WO2017119666A1 - Procédé de séparation chirale de dérivé de n-[4-(1-aminoéthyl)-phényl]-sulfonamide utilisant un solvant aprotique polaire - Google Patents

Procédé de séparation chirale de dérivé de n-[4-(1-aminoéthyl)-phényl]-sulfonamide utilisant un solvant aprotique polaire Download PDF

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WO2017119666A1
WO2017119666A1 PCT/KR2016/015402 KR2016015402W WO2017119666A1 WO 2017119666 A1 WO2017119666 A1 WO 2017119666A1 KR 2016015402 W KR2016015402 W KR 2016015402W WO 2017119666 A1 WO2017119666 A1 WO 2017119666A1
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compound
chiral
group
formula
stereoisomer
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PCT/KR2016/015402
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Korean (ko)
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우병영
이기화
노종화
박제홍
박미영
박영호
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(주)아모레퍼시픽
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Priority to CN201680077743.6A priority Critical patent/CN108473418A/zh
Priority to JP2018534974A priority patent/JP6911033B2/ja
Publication of WO2017119666A1 publication Critical patent/WO2017119666A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • triadimenol can have four isomers, the (-)-(1S, 2R) -isomer is the (+)-(1R, 2R) -isomer and the (-)-(1S, 2S).
  • The) -isomers are more active than the (+)-(1R, 2S) -isomers, respectively.
  • Dichlorobutrazole is known to have high activity of (1R, 2R) -isomer among four isomers.
  • the compound of etaconazole has a higher bactericidal effect than the other isomers of (+)-(2S, 4S)-and (-)-(2S, 4R) -isomers.
  • Vanilloid antagonists including, for example, N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivatives, have been shown to have an effect on pure stereoisomers. [Examples: WO2008-013414 A1, WO2007-133637 A2 , WO2007-129188 A1, WO2010-010934 A1].
  • a synthesis method for preparing a homoisomer for such an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative is known as an asymmetric synthesis method using an Elman adjuvant.
  • WO2008-013414 A1, WO2007-133637 A2, WO2007-129188 A1, and WO2010-010934 A1 provide a method for obtaining a desired stereoisomer by introducing an Elman adjuvant and inducing asymmetric reduction using the same. .
  • this method must maintain a low temperature reaction to increase the optical purity (enantiomer excess,% ee) and is dangerous because it involves excessive hydrogen generation and exotherm at the end of reaction. There are limitations in terms of processing and economics.
  • the present invention is, in one aspect, a chiral auxiliary having an optical activity of the N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative having a structure of Formula 1 Using N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative salt to provide a method of separating the respective compounds with high optical purity.
  • N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a generic name of a compound represented by the following formula (2), TRPV1 (transient receptor potential cation channel subfamily V member 1, Or capsaicin receptor, vanilloid receptor 1) is known to be useful as an intermediate for preparing compounds that act as antagonists.
  • TRPV1 transient receptor potential cation channel subfamily V member 1, Or capsaicin receptor, vanilloid receptor 1
  • N- [4- (1-aminoethyl) -difluorophenyl] -methanesulfonamide is a chiral compound in which carbon bonded to an amine group is present as an asymmetric carbon.
  • a stereoisomer mixture particularly a stereoisomer mixture of a compound having an amine group bonded to an asymmetric carbon atom, can be easily chiral split into a compound having high optical purity.
  • This method is a synthetic method that improves safety and economics at the time of manufacture compared to the asymmetric synthesis method using the Elman assistant, and performs chiral splitting with an optical purity equal to or higher than that, and also shows high economical efficiency and eco-friendliness by collecting and reusing salts. Therefore, this method can be usefully used in the preparation of raw materials in the pharmaceutical and cosmetic fields that require chiral splitting of compounds.
  • the method according to an aspect of the present invention obtains the desired stereoisomer with an optical purity equal to or higher than that of the conventional asymmetric synthesis method using the Elman adjuvant and exhibits an efficient and economical effect in mass production.
  • the filtrate of the stereoisomer mixture with a racemate mixed with the S- and R-isomers in a ratio of about 1: 1, and separate racemization It shows the effect of racemization only through chiral cleavage of stereoisomer compounds with high purity without undergoing a reaction. Therefore, according to one aspect of the present invention, the filtrate can be used in another chiral splitting process without a separate process, and thus, it is possible to economically utilize the compound without losing a compound, unlike a general racemization reaction. Indicates.
  • the invention comprises mixing a stereoisomer mixture of a compound under a solvent with a chiral auxiliary to precipitate an enantiomeric excess of the diastereomeric salt of the compound and the chiral assistant. It may be directed to a chiral resolution method of stereoisomeric mixtures.
  • the chiral auxiliary body is a 2,3-dibenzoyl tartaric acid (2,3-dibenzoyl tartaric acid), O, O '- di - p - toluoyl-tartaric acid (O, O' -di- p -toluoyl tartaric acid), their stereoisomers, and combinations thereof.
  • the term "in the enantiomeric excess” generally encompasses all increases in the proportion of enantiomers, and therefore the ratio of enantiomers as well as the enantiomeric ratio as compared to the racemic mixture is 1: 1 ( Compared to other mixtures (such as semibodies).
  • the term "in mirror image excess” means that the mirror image excess (% ee) is at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, 92 It may correspond to at least%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.
  • the term “high optical purity” herein corresponds to a term well known in the art.
  • the term “high optical purity” is at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at 95%. Or more, 96% or more, 97% or more, 98% or more, or 99% or more.
  • the chiral adjuvant herein can be obvious to those skilled in the art, and specifically, in the synthesis of organic compounds, temporarily to the synthesis process to control the stereochemical results of the synthesis. It can mean a compound to be incorporated, and such chiral auxiliaries may exist as an adjuvant to determine the steric selectivity of one or more series of reactions (see the chiral auxiliary page of Wikipedia (http://en.wikipedia.org/wiki). / Chiral_auxiliary)). Chiral assistants and chiral acids can be used interchangeably herein.
  • 2,3-dibenzoyl-tartaric acid is (+)-2,3-dibenzoyl-D-tartaric acid or (-)-2,3-dibenzoyl-L-tartaric acid which are optical isomers of each other one can, O, O '- di - p - toluoyl-tartaric acid are enantiomers of each other (+) - O, O' - di - p - toluoyl -D- tartaric acid or (-) - O, O ' - Di- p -toluoyl-L-tartaric acid.
  • D-type and L-type can be used individually or mixed, but it is preferable to use them without mixing with each other.
  • the optical purity value is lower than that of using D-type or L-type, respectively.
  • the stereoisomer mixture may be a stereoisomer mixture of a compound having an asymmetric carbon atom.
  • the compound having an asymmetric carbon atom may be bonded to an amine group.
  • the compound may be one having a substituted or unsubstituted phenyl group bonded to an asymmetric carbon atom in addition to the amine group.
  • the compound having an asymmetric carbon atom may be a compound having a structure of formula (1).
  • the method may be a method of obtaining the R-type or S-type optical isomer having high optical purity from the stereoisomer mixture.
  • the method further chiral auxiliary body (+) - 2,3-dibenzoyl -D- tartaric acid, (+) - O, O '- di-p-toluoyl tartaric acid, and -D-
  • it may be a method of obtaining the S type optical isomer of the compound in a high enantiomeric excess.
  • the method further chiral auxiliary bodies (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O '- di-p-toluoyl tartaric acid, and -L-
  • auxiliary bodies (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O '- di-p-toluoyl tartaric acid, and -L-
  • it may be a method of obtaining the R-type optical isomer of the compound in a high enantiomeric excess.
  • the compound may have a structure of formula (1).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are H; -NH 2 ; An alkyl group of C 1-6 ; Alkenyl group of C 2-6 ; Alkynyl groups of C 2-6 ; And halogen is one selected from the group consisting of, R One And R 2 It is to have a different substituent.
  • the halogen may be one or more selected from the group consisting of F, Cl, Br and I.
  • R 1 is one selected from the group consisting of methyl group, ethyl group, propyl group, butyl group, and pentyl group
  • R 2 may be hydrogen
  • R 1 is a methyl group
  • R 3 and R 7 are hydrogen
  • R 4 , R 5 , and R 6 are composed of alkyl groups of F, Cl, Br, I, and C 1-6 It may be one selected from the group.
  • R 4 and R 6 may be F, R 5 may be a methyl group.
  • the compound may be N- ⁇ 4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide.
  • the solvent may be a polar aprotic solvent (polar aprotic solvent).
  • the polar aprotic solvent may be one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone and combinations thereof.
  • the polar aprotic solvent may be acetone.
  • the solvent may be added in an amount to dissolve all the mixture.
  • the solvent may be 2-80 times the total weight of the stereoisomer mixture, specifically 5-30 times, more specifically 5-15 times, more specifically 10 times the number (Ie, volume (solvent) / mass (stereoisomer, or (v / w))
  • the solvent is at least 2 times, at least 5 times, at least 10 times, at least 20 times the total weight of the stereoisomer mixture.
  • the mixing in the method may be carried out by increasing the temperature of the mixture to 40 °C to 70 °C, the boiling point of the solvent or the boiling point of the solvent mixture.
  • the mixing may be to increase the temperature while stirring for 1 hour to 4 hours.
  • the stirring may be reflux stirring.
  • the temperature is at least 30 °C, at least 40 °C, at least 50 °C, at least 60 °C, or at least 70 °C, 70 °C or less, 60 °C or less, 50 °C or less, 40 °C or less, or 30 Or less.
  • the temperature may be 40 ° C. or more and 60 ° C. or less, more specifically 45 ° C. or more and 55 ° C. or less, and more specifically 50 ° C. or more.
  • the stirring time is 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, or 5 hours or more, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2
  • the time may be less than or equal to 1 hour.
  • the stirring time may be 2 hours or more and 4 hours or less, more specifically, the stirring time may be 2 hours 30 minutes to 3 hours 30 minutes, and more specifically 3 hours.
  • the equivalent ratio of chiral auxiliaries to 1 molar equivalent of stereoisomer mixture may be 0.5 to 2.0 equivalents, more specifically 0.8 to 1.5 equivalents.
  • the equivalence ratio of the chiral auxiliary agent is 0.10 equivalents, 0.2 equivalents, 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, 0.7 equivalents to 1 molar equivalent of stereoisomer mixture.
  • It may be up to 0.95 equivalents, up to 0.90 equivalents, up to 0.85 equivalents, up to 0.8 equivalents, up to 0.7 equivalents, up to 0.6 equivalents, up to 0.5 equivalents, up to 0.4 equivalents, up to 0.3 equivalents, up to 0.2 equivalents, or up to 0.10 equivalents.
  • the stereoisomer mixture may have a ratio of R-type isomers to S-type isomers of 1: 9 to 9: 1, and any integer ratio between 1: 9 to 9: 1.
  • the stereoisomer mixture has a ratio of R-type isomers to S-type isomers of 1: 9 or less, 1: 8 or less, 1: 7 or less, 1: 6 or less, 1: 5 or less, 1: 4 or less, 1: 3 or less, 1: 2 or less, 1: 1 or less or 1: 1 or more, 1: 2 or more, 1: 3 or more, 1: 4 or more, 1: 5 or more, 1: 6 or more, 1: 7 or more, 1: 8 or more, or 1: 9 or more.
  • the method comprises recovering the precipitated diastereomeric salts in the mother liquor after the step of enantiomeric precipitation of the diastereomeric salts of the compound having the structure of Formula 1 and the chiral assistant It may further comprise the step of adjusting the ratio of the R isomer: S isomer is 3: 7 to 7: 3 of the stereoisomer mixture.
  • the step of adjusting the ratio of the R-type isomers to the S-type isomers may include the ratios of 3: 7 to 7: 3, 4: 6 to 6: 4, and 7: 8 to 8: 7. , 9:11 to 11; 9, 12:13 to 13:12, or the ratio of about 5: 5.
  • the present invention provides at least 80% ee, at least 82% ee, at least 84% ee, at least 86% ee, at least 88% ee obtained by dividing from the stereoisomeric mixture by the method according to one aspect of the invention. , At least 90% ee, at least 92% ee, at least 94% ee, at least 96% ee, at least 97% ee, at least 98% ee, or at least 99% ee.
  • the stereoisomer is N- ⁇ 4-[(1R) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide or N- ⁇ 4-[(1S)- 1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide.
  • an asymmetric carbon atom refers to carbon when a carbon atom in a molecule is bonded to four different atoms, atomic groups, or functional groups.
  • Compounds containing such asymmetric carbon atoms have optical rotation, optical activity or optical isomers.
  • the stereoisomer mixture may mean that two enantiomers are mixed as an isomeric compound having optical activity, wherein the mixing ratio may be 1: 1 (in this case the racemic mixture is ), Or the mixing ratio may correspond to a ratio of integers between 1:10 and 10: 1.
  • the stereoisomer mixture may be artificially synthesized or may be a mixture in a state in which the ratio of the R-type and S-type optical isomers is unknown. According to the method of the present invention, the ratio of the optical isomers of either the R type or the S type can be significantly increased, so that the optical isomer of the desired type can be obtained with high optical purity irrespective of the ratio of the mixture.
  • N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a compound of CAS No. 1202743-51-8 which corresponds to a molecular weight of 250.27 Da It can be used interchangeably with INT-2 within the present specification, which may be a stereoisomer mixture in which optical isomers of R or S type are mixed.
  • N- ⁇ 4-[(1R) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide hydrochloride corresponds to CAS No. 956901-23-8
  • the molecular weight corresponds to 286.73 Da
  • the component N- ⁇ 4-[(1R) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide corresponds to CAS number 957103-01-4 I mean. It can also be used interchangeably with the R-type isomer of INT-3 within this specification.
  • 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid corresponds to CAS No. 1005174-17-3, the molecular weight of 259.22 Da it means.
  • (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoro Romethyl-pyridin-3-yl) -acrylamide corresponds to CAS number 1005168-10-4 and means molecular weight 491.47 Da.
  • the R- or S-type optical isomers of INT-3 can be obtained according to the following method:
  • the cooling may be to cool to 15 °C ⁇ 30 °C after reflux.
  • the cooling is at least 10 ° C, at least 15 ° C, at least 20 ° C, at least 22 ° C, at least 24 ° C, at least 25 ° C, at least 26 ° C, at least 28 ° C, at least 30 ° C, or at least 35 ° C.
  • the method may further comprise the step of separating the chiral acid from the obtained INT-3 chiral acid salt, specifically the separation step is to the INT-3 chiral acid salt
  • the separation step is to the INT-3 chiral acid salt
  • the present invention may be directed to a chiral splitting method of stereoisomeric mixtures comprising the following steps:
  • the compound may be N- ⁇ 4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide.
  • the chiral auxiliary body in the above-mentioned (1) comprises 2,3-benzoyl- consisting of toluoyl tartaric acid, their stereoisomers, and their combinations - tartaric acid, O, O '- di-p It may be one or more selected from the group.
  • the method may further comprise adding a solvent to the mixture of step (2) (1) after step (1).
  • the solvent may be a polar aprotic solvent.
  • the method may further comprise the step of stirring the reflux (3) the mixed solution to which the solvent is added.
  • the stirring in step (3) is 30 minutes or more, 1 hour or more, 1 hour 30 minutes or more, 2 hours or more, 2 hours 30 minutes or more, 3 hours or more, 3 hours 30 minutes or more, Or stirring for 4 hours or more, 5 hours or less, 4 hours 30 minutes or less, 4 hours or less, 3 hours 30 minutes or less, 3 hours or less, 3 hours 30 minutes or less, 3 hours or less, 2 hours 30 minutes or less, 2 hours or less , 1 hour 30 minutes or less, 1 hour or less, or may be stirred for 30 minutes or less.
  • the method may further comprise the step of cooling the mixture of (4) (3).
  • the method may further comprise the step of (5) filtering the solid produced by cooling to obtain the diastereomeric salt of the compound.
  • the diastereomeric salt of the compound may be an INT-3 diastereomeric salt.
  • the method may further comprise the step (6) removing or separating chiral acid from the obtained diastereomeric salt.
  • the step (6) may include the step 1) injecting water and ammonia aqueous solution to the diastereoisomeric salt of INT-3.
  • the water is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times the weight ratio of the INT-3 diastereoisomeric salts. Or 7 times or less, 6 times or less, 5 times or less, 4 times or less, 3 times or less, or 2 times or less.
  • the aqueous ammonia solution in step (6) is at least 20% by volume, at least 24% by volume, at least 28% by volume, at least 32% by volume, at least 36% by volume, or at least 40% by volume of ammonia Or 40% or less, 36% or less, 32% or less, 28% or less, 24% or less, or 20% or less by volume of an aqueous ammonia solution.
  • the aqueous ammonia solution in step (6) is 0.5 equivalent or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more, or 3 equivalents or more, or 4 equivalents or less, 3.5 equivalents
  • 3 equivalents, 2.5 equivalents, 2 equivalents, 1.5 equivalents, 1 equivalents, or 0.5 equivalents can be added.
  • step (6) may further comprise a step of stirring the mixture after 2) 1).
  • the stirring in the step (6) is 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, 50 minutes or more, 60 minutes or more, or 70 minutes or more Or less than 70 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes.
  • step (6) may further comprise the step of filtering 3) the suspension obtained by stirring.
  • step (6) may further comprise the step 4) removing the filtered suspension with reduced pressure vacuum to obtain the R-type or S-type optical isomer of INT-3.
  • a method of chiral separation of a stereoisomer mixture of a compound having the structure of Chemical Formula 1 by a method according to an aspect of the present invention And converting the divided stereoisomer into a compound having a structure of Formula 3a or 3b.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are H; -NH 2 ; An alkyl group of C 1-6 ; Alkenyl group of C 2-6 ; Alkynyl groups of C 2-6 ; And halogen is one selected from the group consisting of,
  • R 1 and R 2 may be related to a method for preparing a compound having a structure of Formula 3a or 3b having different substituents.
  • the converting step is also described in detail in Korean Patent Application No. 10-2009-7004333.
  • the compound having a structure of formula 3a is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (PAC-14028), wherein the compound having the structure of Formula 1 is N- ⁇ 4-[(1R / S) -1 -Aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide.
  • the step of converting the divided stereoisomer into a compound having a structure of formula 3a or 3b is N- ⁇ 4-[(1R) -1-aminoethyl] -2,6-difluoro And coupling 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7) with rophenyl ⁇ methanesulfonamide (INT-3). .
  • the stereoisomers divided by the method according to one aspect of the present invention can be used as intermediates in the preparation of new drugs described in the application by reacting with the substances described in Korean Patent Application No. 10-2009-700433. Therefore, in one aspect, the present invention is a method for preparing a novel drug described in Korea Patent Application No. 10-2009-700433 or prepared by such a method using stereoisomers divided by the method according to an aspect of the present invention. To a new drug.
  • the present invention provides a (R) -N- [1- () having at least 96%, at least 97%, at least 98%, or at least 99% of the enantiomeric excess produced by the method according to one aspect of the present invention.
  • the present invention provides (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl]-produced by the method according to one aspect of the present invention. It may be related to a TRPV1 antagonist comprising 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (PAC-14028) as an active ingredient. Such TRPV1 antagonists can be used as pharmaceutical compositions for the prevention or treatment of the diseases described below.
  • the invention in one aspect, (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2 according to one aspect of the invention Pain, inflammatory diseases of the joints, including -propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide, its optical isomer, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, Neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastric-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), stool deficiency disease, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurological / allergic / inflammatory skin disease, psoriasis, pruritus, positive, skin irritation, inflammation of the eye or mucous membrane
  • the pain is in the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, fibrositis, myofascial pain syndrome, back pain, migraine and other types of headache It may be the disease selected or pain associated with the disease.
  • chiral auxiliary in one aspect, chiral auxiliary; Polar aprotic solvents; It may be related to the optical splitting kit comprising; and instructions for using the chiral assistant.
  • the chiral auxiliary may be at least one selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluoyl-tartaric acid, their stereoisomers, and combinations thereof. have.
  • the chiral auxiliary may be from 0.5 to 2.0 equivalents per mole equivalent of the stereoisomer mixture to be optically split.
  • the salt-forming auxiliary compound may be from 0.8 to 1.5 equivalents relative to 1 molar equivalent of the stereoisomer mixture to be optically split.
  • the instructions for use in the use of the optical splitting agent 0.5 to 2.0 equivalents, specifically 0.8 to 1.5 equivalents of chiral auxiliary per 1 molar equivalent of the stereoisomer mixture to be optically divided It may include that the content.
  • the instructions for use may include the content of mixing with the stereoisomer mixture under polar aprotic solvents when using chiral auxiliaries.
  • the instructions may be a description of the chiral separation method of the stereoisomer mixture according to an aspect of the present invention.
  • N- ⁇ 2,6-difluoro-4- [1- (2-methyl-propane-2-sulfinylimino) -ethyl] -phenyl ⁇ -methanesulfonamide (1 equiv) of its weight It was added to and dissolved in tetrahydrofuran (THF) (20 mL) corresponding to 10-fold, and further dissolved NaBH 4 (4 equivalents) in the solution, followed by reaction for 10 hours at the temperature shown in Table 1 below. Proceeded. CH 3 OH was then added dropwise until no more hydrogen gas was released.
  • THF tetrahydrofuran
  • the salt thus obtained was subjected to the same process as in the test example below to determine the mirror image excess, and is shown in Table 1 below.
  • the temperature of -40 ° C. or less must be maintained for 10 hours, but according to the present invention, the same optical activity is stirred and solvent at a temperature of 50 ° C. It can be achieved only by the step of refining.
  • the method of the present invention is significantly economical as compared to the conventional method.
  • the present invention has a feature of exhibiting a heterogeneous effect of obtaining stereoisomers having commercially available optical activity without involving dangerous processes such as excessive generation of explosive hydrogen or generation of heat. .
  • the present invention corresponds to a method involving a process that is more economical and safe than the conventional method.
  • Optical purity (over mirror phase excess) of the INT-3 thus obtained was analyzed by a chiral HPLC column (Shiseido Chiral CD-Ph 4.6 mm ⁇ 250 mm, 5 ⁇ m).
  • 0.5 mol / L sodium perchlorate and methanol mixture (75% by volume: 25% by volume) were used as the mobile phase, and the ratio of each chiral acid salt separated into a solid under the following conditions was measured using Waters e2695 Alliance HPLC. Equation 1 can be used based on the ratio of each salt to calculate the optical purity (en%) of each salt.
  • the equivalent weight of the chiral auxiliary was adjusted as follows and the ratio of the R-isomer and S-isomer in the stereoisomer mixture was adjusted. The ratio and yield of the isomer compound to be measured were measured.
  • Theoretical yield the maximum mass of product obtainable from a given mass of reactant
  • the ratio and yield of isomers obtained as a solid vary depending on the equivalent of the stereoisomer mixture and the chiral auxiliary. Separation of the S-type isomer was carried out when the equivalent of the chiral auxiliary to 1 equivalent of the stereoisomer mixture was 1 equivalent or more, and the ratio of the S-isomer was the highest when the equivalent of the chiral auxiliary was 1.2 equivalents, and S The highest yield in the case of separation of the isomers was 1.2 equivalents of the chiral auxiliary.
  • the S-type isomer compound was obtained in higher proportion compared to the stereoisomer mixture before the reaction when the chiral auxiliary was 1 equivalent or more.
  • the ratio of the S-form isomer separated as a solid was 97% and the yield was 74%.
  • the ratio of R isomers to S isomers was controlled to 45:55 in the isomer mixture remaining in the reaction mother liquor after obtaining the S type isomer compound which precipitated as a solid. It shows that only S-types are selectively separated.
  • the S-type isomer compound was obtained at a higher ratio compared to the stereoisomer mixture before the reaction when the chiral auxiliary was 1 equivalent or more with respect to 1 equivalent of the stereoisomer mixture.
  • the chiral auxiliary was 1.0 equivalent
  • the highest ratio of the S-form isomers separated into solids was 88% and 98%, respectively, and the yields were 72% and 76%, respectively.
  • the ratio of R: S remaining in the filtrate after separation of the isomeric compound as a solid is 51:49. You can see that it is adjusted to.
  • the stereoisomer mixture can be separated into the racemate by removing only the S isomer.
  • the separated high optical purity S-type isomeric compounds may be able to obtain racemates of stereoisomer compounds through other racemization processes.
  • the method according to one aspect of the present invention has the advantage that the racemization can be carried out using a stereoisomer mixture while minimizing the loss of R-type isomers, and that the racemates thus obtained can be used again for other reactions.
  • the method according to one aspect of the present invention can minimize the loss of the R-type isomer by the racemization process and can be racemized from the S-type by only racemization of the isolated S-type selectively.
  • the S-type isomer can be separated from the stereoisomer mixture in a high yield under a polar aprotic solvent and prepared similarly to the racemate so that the filtrate can be used again for the chiral splitting method. It is possible to do
  • the method according to one aspect of the present invention uses the same kind of chiral auxiliaries as the process for separating the R-isomers, so there is no cross-contamination by opposing chiral auxiliaries, which is advantageous for the process application. . Therefore, the R type isomer is obtained by changing only the solvent so that the filtrate containing the stereoisomer mixture which has undergone the chiral splitting method can be continuously recycled, and can be simply racemized and put back into the chiral splitting method. It is very economical and eco-friendly.
  • the R-type isomer compound is equivalent to INT-3 Likewise, it can be used in additional processes.
  • N- ⁇ 4-[(1R) -1-aminoethyl] -2,6-difluorophenyl ⁇ methanesulfonamide, HCl salt (62 mg, 0.22 mmol) was added to 3- (2-propyl-6.
  • Reaction with -trifluoromethyl-pyridin-3-yl) -acrylic acid (56 mg, 0.22 mmol) crystallized with ether to give the title compound (81 mg, 73%).
  • the R-type isomer of the compound having the structure of Formula 1 divided according to one aspect of the present invention prepares various novel compounds that can act as TRPV1 antagonists by the materials or methods described in Korean Patent Application No. 10-2009-7004333. It can be usefully used as an intermediate required to do so.

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

Abstract

La présente invention concerne un procédé de séparation chirale pour un mélange stéréoisomérique, le procédé comprenant une étape de mélange d'un mélange stéréoisomérique d'un composé, dans lequel un groupe amine est lié à un atome de carbone asymétrique, et un auxiliaire chiral. Selon l'invention, l'auxiliaire chiral est l'acide 2,3-dibenzoyl-tartrique ou l'acide O, O '-di-p-toluoyltartrique. Un isomère optique ayant un taux élevé de pureté optique peut être obtenu par ce procédé. En outre, selon ce procédé, le rapport du mélange stéréoisomérique contenu dans une liqueur mère peut être ajusté par récupération de l'isomère optique. Par conséquent, dans le domaine pharmaceutique ou médicinal, un procédé selon un aspect de la présente invention peut être utilement utilisé lors de la recherche de l'obtention d'un composé à pureté élevée ayant un seul type d'isomère optique, et peut être utilisé utilement dans la racémisation d'une liqueur mère utilisée dans une autre réaction.
PCT/KR2016/015402 2016-01-04 2016-12-28 Procédé de séparation chirale de dérivé de n-[4-(1-aminoéthyl)-phényl]-sulfonamide utilisant un solvant aprotique polaire WO2017119666A1 (fr)

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JP2018534974A JP6911033B2 (ja) 2016-01-04 2016-12-28 極性非プロトン性溶媒を用いたｎ−［４−（１−アミノエチル）−フェニル］−スルホンアミド誘導体のキラル分割方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111050767A (zh) * 2017-08-31 2020-04-21 株式会社爱茉莉太平洋 预防或治疗睡眠障碍的组合物

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102518632B1 (ko) * 2018-04-18 2023-04-06 (주)아모레퍼시픽 (r)-n-[1-(3,5-다이플루오로-4-메테인설폰일아미노-페닐)-에틸]-3-(2-프로필-6-트라이플루오로메틸-피리딘-3-일)-아크릴아마이드를 함유하는 약학 조성물
CN109608368B (zh) * 2018-10-24 2021-03-09 常州市阳光药业有限公司 N-[4-(1-氨基乙基)-2,6-二氟苯基]甲磺酰胺的合成及拆分方法
KR20200053746A (ko) 2018-11-09 2020-05-19 (주)아모레퍼시픽 졸-겔 조성물
CN111925380A (zh) * 2019-05-13 2020-11-13 北京化工大学 引起手性选择性转变的组合共晶客体拆分剂及其应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968837A (en) * 1989-07-28 1990-11-06 Ethyl Corporation Resolution of racemic mixtures
KR20020051937A (ko) * 1999-11-25 2002-06-29 스타르크, 카르크 광학 활성 아민의 제조 방법
US20070185346A1 (en) * 2006-02-03 2007-08-09 Vaidya Niteen A Kit for automated resolving agent selection and method thereof
KR20080002931A (ko) * 2001-05-31 2008-01-04 화이자 프로덕츠 인코포레이티드 (1-벤질-4-메틸피페리딘-3-일)-메틸아민의 광학 분할, 및단백질 키나아제 억제제로서의 피롤로 2,3-피리미딘유도체의 제조를 위한 이들의 용도
KR20090033916A (ko) * 2006-07-27 2009-04-06 (주)아모레퍼시픽 바닐로이드 수용체 길항제로서의 신규 화합물, 그의 이성질체, 또는 약제학적으로 허용가능한 그의 염, 및 이를함유하는 약제학적 조성물
KR20160101554A (ko) * 2015-02-17 2016-08-25 (주)아모레퍼시픽 N-[4-(1-아미노에틸)-페닐]-메탄술폰아미드 유도체의 카이랄 분할 방법

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1004346C2 (nl) * 1996-10-23 1998-04-24 Dsm Nv Werkwijze voor het scheiden van een mengsel van enantiomeren in een geschikt oplosmiddel.
JP2003226677A (ja) * 2002-02-01 2003-08-12 Sumitomo Pharmaceut Co Ltd 光学活性２−（１−アミノアルキル）アニリン類およびその光学活性な酒石酸類との塩、並びにそれらの製造方法
EP2024272A4 (fr) * 2006-05-10 2010-11-17 Renovis Inc Dérivés d'amides en tant que ligands de canal ionique et compositions pharmaceutiques et méthodes d'utilisation desdits dérivés
WO2007129188A1 (fr) 2006-05-10 2007-11-15 Pfizer Japan Inc. Composé de cyclopropanecarboxamide
EP1882687A1 (fr) * 2006-07-27 2008-01-30 Amorepacific Corporation Composés hétérocycliques, leur utilisation comme antagonistes du récepteur vanilloide et les compositions pharmaceutiques qui les contiennent
JP2011201778A (ja) 2008-07-23 2011-10-13 Mochida Pharmaceut Co Ltd ｐ−置換アリールアセトアミドを有するヘテロシクリデン誘導体
CN101870660A (zh) * 2010-05-10 2010-10-27 青海省青海湖药业有限公司 一种L-(-)-盐酸麻黄碱和d-(+)-盐酸伪麻黄碱制备方法
CN104119240A (zh) * 2013-04-23 2014-10-29 中国人民解放军军事医学科学院毒物药物研究所 (S)-(-)-α-甲胺基苯丙酮的制备方法
CN106660949B (zh) * 2015-02-17 2020-11-13 株式会社爱茉莉太平洋 N-[4-(1-氨基乙基)-苯基]-磺酰胺衍生物的手性拆分方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968837A (en) * 1989-07-28 1990-11-06 Ethyl Corporation Resolution of racemic mixtures
KR20020051937A (ko) * 1999-11-25 2002-06-29 스타르크, 카르크 광학 활성 아민의 제조 방법
KR20080002931A (ko) * 2001-05-31 2008-01-04 화이자 프로덕츠 인코포레이티드 (1-벤질-4-메틸피페리딘-3-일)-메틸아민의 광학 분할, 및단백질 키나아제 억제제로서의 피롤로 2,3-피리미딘유도체의 제조를 위한 이들의 용도
US20070185346A1 (en) * 2006-02-03 2007-08-09 Vaidya Niteen A Kit for automated resolving agent selection and method thereof
KR20090033916A (ko) * 2006-07-27 2009-04-06 (주)아모레퍼시픽 바닐로이드 수용체 길항제로서의 신규 화합물, 그의 이성질체, 또는 약제학적으로 허용가능한 그의 염, 및 이를함유하는 약제학적 조성물
KR20160101554A (ko) * 2015-02-17 2016-08-25 (주)아모레퍼시픽 N-[4-(1-아미노에틸)-페닐]-메탄술폰아미드 유도체의 카이랄 분할 방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111050767A (zh) * 2017-08-31 2020-04-21 株式会社爱茉莉太平洋 预防或治疗睡眠障碍的组合物

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