TW201833071A - Racemization method of enantiomers of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide - Google Patents

Abstract

The present invention discloses a process which is capable of the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (R/S=1/1 The remaining S-form image isomers after selective separation of the R-form mirror isomers included in the conversion are converted to racemic N-[4-(1-aminoethyl)- via racemization. 2,6-Difluoro-phenyl]-methanesulfonamide. This method allows recycling of previously discarded S-form mirror isomers and is therefore economical. In addition, the process enables racemization of the S-form mirror image isomers at higher yields than conventional recycling techniques without contamination due to material changes.

Description

Race-down method of the mirror image isomer of N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide

The present invention discloses a novel racemic process for the mirror image isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide.

Recently, the demand for stereochemically pure compounds has increased rapidly. An important use of such pure stereoisomers is that they are used as intermediates in the pharmaceutical industry. For example, it has become increasingly apparent that mirror-isomerized pure drugs have many advantages over racemic drug mixtures. These advantages typically include fewer side effects and better efficacy of the mirror-isomerized pure compound.

For example, triazolyl can exist as four isomers. The (-)-(1S,2R)-isomer has higher activity than the (+)-(1R,2R)-isomer, and the (-)-(1S,2S)-isomer has a ratio ( +) - (1R, 2S) - Isomers are more active. Among the four isomers of dichlorobutyrazole, the (1R, 2R)-isomer is known to have higher activity. Further among the ethoxime compounds, it is known that the (+)-(2S,4S)- and (-)-(2S,4R)-isomers have better fungicidal effects than other isomers.

Therefore, if only one kind of highly active isomer can be selectively prepared, a smaller amount can be used to obtain a better effect, and thus environmental pollution due to the use of chemicals can be reduced. Especially for drugs, if one of the isomers shows toxicity in the human body, it is very important to selectively prepare only one isomer.

The efficacy of pure stereoisomers of vanilloid antagonists including N- [4-(1-aminoethyl)-phenyl]-sulfonamide derivatives has been elucidated. A known method for the synthesis of a single isomer of N- [4-(1-aminoethyl)-phenyl]-sulfonamide derivatives is the asymmetric synthesis using an Ellman adjuvant. For example, WO2007-133637 A2, WO2007-129188 A1 and WO2010-010934 A1 provide a method for obtaining a desired stereoisomer by introducing an Ellman adjuvant and using the adjuvant to induce asymmetric reduction. However, in this method, since the optical isomer is selectively obtained based only on the specificity of the palmarity aid, the remaining mixed isomer after the selective separation of the optical isomer is discarded. Therefore, this method has problems of inefficiency and environmental pollution.

[technical problem]

Accordingly, the present invention provides a novel method which is capable of preparing an intermediate as a new drug substance (PAC-14028) and having a palmitic N-[4-(1-aminoethyl)-2,6-difluoro -Phenyl]-methanesulfonamide (INT028-3), in the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonate The remaining S-form image isomer after the selective separation of the R-form areomers included in the amine (R/S = 1/1) is converted back to the racemic N-[4 via racemization. -(1-Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide. [Solution to the problem]

In order to achieve the above object, an aspect of the present invention provides a racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, which comprises the steps of: The compound of the following Chemical Formula 1 is added to a dichloromethane solvent and a halogenating agent is added; pyridine is added to the solvent and the reaction is carried out; and a reducing agent is added to the solvent and the reaction is carried out: [Chemical Formula 1] wherein R ₁ and R ₂ are each alkyl or halogen, and R ₃ is -HNSO ₂ CH _3.

Further, an aspect of the present invention provides a process for producing (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, which comprises the steps of: The optical isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide is isolated to obtain the R-form image isomer, (R)-N- [4-(1-Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide; and according to the above-described racemic method, the R-form image isomers obtained at the above steps are not included. The S-form image isomerism is racemized. [Advantageous Effects of the Invention]

In the preparation of a new drug substance (PAC-14028), N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as a middle substance and having a palmarity The optical purity of (INT028-3) is very important. The method according to one aspect of the invention allows for the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (R/S=1/ The remaining S-form smectomers after selective separation of the R-form smectomers included in 1) are converted to racemic N-[4-(1-aminoethyl) via racemization. -2,6-Difluoro-phenyl]-methanesulfonamide, enabling the recycling of previously discarded S-form mirror isomers, and is therefore economical. The process according to the invention improves the low yield of 20-30% for conventional racemic methods for amino acids and the incompatibility with recycling processes due to impurities. This process allows for the racemization of the S-form areomers in a yield of about 50% or greater without contamination due to material changes.

[Examples]

As used herein, the term (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide refers to CAS number 957103-01-4. In this specification, this term is used interchangeably with the R-form isomer of INT028-3.

As used herein, the term (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide refers to CAS number 1005237-71-7. In this specification, this term is used interchangeably with the S-form isomer of INT028-3.

As used herein, the term racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide refers to a mixture of optically active isomer compounds, wherein Its R-form isomer, ie (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide and its S-form isomer, That is, (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide can be mixed, and the R-form isomer and the S-form isomer The ratio of things can be 1:1. In this specification, this term is used interchangeably with INT028-3rac. Racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide has CAS number 1202743-51-8.

As used herein, the term (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl) The base-pyridin-3-yl)-acrylamide (PAC-14028) refers to CAS number 1005168-10-4, which has a molecular weight of 491.47 Da.

Hereinafter, one embodiment of the present invention will be described in detail.

In the preparation of a new drug substance, namely (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6- In the process of trifluoromethyl-pyridin-3-yl)-propenylamine (PAC-14028), its intermediate, ie (R)-N-[4-(1-aminoethyl)-2,6 The optical purity of -difluoro-phenyl]-methanesulfonamide is very important. Although intermediates have been developed for the preparation of higher optical purity, namely (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonate a method of synthesizing an amine, but there is still a problem that (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide remaining after separation is discarded, This is true even when the optical purity is high.

Conventional racemic methods involve the racemization of amino acids using strong bases, and the racemization using some aldehydes is also well known. However, when the above method is applied to the racemization of (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, it has 20-30% Very low yields and increased contamination due to material changes, ie impurities. Therefore, it is virtually impossible to apply these methods to the process.

In order to solve the problem, the present invention provides a racemic method which is applied to the elimination of (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide Higher optical purity is exhibited when spinning, and thus can be effectively applied to the process.

One embodiment of the present invention provides a racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, which comprises the steps of: The compound is added to a dichloromethane solvent and a halogenating agent is added; pyridine is added to the solvent and the reaction is carried out; and a reducing agent is added to the solvent and the reaction is carried out: Chemical formula 1.

In Chemical Formula 1, R ₁ and R ₂ are each an alkyl group or a halogen according to one embodiment, and R ₃ is -HNSO ₂ CH ₃ . Specifically, R ₁ and R _{2 of} Chemical Formula 1 may be a halogen. More specifically, R ₁ and R ₂ may be F.

In one embodiment, the compound of Formula 1 is (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide.

According to one embodiment, the halogenating agent is not limited as long as it can provide a halogenated material such as chlorine, bromine and iodine. For example, the halogenating agent may be selected from the group consisting of trichloroisocyanuric acid, N-chlorosuccinimide, N-bromosinium imine, and N-iodosuccinimide.

In one embodiment, the reducing agent may be selected from the group consisting of palladium on carbon (Pd/C), lithium aluminum hydride (LAH), and sodium borohydride (NaBH ₄ ). Specifically, the weight ratio of palladium (Pd) to carbon (C) in the reducing agent Pd/C may be 1 to 20.

Referring to FIG. 2, if the halogenating agent according to one embodiment is trichloroisocyanate, that is, TCCA, when two TCCAs of -NH ₂ in the chemical formula 1 are added to the solvent of dichloromethane, Each of them is replaced with a chlorine atom. Subsequently, upon addition of pyridine to the solvent and reaction of the mixture, one of the two chlorine atoms is separated and the nitrogen forms a double bond, as shown in the second compound of Figure 2. Subsequently, the double bond is converted to a single bond by a reducing agent, and the hydrogen atom is bonded again to form a racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]- Sulfonamide.

In one embodiment, the volume of the dichloromethane solvent may be (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide added to the solvent. It is 5 to 20 times (v/w), more specifically 10 to 15 times the weight.

In one embodiment, the amount of pyridine is from 0.3 to 2.0 equivalents, more specifically from 1 to 2 equivalents, per compound of Chemical Formula 1 added to the solvent.

In one embodiment, the racemic process may further comprise a cooling step after the reaction of each step. In one embodiment, the step of adding a reducing agent and performing the reaction may include filtering, neutralizing, and extracting to purify the reactant, and may further include the steps of concentrating and purifying them under reduced pressure.

The S-form optical isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide can be obtained in high yield according to the method of one embodiment of the present invention. , that is, the compound of Chemical Formula 1 to provide racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide. The term "high yield" as used herein is well known in the art of the present invention. In one embodiment, it may mean that the S-form optical isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide is used to produce racemization. The yield of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide is 50% or more, 60% or more, 70% or more. 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more. Specifically, the yield of the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide prepared according to one embodiment of the present invention may be 50% to less than 100%.

One embodiment of the present invention provides a process for the preparation of (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, which comprises using a racemic method The step of recycling is shown in Figure 1.

Specifically, the preparation method may include the steps of separating an optical isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide to obtain an R-form Mirror image isomer, (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide; and racemic compound of formula 1 according to the above procedure This compound is an S-form mirror image isomer obtained at the above step and excluding the R-form mirror image isomer.

Further, in one embodiment, the method may further comprise the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonate prepared according to the racemic step. The optical isomer of the amine is again separated to obtain the R-form image isomer.

In one embodiment, the step of obtaining (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide may include any method without limitation, as long as It is a method capable of obtaining an R-form image isomer by separating an optical isomer of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide . For example, this step can include asymmetric synthesis using an Ellman adjuvant.

The R-form isomer obtained by the method according to one embodiment of the present invention can be used as an intermediate for preparation by reaction with a substance described in Korean Patent No. 10-1410318 The novel drug described in this patent. Accordingly, an embodiment of the present invention may be directed to a method of preparing a novel drug as described in Korean Patent No. 10-1410318, using an R-form stereoisomer isolated according to an embodiment of the present invention, or by This method is used to prepare novel drugs.

One embodiment of the present invention provides a TRPV1 antagonist comprising (R)-N-[1-(3,5-difluoro-4-methylsulphonylamino-phenyl)-ethyl]- thus prepared. 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine (PAC-14028) was used as an active ingredient. The TRPV1 antagonist can be used in a pharmaceutical composition for preventing or treating the following diseases.

Furthermore, an embodiment of the present invention may be directed to a pharmaceutical composition for preventing or treating a disease associated with pathological stimulation and/or aberrant expression of a vanilloid receptor selected from the group consisting of pain, arthritic diseases, neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, stomach/duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), stool stress Sense, gastroesophageal reflux disease (GERD) Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathy / allergic / inflammatory skin disease, psoriasis, pruritus, pruritus, skin irritation, eye Or mucosal inflammation, auditory allergy, tinnitus, vestibular allergy, paroxysmal vertigo, myocardial ischemia, hirsutism, hair loss, hair loss, rhinitis and pancreatitis, the pharmaceutical composition comprising (R)-N-[1-(3, 5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine, optical isomerism Or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable Of the carrier.

In one embodiment of the invention, the pain may be a disease selected from or associated with a group consisting of: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, after surgery Pain, toothache, fibromyalgia, myofascial pain syndrome, back pain, migraine and other types of headache. [Example]

Hereinafter, the present invention will be described with reference to the following examples and test examples. However, the following examples and test examples are for illustrative purposes only, and the scope of the disclosure is not limited by such examples. Further, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the scope of the invention.

Test Example 1: Racemization of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide 1

In order to confirm the racemization of (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide by the method according to one embodiment of the present invention The potency of preparing INT-C of Figure 2 for the preparation of racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl ]- Intermediate of metosulfamide.

Specifically, (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide is added to a dichloromethane solvent, followed by the addition of a halogenating reagent . Subsequently, pyridine was added to the solvent and the mixture was reacted to prepare INT-C.

First, 100 g (0.339 mol) of (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide was added to 600 ml of dichloromethane, followed by Cool to 0 ° C. 64 g (0.275 mol) of TCCA was added and the reaction mixture was filtered as the reaction was completed. 2 equivalents of pyridine were slowly added at 0 ° C to the remaining solution after filtration. After completion of the reaction, the reaction mixture was neutralized with 1N aqueous HCl and washed twice with 200 ml of water. The remaining organic solvent layer was dried over magnesium sulfate (MgSO ₄₎ removed, and then concentrated to obtain INT-C (106 g, 94 %).

The NMR data for the structural analysis are as follows: 1H NMR spectrum (300 MHz, DMSO-d ⁶ ), δ, ppm: 9.79 (s, 1H), 7.60 (d, j = 9.0 Hz, 2H), 3.11 (s, 3H) , 2.60(s, 3H).

As shown in Table 1 below, trichloroisocyanate (TCCA) was used as the halogenating agent. The yield is measured by varying the equivalent of TCCA relative to the S-form isomer, the type of base and its equivalent to the S-form isomer and the type of solvent. Table 1

The results show that in the process of preparing INT-C from (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, it is used in the prior art. The base triethylamine (TEA) used in the process results in a lower yield of about 30% or less, but in the presence of a solvent of dichloromethane (CH ₂ Cl ₂ ) or ethylene dichloride (ClCH ₂ CH ₂ Cl) The use of pyridine as a base results in a significant yield of 80% or greater.

All show a lower yield of about 30% or less or no INT-C, except in the case where pyridine is used as a base and dichloromethane (CH ₂ Cl ₂ ) is used as a solvent. Even triethylamine (TEA), which is used to race off the amino acid, also exhibits a yield of less than 10%, regardless of the equivalent of the base, which is meaningless in the racemic process of the present invention. .

Test Example 2: Racemization of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide 2

200 ml of methanol, 20 g (0.070 mol) of INT-C and 2 g of 10% Pd/C of Example 5 prepared in Test Example 1 were added to a high pressure reactor, and the mixture was stirred under a hydrogen pressure of 50 psi 2 hour. After the reaction was completed, the reaction mixture was filtered through a pad of Celite, and adjusted to pH 12 with aqueous ammonia. Subsequently, the filtrate was concentrated. The solid obtained by concentration was crystallized from water to obtain the desired racemic compound N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (17.4 g, 98%).

The NMR data for the structural analysis are as follows: 1H NMR spectrum (300 MHz, DMSO-d ⁶ ), δ, ppm: 7.10 (d, j = 8.7 Hz, 2H), 4.53 (br, 2H), 4.02 (q, j = 6.6 Hz, 1H), 2.91 (s, 3H), 1.26 (d, j = 6.6 Hz, 2H).

The R/S ratio of the obtained racemic compound was analyzed by palmar HPLC analysis under the conditions shown in Table 2 below. The results are shown in Table 3. Table 2 table 3 * INT028-3 S-form: (S)-N-[4-(1-Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide

As shown in Table 3, the ratio of the R-form to the S-form after the reaction was about 1:1, demonstrating the racemization of N-[4-(1- by the racemization according to one embodiment of the present invention. Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide is efficiently derived from N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonate Prepared by the S-form isomer of the amine.

no

Figure 1 shows the separation of racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (INT028-3rac) via a recycle process. (S)-N-[4-(1-Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide produced during optical isomers to racemic back to racemic N-[4 Mechanism of -(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (INT028-3rac).

Figure 2 more specifically shows the preparation of racemic N-[4 from (S)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide Mechanism of -(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide (INT028-3rac).

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Claims (11)

A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, the method comprising the steps of: adding a compound of the following chemical formula 1 to dichloro a methane solvent and a halogenating agent; adding pyridine to the solvent and performing a reaction; and adding a reducing agent to the solvent and performing a reaction: Wherein R ₁ and R ₂ are each an alkyl group or a halogen, and R ₃ is -HNSO ₂ CH ₃ . The racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein R ₁ and R ₂ of the chemical formula 1 are halogen. The racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein R ₁ and R ₂ of the chemical formula 1 are F. A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein the compound of Chemical Formula 1 is (S) -N-[4-(1-Aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide. A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein the halogenating agent is selected from the group consisting of : trichloroisocyanuric acid, N-chlorosuccinimide, N-bromosinium imine, and N-iodosuccinimide. The method for racemization of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide according to claim 1, wherein the reducing agent is selected from the group consisting of : palladium on carbon (Pd/C), lithium aluminum hydride (LAH) and sodium borohydride (NaBH ₄ ). A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein the volume of the dichloromethane solvent is 5 to 20 times the weight of the compound of Chemical Formula 1 added to the solvent. A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 1, wherein each of the chemical formula 1 added to the solvent The amount of the compound, pyridine, is from 0.3 to 2.0 equivalents. A racemic method of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide as claimed in claim 6, wherein the reducing agent Pd/C is palladium The weight ratio of (Pd) to carbon (C) is 1 to 20. A method for preparing (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide, the method comprising the steps of: separating N-[4-( The optical isomer of 1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide to obtain the R-form image isomer, (R)-N-[4-(1 -aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide; and the racemic method of the compound of Chemical Formula 1 according to the racemic method of any one of Claims 1 to 9 The compound is the S-form mirror isomer obtained at the above step and excluding the R-form mirror image isomer. The method for producing (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide according to claim 10, which further comprises the steps of: The optical isomer of the racemic N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide prepared according to the racemic step is again separated, The R-form image isomer is obtained.