[1]Herein is N - [4- (1- Amino-ethyl) -phenyl] The chiral resolution method of sulfonamide derivatives are provided.
BACKGROUND
[2]Recently, with the rapid increase in steric demand for the pure compound. One important use for these pure stereoisomeric is the use as intermediates for synthesis in the pharmaceutical industry. For example, it is becoming increasingly apparent that a number of advantages compared with the enantiomeric mixture into semi-pure drug substance la. These benefits [Reference Example: Stinson, SC, Chem Eng News, Sept. 28, 1992, pp. 46-79] is often include fewer side effects and greater potency are enantiomerically related to the pure compounds.
[3]
For example, triadimenol (Triadimenol) is there may be four isomers (-) - (1S, 2R) - isomer (+) - (1R, 2R) - isomer and (-) - (1S, 2S ) - isomer (+) - (1R, 2S) - larger than the respective active isomers. Dichloro boot rajol (Dichlorobutrazole) is (1R, 2R) isomer of the four-isomer is known as the greater the activity. In addition to Kona ethanone sol (Etaconazole) compounds also (+) of the - (2S, 4S) - and (-) - (2S, 4R) - isomer is known to be a high sterilizing effect than other isomers.
[4]
Thus, if the active is able to selectively produce only larger one isomer it can be obtained a high effect by using a small amount, and therefore has the advantage of reducing environmental pollution caused by the use of chemicals. In particular, it is important to manufacture only one isomer selectively when one isomer in the case of drugs exhibit toxicity to the human body.
[5]
Therefore, it has been a very important issue in the fields of medicine, pharmacy, biochemistry-related industries for the purpose of preventing weakening of the increase per unit of drug or side effects to prepare an optically pure compound.
[6]
For example, N - [4- (1- Amino-ethyl) -phenyl] - vanilloid antagonist comprising a sulfonamide derivatives has been proven the efficacy of the pure stereoisomers thereof [for example, Document: WO2008-013414 A1, A2 WO2007-133637 , WO2007-129188 A1, WO2010-010934 A1].
[7]
The N - [4- (1- Amino-ethyl) -phenyl] Synthetic methods for the preparation of a single isomer of the sulfonamide derivatives is known as an asymmetric synthesis method using Elman auxiliary body. As an example A1 WO2008-013414, WO2007-133637 A2, A1 WO2007-129188, WO2010-010934 A1 and has suggested a way to obtain the desired stereoisomer by inducing asymmetric reduction utilizing Elman auxiliary body and introducing them . However, by this method it is subject also to excessive organic and inorganic waste generated after the completion of the reaction, the risk due to involve the excessive hydrogen generation and heat generation from the need to maintain a low temperature reaction and the completion of the reaction process in order to enhance the optical purity (enantiomer excess,% ee) there is a limit in the process and economic point of view to handle.
[8]
[Prior art document]
[9]
[Patent Document]
[10]
WO2008-013414 A1
[11]
WO2007-133637 A2
[12]
WO2007-129188 A1
[13]
WO2010-010934 A1
Detailed Description of the Invention
SUMMARY
[14]
N - [4- (1- Amino-ethyl) -phenyl] prior art with respect to the asymmetric synthesis of the sulfonamide derivatives is reported, but the recipe for making the commercial level have not been established because of the economical efficiency and safety. In this specification, an object of the present invention to provide a novel way to partition chiral by using a method of solving the problems in the conventional asymmetric synthesis methods of the above, and considering the safety of economy and process, an aprotic solvent polarity a stereoisomeric mixture .
Problem solving means
[15]
And in order to achieve the above object, the present invention has a structure of the following general formula (1), according to one aspect N [4- (1- Amino-ethyl) -phenyl] chiral auxiliary body to a sulfonamide derivative having an optically active the use of the N -provides a method for separating the sulfone in the respective compound an amide salt derivative having a high optical purity [4- (1-aminoethyl) -phenyl].
[16]
Formula 1
[17]
[18]
In more specifically, a polar aprotic solvent (R, S) - N - [4- (1- Amino-ethyl) -phenyl] - a mixture of a chiral auxiliary body having a sulfonamide derivative and the optically active (R) - or (S) - optically active form of N - [4- (1- amino-ethyl) -phenyl] after preparing a sulfonamide diacyl-tartrate salt or solvate thereof, the manufacture of optically active N - [4- ( 1-amino-ethyl) -phenyl] to liberate the sulfonamide salt or solvate thereof with a base of optically active N - [4- (1-aminoethyl) -phenyl] comprising a process for producing a sulfonamide (R, S ) - N - [4- (1-aminoethyl) -phenyl] having a high optical purity from the sulfonamide N , to a method for separating a sulfonamide - [4- (1-amino-ethyl) -phenyl].
[19]
According to this method N - [4- (1- Amino-ethyl) -phenyl] - it is possible to split into individual chiral compound easily with a high optical purity of the sulfonamide derivatives.
[20]
N - a general name of a compound methanesulfonamide is represented by Formula 2, TRPV1 (transient receptor potential cation channel subfamily V member 1, - [4- (1- aminoethyl) -2,6-difluorophenyl] or capsaicin receptor, vanilloid receptor 1) is known to be useful as an intermediate for the preparation of compounds that act as antagonists.
[21]
[Formula 2]
[22]
[23]
As represented by the above formula 2 N [4- (1- Amino-ethyl) - difluoro-phenyl] methanesulfonamide is a chiral compound to a carbon-bonded amine group present in the form of the asymmetric carbon (Chiral center).
Effects of the Invention
[24]
The stereoisomeric mixture according to the chiral resolution method in accordance with one aspect of the invention a mixture of stereoisomers, in particular the amine groups are bonded to an asymmetric carbon atom the compounds may easily be divided into a chiral compound having a high optical purity. This method performs a chiral divided into at least an optical purity equal to a synthetic method with improved safety and economy in the manufacture as compared to the asymmetric synthesis method using Elman auxiliary body, and further shows high cost-effectiveness and environmental friendliness of the salt collected and re-used. Therefore, this method may be useful in the raw material production of pharmaceutical, cosmetic applications that require division of the chiral compound.
[25]
In particular, the method according to one aspect of the present invention is obtained in an optical purity equal to or more efficient the desired stereoisomer to a high production method compared to the asymmetric synthesis method using a conventional Elman auxiliary body and is effective in mass production represents an economic effect.
[26]
Further, according to the method in accordance with one aspect of the invention, the filtrate of the stereoisomeric mixture of about 1: it is possible to control the S-type isomer and the R-type isomer body mixed racemic at a rate of 1 or prepared, and a separate racemization only through the process of dividing the chiral car stereoisomeric compounds, without going through the reaction with a high purity merely indicates that the La be beautification effect. Therefore, an effect that, according to the method according to one aspect of the present invention can immediately again be used by other chiral separation step and standing economically utilized without loss of the general racemization and different compounds through which the filtrate without the need for a separate process It represents.
Best Mode for Carrying Out the Invention
[27]
The invention according to one aspect, a mixture of stereoisomers, a mixture of compound in the chiral auxiliary body (chiral auxiliary) and a solvent, comprising the step of precipitating the compound as a chiral diastereomeric salts of the auxiliary body in mirror image excess chiral divided mixture of stereoisomers may be related to (chiral resolution) method.
[28]
In one aspect of the invention, 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), it may be at least one selected from their stereoisomers, and the group consisting of a combination of the two.
[29]
As used herein, the term "a mirror image excess" is generally intended to include any increase in the ratio of enantiomer, therefore, not only the amount of one enantiomer in excess compared with the racemic mixtures, the ratio of the enantiomers of 1: 1 (La compared to other non-mixture such as a racemate) it means an increase in one enantiomer. In one aspect of the invention, the term "a mirror image excess" is a mirror image of the excess (% ee) is greater than 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, 92 It may be one that corresponds to the%, at least 94%, at least 95%, at least 96%, 97%, 98% or more, or 99% or more. Similarly, in this specification the term "high optical purity" corresponds to a well-known term in the art. In one aspect of the invention, a "high optical purity" as used herein is 80% or more and 82% or more, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, 94%, 95% It may be equal to at least, 96%, 97%, 98% or more, or more than 99% of the amount of enantiomer (% ee).
[30]
Chiral auxiliary body herein is temporarily in the synthesis process in order to control the stereochemical outcome of the synthesis in the synthesis of organic compounds in detail as to recognize apparent to the skilled person belonging to the technical field of the invention may be present as an auxiliary agent in order to determine the number and refer to a compound which is incorporated, such a chiral auxiliary body is a three-dimensional selectivity of one or more series of reactions (see Wikipedia chiral auxiliary page (http://en.wikipedia.org/wiki / Chiral_auxiliary)). It may be used herein as a chiral auxiliary body and the chiral acid is interchangeable with each other ever.
[31]
In one aspect of the present invention, 2,3-dibenzoyl-tartaric acid are enantiomers of each other (+) - 2,3-dibenzoyl -D- tartaric acid or (-) - 2,3-dibenzoyl tartaric acid -L- 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 ' - D - P - toluoyl-tartaric acid can be -L-. For such tartaric acid derivatives, one can be used separately or mixed with the D-type and L-type, it is preferred to use without mixing with each other. When used in the process according to one aspect of the present invention by combining an optical isomer D and L-tartaric acid derivative of the optical purity values are lower than with the D-shaped or L-shaped, respectively.
[32]
In one aspect of the invention, the stereoisomer mixture may be a stereoisomeric mixture of a compound having an asymmetric carbon atom (asymmetric carbon atom). Specifically, according to an aspect of the invention, those compounds having the asymmetric carbon atom may be the amine group is bonded. In one aspect of the present invention in detail, the compound may be one having a, substituted or unsubstituted phenyl group bonded to an asymmetric carbon atom in addition to an amine group. Further, according to an aspect of the present invention in detail, the compound having from the asymmetric carbon atom may be a compound having the structure of formula (1).
[33]
In one aspect of the invention, the method may be a method for obtaining an R-type or S-type optical isomer having a high optical purity from a stereoisomeric mixture.
[34]
In one aspect of the invention, the method further chiral auxiliary body (+) - 2,3-dibenzoyl -D- tartaric acid, (+) - O, O ' - di- p -toluoyl tartaric acid, and -D- If the one selected from the group consisting of a combination thereof, may be a way to obtain an S-type optical isomer of a compound with high enantiomer excess.
[35]
In one aspect of the invention, the method further chiral auxiliary bodies (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O ' - di- p -toluoyl tartaric acid, and -L- If the one selected from the group consisting of a combination thereof, may be a way to obtain an R-type optical isomer of a compound with high enantiomer excess.
[36]
In one aspect of the invention, the compound may be one having the structure of formula (1).
[37]
Formula 1
[38]
[39]
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; -NH 2 ; C 1-6 alkyl; C 2-6 alkenyl (alkenyl) group; C 2-6 alkynyl group (alkynyl) group; And it is one selected from the group consisting of halogen, wherein R 1 and R 2 Is having a different substituent.
[40]
In one aspect of the invention, halogen may be at least one selected from the group consisting of F, Cl, Br and I.
[41]
In one aspect of the invention, R 1 is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and one selected from the group consisting of, R 2 may be hydrogen.
[42]
In one aspect of the invention, R 1 is a methyl group, R 3 and R 7 is hydrogen, R 4 , R 5 , and R 6 is F, Cl, Br, I, and C 1-6 consisting of an alkyl group It may be the one selected from the group.
[43]
In one aspect of the invention, R 4 and R 6 a is F, R 5 may be a methyl group.
[44]
In one aspect of the invention, the compound is N- - may be methanesulfonamide {4 [(1R / S) -1- aminoethyl] 2,6-difluoro-phenyl}.
[45]
In one aspect of the invention, the solvent may be a polar aprotic solvent (polar aprotic solvent).
[46]
In one aspect of the invention, the polar aprotic solvent may be one or more selected from ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and the group consisting of a combination of the two. Specifically, a polar aprotic solvent may be acetone.
[47]
In one aspect of the invention, the solvent may be added in an amount sufficient to dissolve all of the mixture. In one aspect of the present invention in detail, the solvent may be a multiple 2-80 total, based on the weight of the mixture of stereoisomers, in particular 5 to 30 multiples, more specifically with 5 to 15 multiples, more specifically 10 drainage is (that is, the volume (solvent) / mass (stereoisomeric, or (v / w)). one aspect, the solvent is stereoisomers total, based on the weight of the second drain or more mixtures, at least 5 water drain, at least 10 drain 20 drain , at least 30 drain 40 drain than 50 multiple, greater than 60 multiple, at least 70 multiple or 80 multiple, or be greater than or equal to, 80 drain or less, 70 drain or less, 60 drain or less, less than 50 drain 40 drain or less, 30 drain or less, and is less than or equal to a multiple of 20 or less, up to 15 multiples, more than 10, drainage or drain 5.
[48]
In one aspect of the present invention, in the method The mixing can be performed by increasing the temperature of the mixture to the boiling point or the boiling point of the solvent mixture of 40 ℃ to 70 ℃, solvent.
[49]
In one aspect of the invention, the mixing may be to increase the temperature with stirring for 1 hour to 4 hours.
[50]
In one aspect of the invention, the stirring may be stirred under reflux.
[51]
In one aspect of the invention, the temperature is more than 30 ℃, more than 40 ℃, more than 50 ℃, more than 60 ℃, or over 70 ℃ or 70 ℃ or less, less than 60 ℃, less than 50 ℃, less than 40 ℃, or 30 ℃ or less. Specifically, the temperature may be in a range from 40 ℃ 60 ℃, and maybe more specifically a range from 45 ℃ 55 ℃, may be more specifically 50 ℃.
[52]
In one aspect of the invention, the mixing time is 1 hour or more, 2 times or more, 3 times or more, 4 hours or more, or 5 times or more, or 6 hours, 5 hours, 4 hours, 3 hours, 2 It may be up to hours, or one hour. Specifically, the mixing time may be in a range from 2 hours to 4 hours, more specifically, the stirring time may be 2.5 hours to 3.5 hours, may be more specifically 3 hours.
[53]
In one aspect of the invention, the equivalent ratio of chiral auxiliary member for the stereoisomeric mixture of one molar equivalent may be 0.5 to 2.0 equivalents, more specifically 0.8 to 1.5 equivalents.
[54]
In one aspect of the invention, a stereoisomeric mixture of about 1 molar equivalent, chiral equivalent ratio of the secondary body is more than 0.10 equivalent weight, at least 0.2 equivalents, more than 0.3 equivalent, at least 0.4 equivalents, more than 0.5 equivalent, more than 0.6 equivalent, 0.7 eq. , at least 0.8 equivalents, more than 0.85 equivalent weight, 0.90 equivalents, at least 0.95 equivalents, 1.0 equivalent, at least 1.05 equivalents, 1.1 equivalent, at least 1.15 equivalents, more than 1.2 equivalent, at least 1.3 equivalents, more than 1.4 equivalent weight, more than 1.5 equivalent, or is more than 2.0 equivalents of 2.0 equivalent or less, less than 1.5 equivalents, 1.4 equivalents or less, more than 1.3 equivalent weight, more than 1.2 equivalent weight, 1.14 equivalents or less, 1.1 equivalent or less, less than 1.05 equivalent, more than 1.0 equivalents. 0.95 equivalents or less, less than 0.90 equivalent weight, 0.85 equivalents or less, more than 0.8 equivalents, 0.7 equiv., 0.6 eq., More than 0.5 equivalent weight, more than 0.4 equivalents, more than 0.3 equivalents, may be less than 0.2 equivalent, or 0.10 eq.
[55]
In one aspect of the invention, the stereoisomer mixture R-type isomer: the ratio of the S-type isomer 1: 9 to 9: may be 1, 1 may be any integer ratio between 1: 9 to 9. In one aspect of the present invention in detail, the stereoisomeric mixture R-type isomer: the ratio of the S-type isomer 1: 9 or less, 1: 8 or less, 1: 7 or 1: 6 or 1: 5 or less, 1: 4 or less, 1: 3 or less, 1: 2 or less, or 1: 1 or less, or 1: 1 or 1: 2 or 1: 3 or 1: 4 or higher 1: 5 or more, 1:06 or more, 1: 7 or more, 1:08 or more, or 1: 9 may be greater.
[56]
In one aspect of the invention, the method comprises the mother liquor after the step of precipitating the diastereomeric salt of a chiral auxiliary material compound and a car having the structure of formula (I) as enantiomer excess, to recover the precipitated diastereomeric salt the S-type isomer ratio 3:: the R-isomer form of the stereoisomer mixture may be one further comprising the step of adjusting a 3: 7 to 7. In one aspect of the present invention in detail, R-type isomer: the ratio step of adjusting the ratio of the S-form isomers is 3: 7 to 7: 3, 4: 6 to 6: 4, 7: 8 to 8: 7 , 9:11 to 11; to adjust to 9, 12:13 to 13:12, or from about 5: it can be to control a ratio of 5.
[57]
The invention in one aspect, the one by the method according to the side are divided from the stereoisomeric mixture over a 80% ee obtained in the invention, 82% ee or higher, 84% ee or higher, 86% ee or higher, 88% ee or more , it may be one of stereoisomers of a compound having the amount of 90% ee or more, a maximum of 92% ee or higher, 94% ee or higher, 96% ee or higher, 97% ee or higher, 98% ee or more, or 99% ee enantiomer.
[58]
In one aspect of the invention, stereoisomers N- {4 - [(1R) -1- aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4 - [(1S) - a 1-amino-ethyl] -2,6-difluoro may be a phenyl} methanesulfonamide.
[59]
In one aspect of the invention, the asymmetric carbon atom (asymmetric carbon atom) refers to a carbon in the event that the coupling group and a carbon atom with four different atom, group of atoms or features within the molecule. In the case of such asymmetric carbon atoms, which includes the compound has a gwanghoe-conductive, optically active or optical isomers.
[60]
In one aspect of the invention, a stereoisomeric mixture may mean that the two enantiomers mixed as isomeric compounds having an optically active, then the mixing ratio is 1: may be a 1 (this case a racemic mixture ), or the mixing ratio is 1:10 to 10: may be any non-integer between 1. In one aspect of the invention, a stereoisomeric mixture can also be artificially to one or a mixture of not knowing the proportion of the R-type optical isomer and the S-type optical isomer synthesized. Method R-type or S-type form of the desired enantiomer, regardless of the ratio of the mixture so can significantly increase the proportion of any one of the optical isomers according to the present invention can be obtained with high optical purity.
[61]
In one aspect of the invention, N- [4- (1- aminoethyl) -2,6-difluorophenyl] - methanesulfonamide corresponds to the molecular weight as the compounds of CAS No. 1202743-51-8 250.27 Da It means, and the specification can be used in interchangeably and INT-2, which may be an optical isomer mixture of stereoisomeric mixture of R or S type.
[62]
In one aspect of the invention, N- {4 - [(1R) -1- aminoethyl] -2,6-difluorophenyl} methane sulfonamide hydrochloride as corresponding to the CAS number 956901-23-8 is to a molecular weight corresponding to 286.73Da, the components of N- {4 - [(1R) -1- aminoethyl] 2,6-difluoro-phenyl} -methanesulfonamide corresponds to the CAS number 957103-01-4 It means. Furthermore, the specification can be used in interchangeably with R-type isomer of INT-3 enemy.
[63]
In one aspect of the invention, 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylic acid is that the molecular weight as corresponding to CAS No. 1005174-17-3 for the 259.22Da it means.
[64]
In one aspect of the invention, (R) -N- [1- (3,5- Difluoro-4-methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl Romero butyl-pyridin-3-yl) acrylamide (PAC-14028) is meant to correspond to the molecular weight of 491.47 Da as for the CAS No. 1005168-10-4.
[65]
In one aspect of the invention, R-type or S-type optical isomer of INT-3 may be obtained according to the following method:
[66]
INT-2 (N- [4- (1- Amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide) a step of mixing the chiral auxiliary body;
[67]
Adding a polar aprotic solvent in the drain 10 (v / w) for INT-2 weight to the mixture;
[68]
The method comprising stirring a polar aprotic solvent for the mixed solution for 1 hour to 4 hours the addition, refluxing at 30 ℃ to 70 ℃;
[69]
Cooling the mixture was stirred;
[70]
The solid was filtered is generated by a cooling method comprising the step of obtaining a chiral acid salt INT-3 ka.
[71]
In one aspect of the invention, the cooling can be to reflux and then cooled to 15 ℃ ~ 30 ℃.
[72]
In one aspect of the invention, the cooling is more than 10 ℃, more than 15 ℃, more than 20 ℃, more than 22 ℃, more than 24 ℃, more than 25 ℃, more than 26 ℃, more than 28 ℃, more than 30 ℃, or more than 35 ℃ or 40 ℃ or less, less than 35 ℃ below 30 ℃ below 28 ℃ below 26 ℃ or less, 25 ℃ or less, less than 24 ℃, 22 ℃ or less, less than 20 ℃, less than 15 ℃, less than 10 ℃, or 5 ℃ It may be to cool to a temperature.
[73]
In one aspect of the invention, the method may further comprise the step of separating the chiral acid from the acid salt chiral an INT-3 ka obtained, specifically, the separation step is that the INT-3 chiral acid salt then added water and 28% by volume of aqueous ammonia solution 2 equivalents of a weight ratio of 5 drain 20 min to 50 min. stirring was filtered to obtain a suspension, and pressure and vacuum to remove excess water type R of INT-3 or S-shape while It may be to obtain an optical isomer.
[74]
The invention can be directed to the chiral resolution method of stereoisomeric mixture comprising, following step according to an aspect:
[75]
(1) asymmetric carbon atom (asymmetric carbon atom) in the step of mixing the chiral auxiliary body the stereoisomeric mixture of the amine groups are bonded compound.
[76]
In one aspect of the invention, the compound is N- - may be methanesulfonamide {4 [(1R / S) -1- aminoethyl] 2,6-difluoro-phenyl}.
[77]
In one aspect of the invention, the chiral auxiliary body in the above-mentioned (1) comprises the steps of: 2,3-dibenzoyl-tartaric acid, O, O ' - di- p consisting of toluoyl tartaric acid, their stereoisomers, and their combinations It may be at least one selected from the group.
[78]
In one aspect of the invention, the method further comprising the step of adding (2) (1) To a mixture of the solvent phase after a step (1) may further include.
[79]
In one aspect of the invention, the solvent may be daily for a polar aprotic.
[80]
In one aspect of the invention, the method (3) may further comprise the step of stirring the solvent is refluxing the mixture solution was added.
[81]
In one aspect of the invention, (3) stirring in the step is at least 30 minutes, at least 1 hour, 30 minutes 1 hour, 2 hours or more, 2.5 hours or more, at least 3 hours, 3.5 hours or more, or 4 hours or more stirring or 5 hours or less for 4 hours or less, 4 hours, 3 hours and 30 minutes or less, 3 hours, 3.5 hours or less, 3 hours, 2.5 hours or less, more than 2 hours , it may be to stir for 1 hour 30 minutes or less, up to 1 hour, or 30 minutes or less.
[82]
In one aspect of the invention, (3) stirring in the step is at least 20 ℃, more than 25 ℃, more than 30 ℃, more than 35 ℃, more than 40 ℃, more than 45 ℃, more than 50 ℃, above 55 ℃, or 60 to agitation in more than ℃ temperature or 70 ℃ below 65 ℃ or less, less than 60 ℃, 55 ℃ or less, 50 ℃ below 45 ℃ below 40 ℃ or less, less than 35 ℃, less than 30 ℃, less than 25 ℃, or 20 ℃ It may be to stir at a temperature below.
[83]
In one aspect of the invention, the method (4) (3) may further comprise the step of cooling the mixture of step.
[84]
In one aspect of the invention, the method (5) can be filtered off the solid produced by cooling further comprise the step of obtaining a diastereomer salt of the compound. In one aspect of the present invention in detail, the diastereomeric salts of the compound may be a salt INT-3 diastereomers.
[85]
In one aspect of the invention, the method further comprising the step of removing or separating the chiral acid from (6) the resultant diastereomeric salt can be further included.
[86]
In one aspect of the invention, the 6 step may include the step of input of water and aqueous ammonia solution to the diastereomeric salts of 1) INT-3. In one aspect of the present invention in detail, (6) a step in water INT-3 diastereomers two or more multiples of the salt weight ratio, more than three multiple, four or more multiple, more than 5 drained, up to six drain, or 7 or more drain or it may be a multiple greater than 7 or less, 6 or less drainage, drain 5 or less, 4 or less drainage, drain 3 or less, 2 or drainage. In one aspect of the present invention in detail, (6) an aqueous ammonia solution in step is 20 vol% or more, 24 vol% or more, 28 vol% or more, 32 vol% or more, 36 vol% or more, or 40% by volume or more of an aqueous ammonia solution or 40 may be vol%, 36 vol%, 32 vol%, 28 vol%, 24 vol% or less, or 20% by volume aqueous solution of ammonia or less. In one aspect of the present invention in detail, (6) an aqueous ammonia solution in step is at least 0.5 equivalents, more than 1 equivalent, at least 1.5 equivalents, and 2 equivalents or more, more than 2.5 equivalent, or more than 3 equivalents of added or less than 4 equivalents, 3.5 eq. or less, it can be added to or less than 3 equivalents, 2.5 equivalents or less, less than 2 equivalents, more than 1.5 equivalent, one equivalent or less, or 0.5 equivalents.
[87]
In one aspect of the invention, the step (6) comprises the steps of: 2) 1) may be after the step including the step of stirring the mixed solution further. In one aspect of the present invention in detail, the above-mentioned (6) was stirred in step is more than 5 minutes, 10 minutes or more, at least 20 minutes, 30 minutes or more, more than 40 minutes, more than 50 minutes, more than 60 minutes, or 70 minutes or more while it is possible to stirred or agitated for up to 70 minutes or less 60 minutes or less 50 minutes or less 40 minutes or less 30 minutes, less than 20 minutes, or 10 minutes or less.
[88]
In one aspect of the invention, the 6 step may further include the step of filtering the obtained suspension is stirred 3).
[89]
In one aspect of the invention, the 6 step 4) to the filtered suspension to remove water under a reduced pressure vacuum may further comprise the step of obtaining an R-type or S-type optical isomer of INT-3.
[90]
The present invention includes in divided chiral car a stereoisomer mixture of compounds having the structure of Formula 1 by the method according to one aspect of the present invention in one aspect; And a step of converting the divided stereoisomer of a compound having the structure of formula 3a or 3b,
[91]
[Formula 3a]
[92]
[93]
[Formula 3b]
[94]
[95]
Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; -NH 2 ; C 1-6 alkyl; C 2-6 alkenyl (alkenyl) group; C 2-6 alkynyl group (alkynyl) group; And is one selected from the group consisting of halogen,
[96]
Wherein R 1 and R 2 may each be directed to the process for producing the compound having the structure of Formula 3a or 3b with a different substituent. Wherein the conversion is described in detail in Korea Patent Application No. 10-2009-7004333.
[97]
In one aspect of the invention, a compound having a structure of the formula (3a) is (R) -N- [1- (4-methanesulfonyl sulfonyl 3,5-difluoro-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide and (PAC-14028), compounds having the structure of formula (I) is N- {4 - [(1R / S) -1 - aminoethyl] 2,6-difluoro may be a phenyl} methanesulfonamide.
[98]
In one aspect of the invention, the step of converting the divided stereoisomer of a compound having the structure of formula 3a or 3b is N- {4 - [(1R) -1- aminoethyl] -2,6-di-fluoro phenyl} methanesulfonamide (INT-3) and 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylic acid (INT-7) may be one comprising the step of coupling .
[99]
The method stereoisomers divided in accordance with an aspect of the present invention can be used as intermediates in the reaction by material disclosed in Korea Patent Application No. 10-2009-700433 Preparation of new drug disclosed in the instant application. Therefore, the invention in one aspect, by using the stereoisomers divided by the method according to an aspect of the invention Korea prepared by a method or such a method for preparing a novel drug that is described in Patent Application No. 10-2009-700433 that may relate to new drugs.
[100]
The present invention relates to a one aspect, (R) with the present invention one aspect at least 96% produced by the method according to, 97%, 98% or more, or at least 99% enantiomer excess of the -N- [1- ( 3,5-difluoro-4-methanesulfonyl-phenyl) - can relate to acrylamide-ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl).
[101]
The invention In one aspect, the produced by the method according to an aspect of the invention (R) -N- [1- (4-methanesulfonyl sulfonyl 3,5-difluoro-phenyl) -ethyl] 3 may relate to acrylamide TRPV1 antagonists including (PAC-14028) as an active ingredient (2-propyl-6-trifluoromethyl-pyridin-3-yl). The TRPV1 antagonist may be used as a pharmaceutical composition for the prevention or treatment of the following diseases described.
[102]
The invention according to one aspect, -N- (R) in accordance with an aspect of the present invention [1 - (sulfonyl-4-methanesulfonyl, 5-difluoro-phenyl) -ethyl] -3 (2 -propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide, an optical isomer thereof, or a pharmaceutically acceptable acceptable carrier comprising a salt thereof, and a pharmaceutically available, pain, inflammatory disease of the joints, neuropathy, HIV- related neuropathy, nerve injury, neurodegeneration, stroke, incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), increase stool urgency, the above-esophageal reflux disease ( GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, anorexia / allergic / inflammatory skin disease, psoriasis, itching, prurigo, irritation, inflammation of the eye or mucous membrane, auditory hypersensitivity, tinnitus, vestibular hypersensitivity, illustrations vertigo, myocardial ischemia, hairy, selected from the group consisting of hair loss, alopecia, rhinitis and pancreatitis. Carbonyl can relate to a pharmaceutical composition for the prevention or treatment of diseases which are associated with the pathological stimulation and / or over expression of the receptor Lloyd.
[103]
In one aspect of the invention, the pain from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative group consisting of pain, dental pain, fibromyalgia, myofascial pain syndrome and back pain, migraine and other types of headaches or selected disease or may be in pain associated with disease.
[104]
The invention in one aspect, the chiral auxiliary body; A polar aprotic solvent; It may relate to an optical resolution kit including; and operating instructions for the chiral auxiliary body.
[105]
In one aspect of the invention, the chiral auxiliary body is a 2,3-dibenzoyl-tartaric acid, O, O ' - di- p -toluoyl-tartaric acid, their stereoisomers, and be at least one selected from the group consisting of a combination of have.
[106]
In one aspect of the invention, the chiral auxiliary body may be 0.5 to 2.0 equivalents with respect to the stereoisomeric mixture of one molar equivalent to splitting optics.
[107]
In one aspect of the invention, the salt-forming auxiliary compound may be 0.8 to 1.5 equivalents with respect to the stereoisomeric mixture of one molar equivalent to splitting optics.
[108]
In one aspect of the invention, the user's guide is an optical resolution in the use of the optical chiral auxiliary member for the stereoisomeric mixture 1 molar equivalent to split 0.5 to 2.0 equivalents, specifically used in 0.8 to 1.5 equivalents of including the information that may be.
[109]
In one aspect of the invention, the manual may be one containing the content that is mixed with stereoisomeric mixture on using polar aprotic solvent, a chiral auxiliary body.
[110]
In one aspect of the invention, the manual may be one content is described according to a chiral resolution method of stereoisomeric mixtures according to one aspect of the present invention.
Mode for the Invention
[111]
It will be described below through examples and test examples of the present invention to. Examples and test examples are not intended to be limited to the scope of embodiments of the scope of the present invention is intended to illustrate the present invention in more detail. In addition, when a person of ordinary skill in the art that various modifications and mimic all within the appended claims without departing from the scope of the technical idea of ​​the invention possible is obvious.
[112]
[Comparative Test Example 1 Measurement of optical purity by a conventional asymmetric synthesis
[113]
To a conventional asymmetric synthesis it was carried out as in scheme 1.
[114]
[Reaction Scheme 1]
[115]
[116]
{2, 6-difluoro-4- [1- (2-methyl-propane-2-sulfinyl-butylimino) -ethyl] -phenyl} - methanesulfonamide N- of the amide (1 eq), the weight was dissolved by addition of tetrahydrofuran (tetrahydrofuran, THF) (20㎖) corresponding to the drain 10 and, in the solution of NaBH 4 after which the more soluble (4 eq) to a reaction for 10 hours at a temperature shown in Table 1 It was in progress. Then CH 3 was added dropwise until hydrogen gas is no longer the OH emission.
[117]
The mixture was concentrated under reduced pressure and then purified by chromatography, N- {2,6-difluoro-4- [1- (2-methyl-propane-2-sulfinyl) -ethyl] -phenyl} - to obtain the methanesulfonamide. A dropwise an excess of 4M HCl in dioxane was stirred for 30 minutes at room temperature the mixture was concentrated under reduced pressure. To give the crude residue was recrystallized with acetone, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] to give the methanesulfonamide, HCl salt.
[118]
To do this, the obtained salt by following the same process as the method of test to measure its enantiomer excess is shown in Table 1 below.
[119]
TABLE 1
[120]
It must, according to the conventional method continues for the temperature in order to obtain more than 96% of optically active or less -40 ℃ as shown in Table 110 hours maintaining a stirring and a solvent of the same optically active at a temperature of 50 ℃ according to the invention It can be achieved only by a step of purification. Thus, the method of the present invention in comparison with the conventional methods it can be determined that the remarkably economical. In addition, when the scale-up of this reaction to the plant unit, to maintain a temperature of 50 ℃ than maintaining a temperature of -40 ℃ for 10 hours, and much easier to adjust accordingly the method of the present invention is the conventional method compared to an effect that makes it easier to expand the scale of the reaction.

Claims

[Claim 1]A car method chiral partition (chiral resolution) of stereoisomeric mixture, to the mixture under aprotic solvent a stereoisomeric mixture of a polar and a chiral auxiliary body (chiral auxiliary) of a compound having the structure of formula 1, having the structure of formula (1) comprising the step of precipitating the compound as a chiral diastereomeric salts of the auxiliary body in mirror image excess, and [Chemical formula 1] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; -NH 2 ; C 1-6 alkyl; C 2-6 alkenyl (alkenyl) group; C 2-6 alkynyl group (alkynyl) group; And it is one selected from the group consisting of halogen, wherein R 1 and R 2 is a substituent having a different, chiral division of stereoisomeric mixture (chiral resolution) method.
[Claim 2]
2. The method of claim 1, wherein R 2 is hydrogen and the chiral auxiliary body is a 2,3-dibenzoyl-tartaric acid, O, O ' - di- p -toluoyl-tartaric acid, their stereoisomers, and the group consisting of a combination of one or more method selected from the.
[Claim 3]
The method of claim 1, wherein the method is a chiral auxiliary body (+) - 2,3-dibenzoyl -D- tartaric acid, (+) - O, O ' - di- p -toluoyl tartaric acid, and combinations thereof -D- If the one selected from the group consisting of, how to obtain the S-form enantiomer of the compound of formula (I) as enantiomer excess.
[Claim 4]
The method of claim 1, wherein the method is a chiral auxiliary bodies (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O ' - di- p -toluoyl tartaric acid, and combinations thereof -L- If the one selected from the group consisting of, how to obtain the R optical isomers of compounds of formula (I) as enantiomer excess.
[Claim 5]
According to claim 1, wherein said halogen is at least one method selected from the group consisting of F, Cl, Br and I.
[Claim 6]
The method of claim 5, wherein, R 1 is selected from methyl, ethyl, propyl, butyl, and pentyl groups, and the group consisting of, R 2 is a hydrogen method.
[Claim 7]
The method of claim 6 wherein, R 1 is a methyl group, and, R 3 and R 7 are hydrogen, R 4 , R 5 , and R 6 is F, Cl, Br, I and C 1-6 selected from the group consisting of alkyl groups one way.
[Claim 8]
The method of claim 7, wherein, R 4 and R 6 a is F, R 5 is a methyl group, wherein the compound is N- {4 - [(1R / S) -1- aminoethyl] 2,6-difluoro method phenyl} methanesulfonamide.
[Claim 9]
The method of claim 1, wherein the polar aprotic solvent is at least one method selected from ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and the group consisting of a combination of the two.
[Claim 10]
The method of claim 9 wherein the polar aprotic solvent is acetone method.
[Claim 11]
The method of claim 1, wherein the polar aprotic solvent is added in an amount sufficient to dissolve all of the mixture.
[Claim 12]
12. The method of claim 11, wherein the polar aprotic solvent is the method, based on the weight of the total of 5 to 15 multiples (v / w) of a stereoisomeric mixture.
[Claim 13]
The method of claim 1 wherein in the mixing method is carried out by increasing the temperature of the mixture to the boiling point or the boiling point of the solvent mixture of 40 ℃ to 70 ℃, solvent.
[Claim 14]
Claim 1 to claim 13 according to any one of, wherein the equivalent ratio of chiral auxiliary member for the stereoisomeric mixture one molar equivalent of the method of 0.5 to 2.0 equivalents.
[Claim 15]
The method of claim 14 wherein the equivalent ratio of chiral auxiliary body is 0.8 to 1.5 equivalents of a method for the stereoisomeric mixture of one mole equivalent.
[Claim 16]
15. The method of claim 14 wherein the stereoisomer mixture R-type isomer: the ratio of the S-type isomer 1: 9 to 9: 1 method.
[Claim 17]
17. The method of claim 16 wherein the stereoisomer mixture R-type isomer: the ratio of the S-type isomer 1: 3 to 1: 9 methods.
[Claim 18]
15. The method of claim 14, the method comprising the solid contained in the mother liquid after the step of precipitating the diastereomeric salt of a chiral auxiliary material compound and a car having the structure of formula (I) as enantiomer excess, to recover the precipitated diastereomeric salt R-type isomer of the isomer mixture: further comprising the step of adjusting a 3: an S-type isomer ratio of 3: 7 to 7.
[Claim 19]
19. The method of claim 18, wherein the R-type isomer: How would you adjusted to 4 comprising the steps of: adjusting the ratio of the S-type isomer is the ratio 4: 6 to 6.
[Claim 20]
The more than 80% is divided from the stereoisomeric mixture according to the method obtained according to 14, wherein at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, 94%, 96% or more, 97% or higher, 98% or more, or a stereoisomer of the compound of formula (1) at least 99% having a mirror image of the excess.
[Claim 21]
The method of claim 20 wherein the stereoisomer is N- {4 - [(1R) -1- aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4 - [(1S) -1 - aminoethyl] -2,6-difluorophenyl} methanesulfonamide of stereoisomers.
[Claim 22]
A method for producing a compound having the structure of formula 3a or 3b, the method comprising: dividing chiral car a stereoisomeric mixture of compounds having the structure of Formula 1 by the method according to any one of claims 1 to 13 wherein .; And a step of converting the divided stereoisomer of a compound having the structure of formula 3a or 3b, [Formula 3a] [formula 3b] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; -NH 2 ; C 1-6 alkyl; C 2-6 alkenyl (alkenyl) group; C 2-6 alkynyl group (alkynyl) group; And is one selected from the group consisting of halogen, wherein R 1 and R 2The method of one another compound having the formula 3a or 3b of the structure having a different substituent.
[Claim 23]
23. The method of claim 22 wherein the compound has a structure of the formula (3a) is (R) -N- [1- (4-methanesulfonyl sulfonyl 3,5-difluoro-phenyl) -ethyl] -3 (2 -propyl-6-trifluoromethyl-pyridin-3-yl) and acrylamide, a compound having the structure of formula (I) is N- {4 - [(1R / S) -1- aminoethyl] -2,2 method 6-difluoro-phenyl} -methanesulfonamide.
[Claim 24]
The method of claim 22 wherein the step of converting the divided stereoisomer of a compound having the structure of formula 3a or 3b is N- {4 - [(1R) -1- aminoethyl] 2,6-difluoro-phenyl } methanesulfonamide (INT-3) and 3 comprising the step of ring acrylic acid (INT-7) couple (2-propyl-6-trifluoromethyl-pyridin-3-yl).
[Claim 25]
The method of claim 22, wherein in the (R) -N- [1- (3,5- difluoro or more than 96%, 97%, 98% or more, or 99% with the mirror image excess prepared in accordance with 4- methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide.
[Claim 26]
2,3-dibenzoyl-tartaric acid, O, O ' - di- p -toluoyl-tartaric acid, their stereoisomers, and one or more chiral auxiliary material selected from the group consisting of a combination thereof; A polar aprotic solvent; Chiral and optically kit, which includes the instruction manual of the auxiliary body.
[Claim 27]
The method of claim 30, wherein the chiral auxiliary body is 0.5 to 2.0 equivalents of a kit for the stereoisomeric mixture 1 molar equivalent to splitting optics.
[Claim 28]
The method of claim 30, wherein the chiral auxiliary manual of the kit body to the method described in claim 18, claim.