PGM Greene 's Protective Groups in Organic Synthesis; John Wiley & Sons: Hoboken, 2007. pp .: 189-196.
• the trialkylsilyl group is selected from the group consisting of trimethylsilyl, triethylsilyl, tri- ⁇ o- propylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and the preferred halides are selected from chlorine and iodine.
• the trialkylsilyl group is tert-butyldimethylsilyl; and the preferred trialkylsilyl triflate is tert-butyldimethylsilyl trifluoromethanesulfonate.
• the reaction of the compounds of formula (VII) can give rise to two stereo isomers of the compounds of formula (X), according to stereochemistry of the double bond at C2-C3 ((E) or (Z)).
• C2-C3 ((E) or (Z)
• the compounds of formula (V) can be prepared following the synthetic route comprising: (i) reacting said compound of formula (VII) with a trialkylsilyl halide or with a trialkylsilyl triflate in the presence of a base to obtain a compound of formula (X);
• the common intermediate is a compound of formula (VII).
• the compound of formula (VII) is prepared by reacting in the presence of a base a compound of formula (VIII)
• R 1 and R 2 are as defined above; with an oxalic acid diester of formula (IX)
• R is as defined above.
• said base is an inorganic base.
• inorganic base Non-limiting examples of conditions under which this transformation can be carried out can be found in, for example, Dubowchik, G. M .; Padilla, L .;
• said base is sodium hydride.
• the compounds of formula (Ia) and (Ib) can be prepared by dihydroxylation followed by hydrolysis of the compound of formula (II) obtained in the presence of a base and subsequent acidification. Therefore, a further aspect of the invention relates to a process for the preparation of compounds of formula (Ia) and (Ib), their stereoisomers, or mixtures thereof, or mixtures of the compounds of formula (Ia) and (Ib) or mixtures of their stereoisomers, which comprises
• step (iii) acidify the reaction medium; wherein groups R3 and R5 are susceptible to being hydrolyzed under the basic conditions of step (ii).
• a preferred embodiment of the present invention comprises the preparation of compounds of formula (Ia ') and (Ib'), or their enantiomers
• the hydrolysis in basic medium and subsequent acidification (steps (ii) and (iii)) of the compounds of formula (II) involves the hydrolysis of the carboxy ester groups of which R3 and R5 form part to give rise to the corresponding carboxy acids. Therefore, in order to carry out the above-mentioned transformation it is necessary that the carboxy esters of which R3 and R5 are part, are labile in basic medium.
• step (ii) of the process for the preparation of compounds of formula (Ia) and / or (Ib) involves the formation of a triazid, whose hydroxyl lactonization of the C2 position with the carboxy acid group from position C4 (see route A in scheme 2) would generate a compound of formula (Ia).
• the acidic medium used in step (iii) should allow formation of a tertiary carbocation, generated by the loss of the OH group of the C4 position of the trimester facilitated by the acidic medium used (see route B in scheme 2). The subsequent cyclization of the carboxy acid group from the C2 position with said carbocation in the C4 position would generate a compound of formula (Ib).
• Suitable bases for the hydrolysis of carboxylic esters and ring opening in the compounds of formula (II) (step (i)) are known to those skilled in the art, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, carbonate of cesium, barium hydroxide.
• any protic acid will allow the cycle to close to form the Ci and C3 cinnatrins (step (ii)), preferably the acid used is hydrochloric acid.
• R 2 is a C 10 -C 15 alkyl group; its stereoisomers, or mixtures thereof, comprising (i) dihydroxylating the double bond of a compound of formula (III), as defined above, to obtain a compound of formula (II)
• R 2 , R 3 and R 5 are as defined above; its stereoisomers, or mixtures thereof; Y
• Conditions under which it is possible to carry out the transformation of step (ii) are in general those in which it is possible to transform the carboxy ester groups of which R3 and R5 form part, into carboxy acid groups under conditions that do not give rise to the opening of lactone
• Carboxy ester groups that can be transformed into carboxy acid groups under non-basic conditions are known to the person skilled in the art.
• Non-limiting examples are esters derived from p-methoxybenzyl, 1-phenyl-ethyl, or trityl.
• R 3 and R 5 are benzyl groups (- (CH) 2 -
• the acidification of the reaction medium eliminates said R 3 and R 5 groups to form the corresponding carboxy acids, without opening the lactone of the compound of formula (II), thereby providing a compound of formula (Ia), without the formation of significant amounts of a compound of formula (Ib).
• R3 and R5 are ⁇ -butyl, it is possible to obtain the corresponding carboxy acids in an acidic medium (for example, with trifluoroacetic acid) without opening the ring.
• an acidic medium for example, with trifluoroacetic acid
• R 2 is n-dodecyl.
• R 1 is a C1-C3 alkyl, preferably methyl.
• R 3 is a C1-C3 alkyl, preferably methyl.
• R 5 is a C1-C3 alkyl, preferably methyl.
• R> 2 is selected from a C 10 -C 15 alkyl group
• R 3 and R 5 are independently selected from a substituted or unsubstituted C1-C20 alkyl group; its stereoisomers, especially enantiomers, or mixtures thereof; provided that the compound of formula (II) is not
• R 2 in the compounds of formula (III), (V), (VI), (VII), (X), (XI) and (XIII) is n-dodecyl.
• R 1 is methyl.
• R 3 is methyl.
• R 5 is methyl.
• an aspect of the present invention is the use of the compounds of formula (III), (V), (VI), (VII), (X), (XI) and (XIII) for the synthesis of compounds of formula ( Ia) or (Ib), its stereoisomers, or mixtures thereof, as well as mixtures of compounds of formula (Ia) and (Ib) or mixtures of their stereoisomers.
• Alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which does not contain unsaturation and is attached to the rest of the molecule by a single bond. In each case the number of carbon atoms of the alkyl group is specified. For example, when “alkyl is indicated
• C 1 -C 4 refers to an alkyl group of one, two, three or four carbon atoms, ie, methyl, ethyl, propyl, isopropyl or" -butyl. For example, when indicated
• C 10 -C 15 alkyl refers to an alkyl group of ten, eleven, twelve, thirteen, fourteen or fifteen carbon atoms, such as decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl.
• Halide or "halogen” means -F, -Cl, -Br or -I;
• a "stereoisomer” in the present application refers to compounds formed by the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable.
• Enantiomer means the mirror image of a stereoisomerically pure compound.
• an enantiomer may be considered as a mixture of two enantiomers having an enantiomeric excess greater than 95%, preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%.
• “Bn” means benzyl (- (CH 2 ) -phenyl).
• “Trialkylsilyl” means a radical of the formula -Si (R ') (R ") R '" > where each of R ', R “and R'” are independently selected from a phenyl group and an alkyl group Ci-C 6 .
• Non-limiting examples of trialkylsilyl groups can be trimethylsilyl, triethylsilyl, tri- ⁇ -propylsilyl; dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
• alkanoyl such as a Ci-C 6 alkanoyl group, such as acyl and the like
• carboxamido (- (C O) NH 2 )
• trialkylsilyl carbocyclic aryl having 6 or more carbons, particularly phenyl or naphthyl and (Ci-C3) alkyl aryl such as tolyl.
• substituted alkyl includes groups such as cyanoethyl, acetylmethyl, carboxamidomethyl (-CH 2 CONH 2 ), 2-trimethylsilylethyl, benzyl, diphenylmethyl.
• Aryl refers to a C 6 -Ci 4 aromatic hydrocabon radical such as phenyl, naphthyl or anthracil.
• the compounds of the invention also refer to those that include compounds that differ only in the presence of one or more isotopically enriched atoms.
• the compounds having the present structures except for the substitution of a hydrogen for a deuterium or for tritium, or the substitution of a carbon for a carbon enriched in 13 C or 14 C, are within the scope of this invention. .
• the 1 H and 13 C nuclear magnetic resonance spectra were performed at room temperature in the solvent indicated in each case (CDCI3 and CD3OD) using the following devices: Varies Gemini-200 (200 MHz), Varies INOVA- 300 (300 MHz), Bruker Advance-300 (300 MHz) and Vary INOVA-400 (400 MHz).
• the values of chemical shifts are expressed in parts per million ( ⁇ , ppm), using the residual solvent signal as internal reference: CDCl 3 , 7.26 ppm ( 1 H-NMR) and 77.0 ppm ( 13 C-NMR); CD 3 OD, 3.31 ppm ( 1 H-NMR) and 49.0 ppm ( 13 C-NMR).
• the 1 H-NMR spectra are described indicating the number of protons and the apparent multiplicity of each signal.
• the coupling constants (J) are the apparent ones and are expressed in Hz.
• the following abbreviations have been used: s (singlet), d (doublet), t (triplet), c (quadruplet), q (quintuplet) and m (multiplet ).
• the phases were separated, and the aqueous phase was extracted with AcOEt (3 x 30 mL).
• the organic phase was dried with anhydrous Na 2 SO 4 , filtered and the solvent was removed under reduced pressure.
• the product was purified by graphic chromate column (hexane / AcOEt, 10: 1), obtaining (5.63 g, rt. 65%) rac- (7?) - 3- (phenylselenyl) -3- (methoxycarbonyl) -2-methyl oxopentadecanoate, as a colored oil Brown.
• the product was purified by chromatographic column (hexane / AcOEt, 10: 1), obtaining (0.368 g, rto. 60%) rac- (i?) - 3- (phenylselenyl) -3- (methoxycarbonyl) -2-oxopentadecanoate methyl, like a brown oil.
• the product was purified by chromatographic column (hexane / AcOEt, 15: 1), obtaining (4.53 g, rto. 72%) a mixture in 5: 2 ratio of r ⁇ c- (E, i?) - 2- (phenylselenyl) - Methyl 3,4-bis (methoxycarbonyl) -3-hexadecenoate (trans, 51%) and (Z) -3,4-bis (methoxycarbonyl) -3-methyl hexadecenoate (cis, 21%), as an oil of Brown color.
• Cinatrine C 3 ⁇ 176.8, 172.6, 170.3, 82.1, 81.2, 80.8, 33.2, 32.1, 31.4, 30.8, 30.7, 30.5, 30.4, 23.6, 22.6, 14.5; Cinatrine Ci: ⁇ 175.8, 172.0, 88.6, 85.7, 74.8, 33.4, 32.3, 31.6, 30.5, 30.4, 30.3, 30.1, 23.8, 22.4, 14.3.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Epoxy Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=41226503

Family Applications (1)

Country Status (7)

Families Citing this family (3)

Citations (1)

• 2008
  • 2008-05-06 ES ES200801305A patent/ES2328214B1/es not_active Expired - Fee Related
• 2009
  • 2009-05-05 AU AU2009245668A patent/AU2009245668A1/en not_active Abandoned
  • 2009-05-05 WO PCT/ES2009/070139 patent/WO2009135978A1/es not_active Ceased
  • 2009-05-05 JP JP2011507950A patent/JP2011523631A/ja not_active Withdrawn
  • 2009-05-05 US US12/991,523 patent/US20110275838A1/en not_active Abandoned
  • 2009-05-05 CN CN2009801240480A patent/CN102066350A/zh active Pending
  • 2009-05-05 EP EP09742184A patent/EP2287157A4/en not_active Withdrawn

Patent Citations (3)

Non-Patent Citations (33)

Also Published As

Similar Documents

Legal Events