Art
[1]
In the present specification, (R) -N- [1- (3,5- Difluoro-4-methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin- 3-1) - a novel method for producing the intermediate having the chirality of acrylamide (PAC-14028) is disclosed.
[2]
BACKGROUND
[3]
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.
[4]
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.
[5]
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.
[6]
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.
[7]
However, still a lot of medicines are used as a racemic compound which has an inevitable side effect in the presence of a gate enantiomer unwanted [Reference example: Nguyen, et al, Chiral Drugs:. An Overview, Int. J. Biomed. Sci., 2 (2006) 85-100]. While several techniques may be used for chiral division of the pre-analytical or scale, which takes a lot of time and effort to find the division technique in accordance with the desired racemate. Even if successfully enantiomer division (separation), and then the difficulty, that will face the problem to so as to enable the chiral division on an industrial scale.
[8]
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].
[9]
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, this method is because it is way to obtain selectively an optical isomer based solely on the specificity of the chiral auxiliary material, there is a limit to obtain a high optical purity. Further, the method since the demanding processing conditions such as to maintain a low temperature of about -50 ℃ reaction in order to enhance the optical purity (enantiomer excess,% ee) demand, expensive and time, the method is sensitive to the reaction temperature the failure to process high optical purity decreases with temperature control, there was a problem that could have an adverse effect on the quality of drug development.
[10]
Detailed Description of the Invention
SUMMARY
[11]
Thus, the present invention is the intermediate, (R) -N- of the drug substance to Elman methanesulfonamide (INT028-3) - [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl; while it prepared by the chiral auxiliary body, and it seeks to provide a novel method for manufacturing an optical purity in high optical isomers.
Problem solving means
[12]
The present invention to achieve the above object, according to one aspect, N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2, 6-fluoro-phenyl] - N- [4 which is stirred into a mixture of stereoisomers, the optical isomers of the methanesulfonamide mixed in a particular solvent, the precipitation solution - [(1R) -1 - [[(R) - (1,1-dimethylethyl) sulfinyl] amino] ethyl] phenyl] -2,6-difluoro-containing recrystallization steps, including that for obtaining a solid containing a methanesulfonamide, (R) -N - [4- (1-amino-ethyl) -2,6-difluoro-phenyl] provides a process for the preparation of methanesulfonamide.
[13]
Effects of the Invention
[14]
Method in accordance with one aspect of the present invention through a separate re-crystallization of the optical isomer while utilizing Elman selectivity of the chiral auxiliary material, drug substance is (R) -N- [1- (3,5-Difluoro-4-methane methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) intermediate having a chiral of acrylamide (PAC-14028), N- [4- ( with ethyl) -2,6-difluoro-1-amino-phenyl] can be produced methanesulfonamide (INT028-3) in high optical purity. For the method according to one aspect of the present invention is to overcome the limitations of Elman chiral auxiliary member having a low optical purity at room temperature, by introducing a recrystallization separated as a subsequent step, a high optical purity of N- [4- (1-ethyl phenyl] it can be obtained methanesulfonamide (INT028-3)) with 2,6-difluoro. This is avoided in the most demanding extremely low temperature condition of the secondary body Elman process was possible to obtain a high optical purity through. In other words it is possible to avoid the low temperature process, the auxiliary body Elman step of low optical purity at room temperature to implement the method of increasing the optical purity by re-crystallization separation and significantly reducing the losses due to the production process failure rate drug drug substance.
[15]
Brief Description of the Drawings
[16]
1 is N- (4- acetyl-2,6-difluorophenyl) methanesulfonamide (R) -N- from amide (INT028-1) [4- (1- Amino-ethyl) -2,6- difluoro-phenyl] a view showing a mechanism for producing a methanesulfonamide (INT028-3).
[17]
Best Mode for Carrying Out the Invention
[18]
Hereinafter, an embodiment of the present invention will be described in detail with reference to Figure 1 as a reference.
[19]
Drug substance is (R) -N- [1- (3,5- Difluoro-4-methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin- 3-1) for the production of acrylamide (PAC-14028) of the R-type intermediate N- methanesulfonamide (- [4- (1-phenyl-ethyl) -2,6-difluoro; the optical purity of INT028-3) is very important. Intermediate (R) -N- [4- (1- Amino-ethyl) -2,6-difluoro-phenyl] - synthesis method for the production of methanesulfonamide (INT028-3) in high optical purity of the drug a very important element of quality control.
[20]
Using a chiral auxiliary body Elman N- (4- acetyl-2,6-difluorophenyl) -methane-sulfonamide (INT028-1) from the intermediate (R) -N- [4- (1- Amino-ethyl ) -2,6-difluoro-phenyl] - methanesulfonamide in the process for synthesizing the amide (INT028-3) N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-difluorophenyl] the optical purity of the methane sulfonamide (INT028-2) (R) -N- [4- (1- amino-ethyl) 2, 6-difluoro-phenyl] determines the optical purity of the methanesulfonamide (INT028-3). Specifically, the optical purity is determined by the reduction of the Step2 of Figure 1, the N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl ] -2,6-difluorophenyl] - removing the Elman chiral auxiliary body (ellman chiral auxiliary) through Step 3 in methanesulfonamide (INT028-2) (R) -N- [4- (1- amino are prepared is methanesulfonamide (INT028-3) - ethyl) -2,6-difluoro-phenyl].
[21]
In this specification, N- (4-acetyl-2,6-difluorophenyl) -methane-sulfonamide is a compound of the CAS number 956901-21-6, refers to a molecular weight of 249.23 Da corresponds to, herein in in INT028-1 and it can be used as interchangeably.
[22]
In this specification, N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-difluoro-phenyl] -methanesulfonamide amide is meant a molecular weight of 354.44 Da for the compounds of CAS No. 956901-22-7 and herein may be used within the INT028-2 and interchangeably.
[23]
In this specification, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] - methanesulfonamide means for the CAS No. 956901-23-8 and , the specification can be used in the R-type isomer and interchangeably in INT028-3.
[24]
In this specification, (R) -N- [1- (3,5- Difluoro-4-methanesulfonyl-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridine 3-yl) acrylamide and (PAC-14028) is a means which corresponds to the molecular weight of 491.47 Da as for the CAS No. 1005168-10-4.
[25]
In this specification, the Elman chiral auxiliary material means a material effective chiral auxiliary for the preparation of a chiral amine.
[26]
In the method using the conventional Elman chiral auxiliary body which the reaction temperature in the above Step 2 has a problem emerges when the optical purity is significantly lower than -5. Thus a high optical purity (R) -N- [4- (1- Amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide (INT028-3) of -48 cares to produce a low was the difficulty in the process need to control the reaction temperature to a temperature, the reaction is sensitive to temperature higher the failure rate of the process temperature control.
[27]
Thus, the present invention is of high optical purity in the reaction with a chiral auxiliary Elman body at room temperature (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] methanesulfonamide the method to provide a capable of producing an amide (INT028-3).
[28]
One embodiment of the invention (R) -N- by the production process of methanesulfonamide (INT028-3), - [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl;
[29]
The lower the optical purity of N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-difluoro-phenyl] -methanesulfonamide by stirring into a mixture of stereoisomers, the optical isomers of the amide to a mixed solvent of a high optical purity of the solution to be precipitated N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl It may include a re-crystallization step comprising obtaining a solid containing methanesulfonamide -) sulfinyl] amino] ethyl] -2,6-diphenyl] fluoro.
[30]
Solvent in the recrystallization step according to one embodiment the group consisting of isopropyl alcohol (Isopropyl alcohol, IPA), methanol (MeOH), ethyl acetate (Ethyl acetate, EtOAc), toluene (toluene) and isopropyl acetate (Isopropyl acetate) at least one selected from can include.
[31]
More specifically, one embodiment is a solvent for the recrystallization step, isopropyl alcohol (Isopropyl alcohol, IPA), methanol: ethyl acetate (MeOH: EtOAc) (1: 8), methanol: ethyl acetate (1: 6), ethyl acetate (ethyl acetate, EtOAc), ethyl acetate: toluene (EtOAc: toluene) (1: 2), ethyl acetate: toluene (1: 1) and isopropyl acetate (isopropyl acetate) to may include one selected from the group consisting of have. The recrystallization step reacts specifically to the solvent, N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6 -difluorophenyl] - N- in the R-type from a mixed stereoisomeric mixture of optical isomers of methanesulfonamide [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl it is possible to obtain the methanesulfonamide (INT028-2) in high optical purity - carbonyl] amino] ethyl] -2,6-difluorophenyl]. More specifically, the solvent can be isopropyl alcohol (Isopropyl alcohol, IPA).
[32]
In one embodiment stirring temperature of the recrystallization step may be a -5 ℃ to 35 ℃, but is not limited thereto. Specifically, the stirring temperature is more than -5 ℃, 0 ℃ may be at least, more than 5 ℃, 10 ℃ or more, or more than 35 ℃, 30 ℃ ℃ than 15, more than 20 ℃, more than 25 ℃, less than 50 ℃, It may be less than 45 ℃, 40 ℃ or less, 35 or less ℃, 30 ℃ or less, 25 or less ℃, 20 ℃ or less, 15 or less ℃, 10 ℃ or less, 5 or less ℃, 0 ℃, or not greater than -5 ℃ days. More specifically, the stirring temperature may be a -5 ℃ to 5 ℃, -5 ℃ to 10 ℃, 10 ℃ to 20 ℃ or 20 ℃ to 35 ℃, but is not limited thereto.
[33]
The re-crystallization step in one embodiment is a solid that is filtered off the precipitate N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] - 2,6-diphenyl; fluoro-a to obtain the methanesulfonamide (INT028-2) may further include.
[34]
In one embodiment of the present invention, the stirring time is more than 1 hour, 3 hours or more, 5 hours or more, 8 hours or more, 10 hours or more, about 11 hours, more than 12 hours, more than 13 hours, more than 14 hours, 15 hours later, 16 hours later, 17 hours later, 18 hours later, 19 hours later, 20 hours later, 30 hours, 40 hours, at least 50 hours, or 100 hours 100 hours, 80 hours, less than 50 hours , 40 hours, 30 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 8 hours, 5 hours, can be not more than 4 hours, less than 3 hours or 1 hour. Specifically, the stirring time may be 50 hours or less for 5 hours or more, may be more specifically the stirring time is 10 hours to about 15 hours.
[35]
In one embodiment of the present invention, the N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-di-fluoro phenyl] -methanesulfonamide a stereoisomeric mixture of optical isomers are a mixture of amides can mean that the two diastereomers as isomeric compounds having an optically active mixture, then the mixture ratio R, R-type optical isomer: R , optical isomer = 1 other than the R-type: be 1, and (racemic mixture with the corresponding), or the mixing ratio is R, R-type optical isomer: integer between 3: R, optical isomers other than R-type = 1: 1 to 97 rain may be applicable in. In one embodiment of the invention, the stereoisomer mixture may be that synthesized artificially with or or a mixture of not knowing the proportion of the R-type optical isomer and an S type optical isomers. 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. As a more specific example, in the case of the mixing ratio of 1:10 it may obtain an optical purity of about 90%, wherein the mixing ratio of 97: 3 when the can to obtain an optical purity of about 94%.
[36]
Further, according to one embodiment of the invention, the method is a synthesis step of the stereoisomeric mixture before the recrystallization step, N- (4- acetyl-2,6-difluorophenyl) -methane-sulfonamide (N- (4-acetyl-2,6-difluorophenyl ) -methanesulfonamide) (INT028-1 R-2- methyl to a solution containing a) - propane sulfinic amide (R-2-methyl-propanesulfinamide ) and titanium (ethoxide) 4 ( Ti (OEt) 4 ) was added to the mixture, followed by the addition of borohydride (borohydride) and the reaction N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) may further comprise the synthesis of methane sulfonamide-sulfinyl] amino] phenyl] ethyl] 2,6-difluoro.
[37]
In one embodiment, the borohydride is a borohydride may include all without reduction reaction (borohydride reduction) is as long as possible limited, as a specific example sodium view it hydride (Sodiumborohydride, NaBH 4 ), sodium cyanoborohydride hydro fluoride (Sodium cyanoborohydride, NaBH 3 CN) or triacetoxyborohydride in hydride (triacetoxyborohydride, NaHB (OAc) 3 ) may include. The reaction temperature with the borohydride may be -50 ℃ to 35 ℃, specifically -5 ℃ to 35 ℃. That is, the present invention eliminates the need to maintain a low temperature of -48 ℃ as in the prior art the temperature of Step 2, by including the re-crystallization step, it is possible in the above -5 ℃ proceed to the Step 2. Specifically, the reaction with the borohydride may be carried out with stirring, the stirring temperature is more than -5 ℃, more than 0 ℃, more than 5 ℃, more than 10 ℃, more than 15 ℃, more than 20 ℃, 25 ℃ or more, 30 ℃ or more or 35 ℃ may be more than, 50 ℃ below 45 ℃ below 40 ℃ below 35 ℃ below 30 ℃ or less, less than 25 ℃, less than 20 ℃, less than 15 ℃, less than 10 ℃, 5 ℃ or less, and may be below 0 ℃ or below -5 ℃. More specifically, the stirring temperature may be a -5 ℃ to 5 ℃, -5 ℃ to 10 ℃, 10 ℃ to 20 ℃ or 20 ℃ to 35 ℃, but is not limited thereto.
[38]
In one embodiment of the present invention, the stirring time is more than 1 hour, 3 hours or more, 5 hours or more, 8 hours or more, 10 hours or more, about 11 hours, more than 12 hours, more than 13 hours, more than 14 hours, 15 hours later, 16 hours later, 17 hours later, 18 hours later, 19 hours later, 20 hours later, 30 hours, 40 hours, at least 50 hours, or 100 hours 100 hours, 80 hours, less than 50 hours , 40 hours, 30 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 8 hours, 5 hours, can be not more than 4 hours, less than 3 hours or 1 hour. Specifically, the stirring time may be 50 hours or less for 5 hours or more, may be more specifically the stirring time is 10 hours to about 15 hours.
[39]
In one embodiment, the N- (4-acetyl-2,6-difluorophenyl) - solution containing the methane sulfonamide (INT028-1) are the N- (4-acetyl-2,6-difluoro phenyl) - but it may be prepared by dissolving the methane sulfonamide in an aprotic solvent, wherein the aprotic solvent is N- (4-acetyl-2,6-difluorophenyl) - capable of dissolving the methane sulfonamide solvents, if not limited to, for example, tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 , dicloromethane), diethyl ether (Et 2 can include O, Diethylether), toluene (tOLUENE) and the like.
[40]
{2, 6-difluoro-4- [1- (2-methyl-propane-2-sulfinyl-butylimino) -ethyl] -phenyl} - N- wherein one embodiment methanesulfonamide an aprotic R-2- methyl added to the solution of the solvent-propane sulfinic amide (R-2-methyl-propanesulfinamide ) and titanium (ethoxide), 4 (Ti (OEt) 4 equivalent ratio of) is from 1: 1 to 1: 0.5 days can.
[41]
In one embodiment, the synthesis step of the stereoisomer mixture may further comprise the step of cooling the mixture after the synthesis reaction of the mixture. In one embodiment, the synthesis step of the stereoisomer mixture may be filtered, neutralized, extracted for purification to give the mixture may further comprise the step of purification was concentrated under reduced pressure.
[42]
In addition, the method in accordance with one embodiment of the present invention, since the re-crystallization step the N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl ] -2,6-difluorophenyl] - methanesulfonamide solids containing hydrochloric acid (HCl) solution was mixed with (R) -N- [4- (1- amino-ethyl) -2,6- fluoro-phenyl] may further include the step of obtaining a methanesulfonamide. More specifically, the step may be mixed with a hydrochloric acid solution having a normality of 3N to 6N solids in methanol. The steps in one embodiment, after the above solid was mixed with hydrochloric acid solution with a normality of 3N to 6N, (R) and concentrated under reduced pressure and purified with acetone -N- [4- (1- Amino-ethyl) with 2,6-difluoro-phenyl] may further include obtaining a methanesulfonamide.
[43]
According to one embodiment of the method of the present invention described above, N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] methanesulfonamide in the R-type optical isomer, i.e., (R may provide the methanesulfonamide as a high optical purity -) -N- [4- (1- amino-phenyl-ethyl) -2,6-difluoro. As used herein, the term "high optical purity" is the term "high optical purity" in one embodiment as a well-known term in the art, the optical purity value (enantiomeric excess, ee%) is 80% or more, 90 % may be one or more or more, 95% or higher, 96% or higher, 97% or higher, 98% or 99%. [--2,6-difluoro-4- (1-amino-ethyl) -phenyl] Specifically, one embodiment (R) is prepared according to Example -N- of the present invention the optical purity of the methanesulfonamide 96 % may be less than 100%.
[44]
The R-isomer form divided into a method according to an embodiment 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. Thus, the method of the present invention, in one embodiment, to prepare a new medication that by using the above-mentioned R-type stereoisomers divided by the method according to one embodiment of the present invention is described in Korea Patent Application No. 10-2009-700433 or it can relate to a novel drug prepared in such a way.
[45]
The invention in one embodiment, has a mirror image excess of at least 96% produced by the method according to one embodiment of the invention, 97%, 98%, 99% or more, or 96% to 99% ( R) -N- [1- (4-methanesulfonyl sulfonyl 3,5-difluoro-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) - it can relate to acrylamide.
[46]
The present invention is one embodiment a method of (R) -N- [1- (4-methanesulfonyl sulfonyl 3,5-difluoro-phenyl) -ethyl] prepared in accordance with one embodiment of the present invention; it is possible to provide a TRPV1 antagonist containing acrylamide (PAC-14028) as an active ingredient, 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl). The TRPV1 antagonists may be used in pharmaceutical compositions for the prevention or treatment of the following diseases described.
[47]
Furthermore, the present invention according to one embodiment, -N- (R) according to one embodiment of the present invention [1 - (4-methanesulfonyl amino-3,5-difluoro-phenyl) -ethyl] 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) acrylamide, an optical isomer thereof, or, pain, joint comprising an acceptable carrier into a salt thereof and a pharmaceutically available pharmaceutically acceptable inflammatory disorders, neurological disorders, 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 - gastroesophageal 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, the group consisting of vertigo episode, myocardial ischemia, hairy, hair loss, alopecia, rhinitis and pancreatitis. Selected banil 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.
[48]
In the practice of the present invention the herein disclosed one example, the pain osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, dental pain, fibromyalgia, myofascial pain syndrome and back pain, migraine, and other types diseases selected from the group consisting of headache or pain, or may be associated with the disease.
[49]
Mode for the Invention
[50]
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.
[51]
[52]
[Comparative Test Example 1]
[53]
Proceeds to N- [4, such as to a conventional asymmetric synthesis - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] 2,6-difluoro phenyl] - it was synthesized stereoisomeric mixture of methanesulfonamide (INT028-2).
[54]
Specifically, N- (4-acetyl-2,6-difluoro-phenyl) methane sulfonamide (INT028-1) 30g (1 equivalent) of the solution was dissolved by addition of tetrahydrofuran (THF), 300ml R-2- methyl-propane sulfinic amide (R-2-methyl-propanesulfinamide ) N- ( 4-acetyl-2,6-difluoro-phenyl) - with respect to 1 equivalent of methane sulfonamide (INT028-1) 1.3 equivalents, titanium (ethoxide), 4 (Ti (OEt) 4 ) the N- (4-acetyl-2,6-difluorophenyl) was added to 2 equivalents relative to 1 equivalent of methane sulfonamide (INT028-1) did. Then, in the heating under reflux conditions, the mixture was stirred for 16 hours.
[55]
Was lowered and the solution is completed, the stirring at a temperature of Comparative Example 1 (-48 ℃), Comparative Example 2 (-5 ~ + 5 ℃) , Comparative Example 3 (20 ~ 25 ℃), NaBH 4 to 1 mixture of diastereomers with respect to the equivalents added to 4 equivalents, and is stirred again for 12 hours. After addition of saturated NaCl (aq) and the resulting solid was removed by filtration, neutralized and the filtrate was extracted with ethyl acetate (ethyl acetate) and concentrated.
[56]
TABLE 1
Stirring the reaction temperature (℃) INT028-2 (in%)
Comparative Example 1 -48 96.4
Comparative Example 2 -5~+5 74.1
Comparative Example 3 20~25 72.2

[57]
[58]
As a result, in order to produce the INT028-2 of high optical purity in the prior art and the reaction temperature control is required at a low temperature as in Comparative Example 1, optical, if the reaction temperature is less than -5 ℃ As shown in Table 1 you can see the purity (diastereomer excess, de) and fumes significantly lower.
[59]
[60]
Test Example 1
[61]
According to one embodiment of the present invention (R) -N- was prepared methanesulfonamide (INT028-3) - [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl].
[62]
First, the Comparative experimental example 1] After re-crystallization of the solid-state method of the comparative example 2 (INT028-2) prepared by adding a solvent described in Table 2 below, respectively, the mixture was stirred at various temperatures for filtering solids which precipitated phase solution It was carried out this step.
[63]
TABLE 2
Mixing temp (℃) menstruum INT028-2 (in%)
Comparative Example 2 20~35 - 74.1
Example 1 IPA 99.1
Example 2 MeOH:EtOAc=1/8 98.4
Example 3 MeOH:EtOAc=1/6 98.7
Example 4 EtOAc 96.3
Example 5 EtOAc:Toluene=1:2 96.1
Example 6 EtOAc:Toluene=1:1 96.7
Example 7 Isopropyl acetate 96.6
Comparative Example 4 Methanol -
Comparative Example 5 Ethanol -
Comparative Example 6 Toluene 76.4
Example 8 -5~+10 IPA 96.4
Example 9 MeOH:EtOAc=1/8 96.1
Example 10 Isopropyl acetate 94.1
Example 11 +10~+20 IPA 97.6
Example 12 MeOH:EtOAc=1/8 97.2
Example 13 Isopropyl acetate 96.0

[64]
The results [Table 2] carried out via the re-crystallization step at the same temperature stirring in order to compare the result of the optical purity according to a comparative example 2 of the solvents INT028-2 low optical purity, as in the examples 1 to 7, the optical purity 96 We can see that it has dramatically increased% de or higher. The Examples 1 to 7, Examples 8 to 10 and carrying out re-crystallization steps from Examples 11 to 13 exhibited a high optical purity of all even at room temperature without being affected by the stirring temperature of at least 96% de. This can be avoided if a low temperature process According to the present invention can more easily increase the processing scale.
[65]
Further, the recrystallization step was the case of using methanol and ethanol as the reaction only in a specific solvent, and the Comparative Examples 4 to 6 as a solvent has been INT028-2 dissolves both the solvent did not re-crystallization is achieved, when toluene as the solvent There was low optical purity. The IPA was the solvent of the first embodiment of the optical purity of the various solvents was good, because it is a single solvent is determined to be most effectively applied in the process conditions.
[66]
The results show that the synthesized INT028-2 according to conventional methods by giving significantly increase the optical purity by the recrystallization step, even if the mixture has a lower optical purity from the ambient conditions, can be obtained in more than 96% optical purity of the INT028-3 it means.
[67]
[68]
Table 3 shows that as a result subjected to three times to the procedure of Example 1, a method according to an embodiment of the present invention exhibits a repetitive reproducibility can be produced under stable INT028-3 process at a high optical purity it means.
[69]
TABLE 3
Example INT028-1 inputs INT028 -2 ( to% ) INT028 -3 ( in% )
1 30g 99.7 99.9
1 30g 99.7 99.9
1 30g 99.7 99.9

Claims
[Claim 1]
N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-difluorophenyl] - enantiomer of methanesulfonamide is to a stereoisomeric mixture stirred and mixed into a solvent, N- precipitated the solution [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] 2,6-difluorophenyl] - include a recrystallization step, a solvent in the recrystallization step comprises obtaining a solid containing methanesulfonamide is isopropyl alcohol (isopropyl alcohol, IPA), methanol (MeOH) , ethyl acetate (ethyl acetate, EtOAc), toluene (toluene) and isopropyl acetate (isopropyl acetate) containing at least one selected from the group, (R) -N- [4- (1- amino-ethyl) consisting of with 2,6-difluoro-phenyl] - method of methanesulfonamide.
[Claim 2]
The method of claim 1 wherein the solvent in the recrystallization step is isopropyl alcohol (Isopropyl alcohol, IPA), methanol: ethyl acetate (MeOH: EtOAc) (1: 8), methanol: ethyl acetate (1: 6), ethyl acetate ( ethyl acetate, EtOAc), ethyl acetate: toluene (EtOAc: toluene) (1: 2), ethyl acetate: 1) and isopropyl acetate (is selected from the group consisting of: isopropyl acetate), (R) - toluene (1 N- [4- (1- amino-ethyl) -2, 6-difluoro-phenyl] - method of methanesulfonamide.
[Claim 3]
The method of claim 1 wherein the solvent in the recrystallization step of isopropyl alcohol, (R) -N- (Isopropyl alcohol, IPA) [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl; - the method of methanesulfonamide.
[Claim 4]
The method of claim 1, wherein the stirring temperature of the recrystallization step of -5 ℃ to 35 ℃, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] methanesulfonamide the method of insertion phone amide.
[Claim 5]
The method of claim 1, wherein the stirring temperature of the recrystallization step of 20 ℃ to 35 ℃, (R) -N- [4- (1- Amino-ethyl) -2,6-difluoro-phenyl] methanesulfonamide the method of von amide.
[Claim 6]
The method of claim 1, wherein the stirring temperature of the recrystallization step of -5 ℃ to 5 ℃, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] methanesulfonamide the method of insertion phone amide.
[Claim 7]
The method of claim 1, wherein the re-crystallization step, further comprising the step of filtering the solid that is the precipitate, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl ] the method of methanesulfonamide.
[Claim 8]
The method of claim 1, wherein the method is a synthesis step of the stereoisomeric mixture before the recrystallization step, N- (4-acetyl-2,6-difluoro-phenyl) - R-2 To a solution containing methane sulfonamide -methyl-propane sulfinic amide (R-2-methyl-propanesulfinamide ) and titanium (ethoxide), 4 (Ti (OEt) 4 was added) were mixed then added, borohydride (borohydride) and the reaction N- [ 4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2,6-difluorophenyl] - further comprises the synthesis of methane sulfonamide [--2,6-difluoro-4- (1-amino-ethyl) -phenyl] of, (R) -N- method of methanesulfonamide.
[Claim 9]
9. The method of claim 8 wherein the borohydride reaction and the temperature of the hydride is -5 ℃ to 35 ℃, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl; - the method of methanesulfonamide.
[Claim 10]
9. The method of claim 8 wherein the N- (4- acetyl-2,6-difluorophenyl) - solution containing the methane sulfonamide is, the N- (4- acetyl-2,6-difluorophenyl) - the methane sulfonamide is, (R) -N- manufactured by dissolving in an aprotic solvent - - a-2,6-difluoro-4- (1-amino-ethyl) -phenyl] methanesulfonamide Preparation of Way.
[Claim 11]
The method of claim 10 wherein the N- (4-acetyl-2,6-difluoro-phenyl) - R-2- methyl which the methane sulfonamide is added to the solution in an aprotic solvent-propane sulfinic amide (R-2 -methyl-propanesulfinamide) and titanium (ethoxide), 4 (Ti (OEt) 4 equivalent ratio of) is from 1: 1-1: 0.5, (R) -N- [4- ( 1- amino-ethyl) -2, 6-difluoro-phenyl] - method of methanesulfonamide.
[Claim 12]
The method of claim 8 wherein the synthetic steps of the stereoisomeric mixture, further comprising the step of purification and then the mixture was concentrated under reduced pressure, (R) -N- [4- (1- Amino-ethyl) -2, 6-difluoro-phenyl] - method of methanesulfonamide.
[Claim 13]
The method of claim 1, wherein the method after the re-crystallization step, wherein the N- [4 - [(1R) -1 - [[(R) - (1,1- dimethylethyl) sulfinyl] amino] ethyl] -2, 6-difluorophenyl] - methanesulfonamide solids containing hydrochloric acid (HCl) was mixed with solution of (R) -N- [4- (1- amino-ethyl) -2, 6-difluoro-phenyl ] - methanesulfonamide, comprising the step of obtaining a phone amide, (R) -N- [4- (1- amino-ethyl) -phenyl] -2,6-difluoro a method of producing a methanesulfonamide.
[Claim 14]
The method of claim 13, wherein said (R) -N- [4- (1- Amino-ethyl) -phenyl-2,6-difluoro] to obtain the methanesulfonamide is, to the above solid 3N [--2,6-difluoro-4- (1-amino-ethyl) -phenyl] was mixed with hydrochloric acid solution with a normality of 6N, and concentrated under reduced pressure, and purified with acetone (R) -N- - [--2,6-difluoro-4- (1-amino-ethyl) -phenyl] methane, which comprises obtaining a scaling phone amide, (R) -N- method of methanesulfonamide.
[Claim 15]
Claim 1 to claim 14, wherein of the method according to any of the preceding, (R) manufactured according to the method methanesulfonic -N- [4- (1-amino-ethyl) -phenyl-2,6-difluoro; the optical purity of the phone amide is (R), it is less than 100% to 96% -N- [4- (1- amino-ethyl) -phenyl-2,6-difluoro] the method of methanesulfonamide.