KR101447574B1 - Method for preparing silodosin using new intermediates - Google Patents

Abstract

The present invention relates to a novel intermediate compound and a method for producing novel silodosin using the same. More specifically, the present invention relates to a method for producing novel silodosin and a novel intermediate compound used for the method, wherein a compound of chemical formula 3 reacts with a compound of chemical formula 4, so that a compound of chemical formula 2 is obtained in order to be amino-decomposed and a compound of chemical formula 1 is provided thereby. In the formulas, R_1 is hydrogen, substituted or non-substituted alkyl, or substituted or non-substituted aryl; R_2 is hydrogen or a hydroxyl protecting group; and X represents a leaving group.

Description

TECHNICAL FIELD The present invention relates to a novel method for preparing silodosin using new intermediates,

The present invention relates to novel intermediates, and to a novel process for the preparation of tylosin using the same. More specifically, the present invention relates to a process for the preparation of a novel intermediate of the formula (2) by reacting a novel amine derivative having optical activity of the following formula (3) with a phenoxyethane compound of the following formula (4) The present invention relates to a novel process for the preparation of trilodocins which provides the compounds of formula (I) and to novel intermediates used in such processes.

화학식 1

Formula 1

화학식 2

(2)

화학식 3

화학식 4

(3)

Formula 4

Shiloh is a structurally modified form of tamsulosin that has been widely used. It blocks the α1A receptor of the prostate and relaxes the tension of the urethra by increasing the selectivity for the α1A-adrenoceptor mainly present in the prostate. Thereby improving the urethral resistance, thereby increasing the therapeutic effect of the urination disorder associated with benign prostatic hyperplasia (BPH). It has also been demonstrated in clinical trials that it does not affect blood vessels and is safe even without long-term use, without the side effects of cardiovascular events such as hypotension and dizziness in existing treatments.

Shirotoshin improves the urinary incontinence after taking the medicine compared with the existing drugs and has the characteristic of improving not only the genitals but also the pain of urination. Although it has been known that pain at the time of urination and urination may significantly lower the quality of life (QOL) of the patient, the usefulness of such pain relief from mild pain to severe pain patients has been verified by the development of this method. Offering a wide range of choices.

Patients with prostate hyperplasia are increasing in number as the population ages, and interest in economically and efficiently synthesizing compounds is increasing.

Shiloh is developed for the first time by KISSEI and is available under the trade name Rapaflo or Urief. Siloxane has a structural formula of the following formula (1), the original patent being EP 0 600 675.

화학식 1

Formula 1

The original patented EP 0 600 675 synthetic method for gypsum compounds has the problem that the yield is low and the production cost is high because the racemate amine compound and the phenoxyethane compound are reacted with each other and then separated using an optically active acid.

In WO 2012/014168, a carboxyl group was introduced instead of a protecting group in the hydroxyl group portion in the indoline structure, and a siloxane compound was synthesized through a reduction reaction in the last step, as shown in Reaction Scheme 1 below. However, this method requires a column process after reacting an amine compound with a phenoxyethane compound, and the yield of the final process is 25.2%, which is very poor.

[Reaction Scheme 1]

.

.

In WO 2012/006229, secondary amine derivatives are synthesized through a reductive amination reaction in order to remove the side reactants generated during the reaction between the amine compound and the phenoxy compound, as shown in the following Reaction Scheme 2, and then the phenoxyethane compound , The conversion of the cyano group into the carbamoyl group, and the hydroxyl group deprotection reaction. However, this method also has low yields in the first step ("1-step") and the fourth step ("4-step"), and trimethylsilyl iodide used in the 4-step hydroxy- There is a risk of explosion and high production costs:

[Reaction Scheme 2]

.

.

In Korean Patent No. 10-0990046, an optically active amine compound is reacted with a phenoxyethane compound to improve the yield as shown in Reaction Scheme 3 below, and by-products are removed using salt formation with oxalic acid to give (2- a step of hydrolysis of basic conditions to deprotection reaction of hydroxy group and hydrolysis of acidic condition to carry out two hydrolysis to convert cyano group to carbamoyl group, It has:

[Reaction Scheme 3]

.

.

Therefore, the inventors of the present invention have recognized that the conventional methods for synthesizing tridentate compounds have problems of low final yield or efficiency due to various steps, and have conducted studies to develop a more economical and efficient synthesis method of tridentate .

As a result, a novel intermediate compound that is optically active is obtained, and a novel intermediate compound is obtained by using the optically active novel amine compound, thereby reducing the two-step hydrolysis reaction of base and acid conditions into a single step of amino decomposition reaction, The present inventors have completed the present invention by developing a novel process for producing siloxane which is suitable for high-yield and high-purity commercial mass production. The process for the preparation of the siloxadine using the novel intermediate compound according to the present invention can produce a high yield and high purity siloxane in a very economical and efficient manner.

An object of the present invention is to provide a novel method for preparing a siloxane compound by reacting a novel amine compound having an optical activity with a phenoxyethane compound to obtain a novel siloxane intermediate, .

It is another object of the present invention to provide a novel process for the preparation of cilostazol which is suitable for commercial mass production with high yield and high purity.

It is still another object of the present invention to provide a novel intermediate compound used in the novel process for the preparation of the present invention.

SUMMARY OF THE INVENTION

According to an aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising: 1) reacting a compound of formula (3) and a compound of formula (4) 2) mixing the compound of formula 2 obtained in step 1) with an organic acid to obtain a salt compound; And 3) aminolysis of the salt compound obtained in the above step 2) to obtain a siloxane compound of formula (1): < EMI ID =

화학식 1

Formula 1

화학식 2

(2)

화학식 3

화학식 4

(3)

Formula 4

In this formula,

R ₁ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;

R ₂ is hydrogen or a hydroxy protecting group;

X represents a leaving group.

According to another aspect of the present invention, there is provided a novel intermediate compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof:

화학식 2

(2)

Wherein R < ₁ > is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R < _{2 >} is hydrogen or a hydroxy protecting group.

According to another aspect of the present invention, there is provided a novel intermediate compound represented by the following formula (3), or a pharmaceutically acceptable salt thereof:

화학식 3

(3)

Wherein R < ₁ > is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R < _{2 >} is hydrogen or a hydroxy protecting group.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, terms used in the present invention are defined.

The term "substituted or unsubstituted," as used herein, unless otherwise indicated, includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle, , Cyano, nitro group and the like. More specifically, the term "substituted or unsubstituted" refers to C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl , C ₆ -C ₁₂ aryl, 5 to 12 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O or S, 4 to 12 heteroatoms containing 1 to 3 heteroatoms selected from N, O or S, heterocycle of the 6-, halo, halo -C ₁ -C ₄ - alkyl, cyano, or nitro groups or substituted indicate that may not be substituted.

The term "alkyl ", as used herein, unless otherwise indicated, refers to a linear or branched hydrocarbon chain having 1 to 10 carbon atoms. Preferably "alkyl" has 1 to 4 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, sec-butyl, isobutyl, .

The term "alkenyl ", as used herein, unless otherwise indicated, refers to a linear or branched hydrocarbon chain consisting of 2 to 10 carbon atoms and having 1 to 3 carbon-carbon double bonds. Preferably "alkenyl" has 2 to 4 carbon atoms. Examples of "alkenyl" as used herein include, but are not limited to ethenyl and propenyl.

The term "alkynyl ", as used herein, unless otherwise indicated, refers to a linear or branched hydrocarbon chain consisting of from 2 to 10 carbon atoms and having from 1 to 3 carbon-carbon triple bonds. Preferably "alkynyl" has 2 to 4 carbon atoms. Examples of "alkynyl" as used herein include, but are not limited to, ethynyl and propynyl.

The term "cycloalkyl" as used herein, unless otherwise indicated, denotes a saturated monocyclic or carbocyclic ring having 3 to 8 carbon atoms. Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred cycloalkyl groups include substituted or unsubstituted C ₃ -C ₆ cycloalkyl.

The term "alkoxy" as used herein, unless otherwise indicated, denotes C ₁ -C ₁₀ alkoxy having 1 to 10 carbon atoms. Preferably "alkoxy" has 1 to 4 carbon atoms.

The terms " halo "and" halogen ", as used herein, are synonymous with fluoro, chloro, bromo and iodo.

As used herein, "haloalkyl" refers to an alkyl as defined above substituted with one or more halogen atoms, fluoro, chloro, bromo, or iodo. If a haloalkyl group having less than 8 carbon atoms, the number of carbon atoms in the group are, for example, there is indicated as a "halo C ₁ -C ₃ alkyl", which one is a haloalkyl group, two or three carbon It specifies the atom. Examples of haloalkyls used herein include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl, and the like.

The term "heterocycle ", as used herein, unless otherwise indicated, includes monocyclic saturated or unsaturated monocyclic saturated or unsaturated monocyclic, bicyclic or tricyclic heterocyclic rings containing 1, 2 or 3 heteroatoms selected from N, Represents a non-aromatic group. In all embodiments in which the heterocycle comprises two or more heteroatoms, the heteroatoms, which may be the same or different, can be independently selected from N, O or S. Examples of heterocycles are tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane, 1,4-dioxane, 1,3-dioxane, 1,3- dioxane, piperidine, But are not limited to, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene.

The term "heteroaryl ", as used herein, unless otherwise indicated, refers to a 5 to 12 membered aromatic, monocyclic group containing 1, 2 or 3 heteroatoms selected from N, In all embodiments in which the heteroaryl comprises two or more heteroatoms, the heteroatoms may be the same or different and may be independently selected from N, O or S. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine , Pyrazine, pyrimidine, triazine, and the like. Preferably, "heteroaryl" includes 1, 2 or 3 heteroatoms selected from N, O or S from 5 to 6 members.

The term "aryl ", as used herein, unless otherwise indicated, denotes a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, 1-naphthyl, 2-naphthyl, substituted versions thereof.

The term "pharmaceutically acceptable salt " as used herein means a salt that is formed from a pharmaceutically acceptable (i.e., non-toxic) inorganic or organic acid, or inorganic or organic base, as well as a quaternary ammonium salt, . Representative salts include the following compounds: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate , Citrate, dihydrochloride, edetate, eddylate, esterolate, ethylate, ethanolamine, fumarate, glucosate, gluconate, glutamate, glycolylarsanylate, hexylresorcinate, hydra But are not limited to, benzene, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, Sulfonate), methyl bromide, methyl nitrate, methyl sulfate, monopotassium malate, mucate, naphthyl Phosphate, diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, lactate, lactate, lactate, lactate, lactate, lactate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, Succinate, tartrate, theoclate, tosylate (methylbenzene sulfonate), triethiodide, trimethylammonium, and valerate.

Hereinafter, the present invention will be described in detail.

The present invention provides a process for preparing a compound of formula (I), comprising the steps of: 1) reacting a compound of formula (3) and a compound of formula (4) 2) mixing the compound of formula 2 obtained in step 1) with an organic acid to obtain a salt compound; And 3) aminolysis of the salt compound obtained in step 2) to obtain a tridodicin compound of formula (1): < EMI ID =

화학식 1

Formula 1

화학식 2

(2)

화학식 3

화학식 4

(3)

Formula 4

Wherein R ₁ represents hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In the above, "alkyl" is preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₄ alkyl, and most preferably methyl. In the above "aryl" is preferably C ₆ -C ₁₂ aryl, more preferably phenyl.

In the above formula, R ₂ represents hydrogen or a hydroxy-protecting group. In the above, the "hydroxy-protecting group" includes, but is not limited to, substituted or unsubstituted arylcarbonyl or substituted or unsubstituted alkylcarbonyl. Examples of arylcarbonyls include, but are not limited to, benzoyl. Examples of alkylcarbonyls include, but are not limited to, acetyl, and propionyl. A particularly preferred hydroxy protecting group in the present invention is benzoyl.

In the above formula, X represents a leaving group. Examples of the "leaving group" used in the present invention include, but are not limited to, halo, -OMs (mesylate), -OTs (tosylate) and the like. Particularly preferred leaving groups in the present invention are -OMs or -OTs.

In one embodiment of the invention, the compound of Formula 2 is preferably (R) -methyl 1- (3- (benzoyloxy) propyl) -5- (2- , 2-trifluoroethoxy) phenoxy) ethyl) amino) propyl) indoline-7-carboxylate.

In one embodiment of the invention, the compound of Formula 3 is preferably (R) -methyl 5- (2-aminopropyl) -1- (3- (benzoyloxy) propyl) indoline-7- carboxylate .

The process for preparing the novel tridododecyls of the present invention will be described below step by step (Reaction formulas 4 and 5 - total 3 steps):

[Reaction Scheme 4]

[Reaction Scheme 5]

Step 1)

(3) is a novel amine compound having an optical activity, and (4) is a phenoxyethane compound.

In one embodiment of the present invention, said step 1) is carried out using an inorganic base in a polar organic solvent. The term "polar organic solvent" in the present invention means an organic solvent such as dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone, hexamethylphosphoramide (HMPA) Pyridine may be used but is not limited thereto, and preferably dimethylacetamide (DMAC) is used. In the present invention, "inorganic base" may be a metal or a non-metal carbonate. Specific examples include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, barium carbonate, ammonium carbonate and the like. The inorganic base preferably used in the present invention is sodium carbonate or potassium carbonate.

Step 2)

The step of obtaining a salt compound by mixing the compound of formula (2) obtained in step 1) with an organic acid. In the present invention, "organic acid" may be, but is not limited to, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, tartaric acid, succinic acid, citric acid, benzoic acid and acetic acid. Preferably, the organic acid used in step 2) is oxalic acid or tartaric acid, more preferably oxalic acid.

In one embodiment of the present invention, the step 2) is carried out in a single solvent of alcohol, or a mixed solvent of alcohol and acetone, preferably in a single solvent of isopropyl alcohol or a mixed solvent of isopropyl alcohol and acetone.

Step 3

Step 2) is a step for amino-decomposing the salt compound obtained in step 2) to obtain a siloxane compound.

In one embodiment of the present invention, the amino decomposition reaction of step 3) is carried out using formamide and a metal alkoxide in a dimethylacetamide solvent, wherein the metal alkoxide is preferably potassium-tert-butoxide -butoxide, sodium methoxide, and particularly preferably potassium t-butoxide.

The present invention also provides a novel intermediate compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof:

화학식 2

(2)

Wherein R ₁ represents hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In the above, "alkyl" is preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₄ alkyl, and most preferably methyl. In the above "aryl" is preferably C ₆ -C ₁₂ aryl, more preferably phenyl.

In the above formula, R ₂ represents hydrogen or a hydroxy-protecting group. In the above, the "hydroxy-protecting group" includes, but is not limited to, substituted or unsubstituted arylcarbonyl or substituted or unsubstituted alkylcarbonyl. Examples of arylcarbonyls include, but are not limited to, benzoyl. Examples of alkylcarbonyls include, but are not limited to, acetyl, and propionyl. A particularly preferred hydroxy protecting group in the present invention is benzoyl.

In one embodiment of the invention, the compound of Formula 2 is preferably (R) -methyl 1- (3- (benzoyloxy) propyl) -5- (2- , 2-trifluoroethoxy) phenoxy) ethyl) amino) propyl) indoline-7-carboxylate.

The present invention also provides a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof:

화학식 3

(3)

Wherein R ₁ represents hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In the above, "alkyl" is preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₄ alkyl, and most preferably methyl. In the above "aryl" is preferably C ₆ -C ₁₂ aryl, more preferably phenyl.

In the above formula, R ₂ represents hydrogen or a hydroxy-protecting group. In the above, the "hydroxy-protecting group" includes, but is not limited to, substituted or unsubstituted arylcarbonyl or substituted or unsubstituted alkylcarbonyl. Examples of arylcarbonyls include, but are not limited to, benzoyl. Examples of alkylcarbonyls include, but are not limited to, acetyl, and propionyl. A particularly preferred hydroxy protecting group in the present invention is benzoyl.

In one embodiment of the invention, the compound of Formula 3 is preferably (R) -methyl 5- (2-aminopropyl) -1- (3- (benzoyloxy) propyl) indoline-7- carboxylate .

The present invention provides a novel method for producing a tridentate compound, which comprises a total of three steps, thereby shortening the synthesis step as compared with the prior art, thereby effectively synthesizing the tridentate compound in a short time and thus being useful for commercial mass production. In addition, by using the method of the present invention, a high yield and high purity siloxane can be produced. In particular, the production time is shortened by 12 hours or more compared with the conventional four-step synthesis method, There is an advantage that it is increased by about 15% or more as compared with the yield according to

Hereinafter, the specific structure and function of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are only illustrative of the present invention, but are not limited thereto.

Manufacturing example  1: (R) - methyl  5- (2-Aminopropyl) -1- (3- ( Benzoyloxy )profile) Indolin -7-carboxylate (Formula 3) Mono-tartarate  Produce

10 g of methyl-1- (3- (benzoyloxy) propyl) -5- (2-oxopropyl) indoline-7-carboxylate, 3.64 g of S-2-phenylglycine, 92 mg of platinum oxide, 100 ml of furan was added, and the mixture was stirred at 50 DEG C under normal pressure overnight in a hydrogen atmosphere. 130 ml of ethanol, 12.65 ml of 3 molar hydrochloric acid and 2.6 g of 10% Pd / C (50% wet) were added to the reaction mixture, and the mixture was stirred at 60 DEG C under normal pressure overnight in a hydrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was filtered and concentrated. To this, 100 ml of ethyl acetate and 200 ml of a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring for 10 minutes. The aqueous layer was re-extracted with 50 ml of ethyl acetate and the organic layer was collected and washed with 100 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a black oil concentrate.

100 ml of acetone was added to the concentrate obtained above, and the mixture was stirred at room temperature. A mixture of 3.79 g of L-tartaric acid dissolved in 100 ml of purified water was slowly added dropwise thereto. The resulting crystals were filtered, washed with a mixed solvent of acetone and water (1: 1), and dried under hot air at 50 캜 to obtain 9.95 g of white title compound (yield: 72%).

^{1 H-NMR (DMSO-d} 6) δ ppm: 1.09 (3H, d, J = 6.4 Hz), 1.88-1.97 (2H, m), 2.09 (5H, s), 2.54 (1H, dd, J = 5.2 (2H, t, J = 8.6 Hz), 2.81 (1H, dd, J = 5.2,13.2 Hz), 2.96 (2H, t, J = 6.2 Hz), 7.08 (1H, s), 3.69 7.6 Hz), 7.68 (1H, t, J = 7.4 Hz), 8.00 (2H, d, J = 3.6 Hz).

Manufacturing example  2: Indeed  synthesis

Step 1: (R) - methyl -1- (3- ( Benzoyloxy ) Propyl) -5- (2 - ((2- (2- (2,2,2- Trifluo Lt; / RTI > Phenoxy ) Ethyl) amino) propyl) Indolin -7- Carboxylate  Produce

10 g of (R) -methyl-5- (2-aminopropyl) -1- (3- (benzoyloxy) propyl) indoline-7- carboxylate monotartarate, 12.64 g of potassium carbonate, 100 ml of ethyl acetate, And the mixture was stirred at room temperature for about 1 hour. The organic layer was separated, washed with 0.5% aqueous potassium carbonate solution, and water was removed using anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil-like concentrate. The concentrate was dissolved in 47 ml of dimethylacetamide, 5.75 g of 2- (2- (2,2,2-trifluoroethoxy) phenoxy) ethylmethanesulfonate and 2.91 g of sodium hydrogencarbonate were added, and 90 C < / RTI > overnight. After cooling at room temperature, 30 ml of purified water was added to the reaction mixture and extracted with 30 ml of ethyl acetate. The organic layer was washed three times with 30 ml of purified water, and the aqueous layer was re-extracted with 40 ml of ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -methyl-1- (3- (benzoyloxy) propyl) -5- , 2,2-trifluoroethoxy) phenoxy) ethyl) amino) propyl) indoline-7-carboxylate (yield: 108%).

_{^{1 H-NMR (CDCl 3)}} δ ppm: 1.06 (3H, d, J = 6.4 Hz), 1.70 (2H, bs), 2.07 (2H, m), 2.47 (2H, dd, J = 7.0 Hz, 13.4Hz ), 2.67 (2H, d, J = 6.4 Hz, 13.6 Hz), 2.91 (1H, q, J = 6.4 Hz) (2H, t, J = 8.8 Hz), 3.79 (3H, s), 4.08 2H, m), 6.99 (3H, m), 7.31 (1H, s), 7.44 (2H, t, J = 7.6 Hz), 7.56 = 7.2 Hz).

Step 2: (R) - methyl -1- (3- ( Benzoyloxy ) Propyl) -5- (2 - ((2- (2- (2,2,2- Trifluo Lt; / RTI > Phenoxy ) Ethyl) amino) propyl) Indolin -7- Carboxylate Monooxalate  Produce

5- (2 - ((2- (2- (2,2,2-trifluoroethoxy) phenoxy) -pyrrolidine obtained in Step 1 ) Ethyl) amino) propyl) indoline-7-carboxylate was added to 120 ml of isopropyl alcohol and stirred. 0.86 g of oxalic acid dihydrate was added at room temperature, and the mixture was heated to 80 DEG C and stirred for 1 hour. Stirring was stopped, and the mixture was allowed to stand overnight while being slowly cooled to room temperature. The precipitated crystals were stirred at 5 캜 for 1 hour, filtered, washed with isopropyl alcohol, and then dried with hot air at 50 캜 for 12 hours to obtain 11.28 g of white title compound (yield: 81%).

^{1 H-NMR (DMSO-d} 6) δ ppm: 1.14 (3H, d, J = 6.4 Hz), 1.94 (2H, m), 2.51 (1H, t, J = 1.6 Hz), 2.56 (1H, dd, J = 2.8 Hz, 13.2 Hz), 2.95 (2H, t, J = 8.6 Hz), 3.07 (1H, dd, J = (3H, s), 4.71 (3H, q, J = 8.9 Hz), 6.99 (1H, t, J 7.6 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.08 (1H, s), 7.13 (2H, t, J = 6.6 Hz), 7.20 = 7.8 Hz), 7.67 (1H, t, J = 8.8 Hz), 8.00 (2H, d, J = 7.2 Hz).

Step 3: 1- (3-Hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- Trifluoroethoxy city) Phenoxy ] Ethyl} amino) propyl] -2,3- Dihydro -1H-indol-7- Carboxamide  ( Indeed )

To a reactor were added (R) -methyl-1- (3- (benzoyloxy) propyl) -5- (2 - ((2- (2- (2,2,2- trifluoroethoxy) Phenoxy) ethyl) amino) propyl) indoline-7-carboxylate monooxalate, 1.91 g of potassium carbonate, 20 ml of ethyl acetate and 20 ml of purified water, and the mixture was stirred at room temperature for about 1 hour. The organic layer was separated, and the aqueous layer was reextracted with 10 ml of ethyl acetate. The organic layer was collected, the water was removed using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil-like concentrate. 13.63 ml of dimethylacetamide was added to the obtained concentrate, and the mixture was stirred at 60 캜. Then, 30 ml of dimethylacetamide, 1.1 ml of formamide and 1.55 g of potassium t-butoxide were added, and the mixture stirred at room temperature for 1 hour was slowly added. The reaction mixture was stirred at 60 < 0 > C for 8 hours. After cooling to room temperature, ethyl acetate and purified water were added, and the mixture was stirred for 10 minutes, and the organic layer was separated. The separated organic layer was washed with purified water, and the aqueous layer was collected and re-extracted with ethyl acetate. The organic layer was extracted with a dilute aqueous hydrochloric acid solution and washed several times with ethyl acetate. The dilute aqueous hydrochloric acid solution was then neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil-like concentrate. The obtained concentrate was dissolved by heating in toluene, cooled, filtered, and dried under hot air at 50 캜 to obtain 1.11 g (yield: 81%) of the title compound as white.

¹ H NMR (400 MHz, CDCl ₃ )? (Ppm): 1.08 (3H, d, J = 6.2 Hz), 1.77-1.83 (2H, m), 2.53 (1H, dd, J = 13.6HZ, 6.7 Hz) (2H, t, J = 8.5 Hz), 2.67 (1H, dd, J = 13.6 Hz, J = 6.6 Hz), 2.90-3.10 (2H, m, J = 8.4 Hz), 5.89 (1H, brs), 6.64 (1H, brs), 6.88 to 7.05 (5 H, m), 7.15 (1 H, s).

As a result of conducting the experiment according to the production method of the present invention, the total production time could be reduced by more than 12 hours as compared with the conventional four-step synthesis method. In addition, by using the method of the present invention, it was possible to produce a high yield and high purity siloxane chain. In particular, the siloxane chain produced by the method of the present invention has a yield of about 15% or more And the yield was also remarkably increased.

Claims (25)

1) reacting a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof, and a compound represented by the following formula (4) to obtain a compound represented by the following formula (2);
2) mixing the compound of formula 2 obtained in step 1) with an organic acid to obtain a salt compound; And
3) Aminolysis of the salt compound obtained in the above step 2) with formamide and metal alkoxide in a dimethylacetamide solvent to obtain a siloxane compound represented by the following formula (1): < EMI ID = Way:

Formula 1

(2)

(3)

Formula 4
In this formula,
R ₁ is substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted C ₆ -C ₁₂ aryl,
R ₂ is hydrogen or a hydroxy protecting group selected from substituted or unsubstituted C ₆ -C ₁₂ arylcarbonyl or substituted or unsubstituted C ₁ -C ₄ alkylcarbonyl,
X is a leaving group,
In the above, "substituted or unsubstituted" refers to C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, N, O, or a 4 to 6 membered containing 1 to 3 heteroatoms selected from heteroaryl, N, O, or S of 5 to 12 members comprising one to three heteroatoms selected from S a heterocycle, halo, halo -C ₁ -C ₄ - alkyl, cyano, or nitro groups or substituted indicate that may not be substituted. 2. A process according to claim 1, wherein R < ₁ > is methyl. 2. A process according to claim 1, wherein R < ₂ > is benzoyl, acetyl, or propionyl. The method according to claim 1, wherein X is halo, -OMs, or -OTs. 5. Process according to any one of claims 1 to 4, characterized in that step 1) is carried out in the presence of a base such as dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone, An inorganic base selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, barium carbonate and ammonium carbonate is used in a polar organic solvent selected from the group consisting of amines (HMPA), triethylamine and pyridine ≪ / RTI > 6. The process according to claim 5, wherein the polar organic solvent is dimethylacetamide (DMAC). The process according to claim 5, wherein the inorganic base is sodium carbonate or potassium carbonate. The method according to any one of claims 1 to 4, wherein the organic acid is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, tartaric acid, succinic acid, citric acid, benzoic acid and acetic acid ≪ / RTI > The process according to claim 8, wherein the organic acid is oxalic acid or tartaric acid. The process according to any one of claims 1 to 4, wherein step 2) is carried out in a single alcoholic solvent or a mixed solvent of alcohol and acetone. 11. The process according to claim 10, wherein step 2) is carried out in a mixed solvent of isopropyl alcohol and a single solvent or an isopropyl alcohol and acetone. delete The process according to claim 1, wherein the metal alkoxide is potassium t-butoxide. A compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof:

(2)
In this formula,
R ₁ is substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted C ₆ -C ₁₂ aryl,
R ₂ is a hydroxy protecting group selected from hydrogen, substituted or unsubstituted C ₆ -C ₁₂ arylcarbonyl or substituted or unsubstituted C ₁ -C ₄ alkylcarbonyl,
In the above, "substituted or unsubstituted" refers to C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, N, O, or a 4 to 6 membered containing 1 to 3 heteroatoms selected from heteroaryl, N, O, or S of 5 to 12 members comprising one to three heteroatoms selected from S a heterocycle, halo, halo -C ₁ -C ₄ - alkyl, cyano, or nitro groups or substituted indicate that may not be substituted. 15. The compound of claim 14, wherein R < ₁ > is methyl. 15. The compound of claim 14, wherein R < ₂ > is benzoyl, acetyl, or propionyl. A compound represented by the following formula (3), or a pharmaceutically acceptable salt thereof:

(3)
In this formula,
R ₁ is hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, or substituted or unsubstituted C ₆ -C ₁₂ aryl,
R ₂ is hydrogen or a hydroxy protecting group selected from substituted or unsubstituted C ₆ -C ₁₂ arylcarbonyl or substituted or unsubstituted C ₁ -C ₄ alkylcarbonyl,
In the above, "substituted or unsubstituted" refers to C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, N, O, or a 4 to 6 membered containing 1 to 3 heteroatoms selected from heteroaryl, N, O, or S of 5 to 12 members comprising one to three heteroatoms selected from S a heterocycle, halo, halo -C ₁ -C ₄ - alkyl, cyano, or nitro groups or substituted indicate that may not be substituted. 18. A compound according to claim 17, wherein R < ₁ > is methyl. 18. The compound of claim 17, wherein R < ₂ > is benzoyl, acetyl, or propionyl.
delete delete delete delete delete delete