신규의 설폰아마이드 중간체 및 이를 사용한 실로도신의 제조방법

The present invention refers to novel intermediates or pharmaceutically acceptable salt bath method via a number a number substrate. I.e., the present invention refers to compounds of formula 2 - containing molecular weight to number on alkali metal carbonate or alkali metal alkoxide (thiol group a-containing agent for forming Meisenheimer complex) my complex formation in the presence of including reacting, or a pharmaceutically acceptable salt manufacturing method number substrate:

<>Formula 2

According to the present invention compounds of formula 2 in the presence of alkali metal carbonate or alkali metal alkoxide is reacted with a complex formation on the number molecular weight - my containing, a compound such as 1, form a complex which my (Meisenheimer complex), 2 - (or 4 -) knit said from the composites (or alkyl) thioether and sulfur dioxide (SO₂ ) Gas saver is provided in the form of In Situ The wetting ability to number to the heating chamber. (Work a-up process) with an aqueous medium in a acid isolated process really escaping while report, said 2 - (or 4 -) knit (or alkyl) stratum that number to the 1308. volatile organic thioether for hereinafter.

1><Reactive

My - abnormal number molecular weight containing said complex formation is phenol, thio the glycol [lik it buys, 2 - [me cop toe ethanol, 1 - space mote this year, and 1 - 1 can be at least one selected from the group consisting of boron atoms at space mote this year, preferably 1 - space mote this year and/or 1 - be of boron atoms. The compounds of said formula 2 - 1 equivalents of my number molecular weight containing said complex formation for 1 ∼ 2 equivalent, preferably 1. 1 ∼ 1. 2 Equivalent of ratio can be used. In addition, molecular weight with compounds of said formula 2 - containing complex formation in the presence of reaction with alkali metal carbonate or alkali metal alkoxide my number preferably carried out. Said alkali metal carbonate or alkali metal alkoxide is K₂ CO₃ , Na₂ CO₃ , Li₂ CO₃ , KHCO₃ , NaHCO₃ , LiHCO₃ , NaOMe, and KOMe 1 can be selected from the group consisting of at least one, preferably K₂ CO₃ , Na₂ CO₃ , Or NaOMeImplementation being. Said alkali metal carbonate or alkali metal alkoxide 1 equivalents of the compounds of said formula 2 for 1. 5 ∼ 2. 4 Equivalent of ratio but can be used, the one number are not disclosed. In addition, the number molecular weight with compounds of said formula 2 - containing complex formation reaction with my N, N - dimethylformamide amide, N, N - dimethyl acetamide, dimethyl sulfoxide such as in organic solvent, preferably N, N - dimethylformamide a preferred amide can be performed. In addition, said reaction at room temperature to 100 °C, preferably 20 to 60 °C, more preferably can be performed at room temperature.

In of the present invention manufacturing method, including manufacturing method comprises the steps of compounds of said formula 2 by number bath 1308.:

(A) a compound of formula 6 to a compound of formula 6 to obtain compounds of formula 5 by reacting compounds of formula 7 to fluoro zincates tartaric acid;

(B) compounds of formula 8 by reacting compounds of formula 4 to obtain a compound of said formula 5;

(C) hydrolyzing the compound of formula 3 to obtain the compounds of said formula 4 alkali metal hydroxide; and

(D) compounds of said formula 3 alkali metal hydroxide or alkali metal carbonate, in the presence of oxidation number, to obtain a hydrolyzed to compounds of formula 2.

<>Formula 3

<>Formula 4

<>Formula 5

<>Formula 6

<>Formula 7

<>Formula 8

The composition, and X is hydrogen or halogen,

Y is methane methylsulfonyl, 4 - toluene methylsulfonyl, or Br are disclosed.

In the reaction of step (a), compounds of the 2 - nitro 4 - knit with neel benzene opinion gun can be said formula 7 with neel benzene opinion gun chloride or chloride, preferably 2 - knit with neel benzene opinion gun be a chloride. SaidCompounds of formula 7 with a compound of formula 6 reaction is preferably performed in the presence of organic base or inorganic base inclusive tartaric acid can be. Examples of said organic base or inorganic base triethylamine, pyridine, 1, 8 - diazabicyclo java two:00 claws [5. 4. 0] Fortune deck - 7 - ene (1, 8 a-Diazabicyclo [5. 4. 0] undec-a 7 a-ene, DBU), K₂ CO₃ , Na₂ CO₃ , LiOH, KOH, NaOH or the like, the number one are not disclosed. For example, be said a base triethylamine. Said base is an compound of said formula 6 can be used but at a rate of 1 ∼ 6 equivalent to 1 equivalents of tartrate, the one number are not disclosed. In addition, said reaction is dichloro methane, dichloroethane, ethyl acetate, tetrahydrofuran mixable, water, acetone, and their mixed solvent can be carried out in a solvent selected from, preferably dichloro methane, ethyl acetate, ethyl acetate mixed solvent of dichloro methane, or tetra situby mixing solvent can be performed. Said reaction is e.g. 4 hours but can be performed at room temperature, the number one are not disclosed.

In step (b) reaction of a compound of said formula 8 Y is methane methylsulfonyl, 4 - toluene methylsulfonyl, or Br and, preferably (i.e., 2 - [2 - (2, 2, 2 - trifluoroethoxy) phenoxy] ethyl methane sulfonate) methane methylsulfonyl are disclosed. Compounds of formula 5 with compounds of formula 8 dimeric impurity (i.e., a formula 11 said impurities) avoid the generation reaction can be, oxalic acid salts can be acid addition salts thereof forming process essentially is effectively avoided. I.e., according to the present invention in stages of (b) when performing an electrochemical reaction, a compound of the formula 4 dimer impurity without the formation of a high yield and high purity can be obtained is, pharmaceutical composition does not forming processes. Said reaction is carried out in the presence of a base or; or shortened to extract base and catalyst can be performed in the presence of reaction time. Said base is an K₂ CO₃ , Na₂ CO₃ , Li₂ CO₃ , KHCO₃ , NaHCO₃ , And LiHCO₃ 1 Can be selected from the group consisting of at least one, preferably Na₂ CO₃ Implementation being. 1 Equivalents of said compounds of said formula 5 a base can be used at a rate of 1 ∼ 6 equivalent to but, the one number are not disclosed. In addition, said catalyst and/NaI or KI without using a tool. 0 To 1 equivalents of said catalyst compounds of said formula 5. 1 To 1. 0 Equivalent, preferably 0. 1 To 0. 5 Equivalent, more preferably 0. 1 To 0. 3 Equivalent of ratio can be used. The compounds of said formula 5 with compounds of formula 8 reaction N, N - dimethylformamide amide, N, N - dimethyl acetamide, dimethyl sulfoxide such as in organic solvent, preferably N, N - dimethylformamide can be conducted in amide. In addition, in said reaction is 60 to 100 °C, preferably about 110 °C can be performed. In addition, said reaction, reaction temperature or on hereinafter, can be carried out during the time 6 to 12.

Reaction of step (c), i.e. the hydrolysis of compounds of formula 4 can be carried out using an alkali metal hydroxide. For example said alkali metal hydroxide is KOH, NaOH, LiOH and 1 from the group consisting at least one can be selected. Step (c) hydrolysis of water, methanol, ethanol, N, N - dimethylformamide amide or a combination of red can be performed in a solvent, preferably methanol can be conducted in. In addition, step (c) can be performed for example hydrolysis of about 10 hours at room temperature.

The reaction of step (d), an alkali metal hydroxide or alkali metal carbonate hydrolysis of compounds of formula 3 i.e. using oxidation can be performed in the presence number. For example said alkali metal hydroxide is KOH, NaOH, LiOH and CsOH 1 from the group consisting of at least one can be selected. Said alkali metal carbonate is K₂ CO₃ , Na₂ CO₃ , Li₂ CO₃ , KHCO₃ , NaHCO₃ , And LiHCO₃ 1 From the group consisting of at least one can be selected. In addition, said oxidation number is H₂ O₂ , NaClO, and H₂ SO₅ 1 From the group consisting of at least one can be selected. Step (d) the hydrolysis of dimethyl opinion bombing death id and mixing in a solvent but can be carried out, the one number are not disclosed.

The administration of a manufacturing method of the present invention refers to in addition said number intermediates substrate. I.e., of the present invention according to one aspect, a pair of ball number encoded to formula 2:

<>Formula 2

According to another aspect of the present invention, compounds represented by encoded number ball to formula 3:

<>Formula 3

Another of the present invention according to one aspect, a pair of ball number encoded to formula 4:

<>Formula 4

Another of the present invention according to one aspect, a pair of ball number encoded to formula 5:

<>Formula 5

One example of manufacturing method of the present invention indicates a compound generally known as said overall 2 a compound such as disclosed.

2><Reactive

In addition, the present invention refers to, a compound such as 3, a compound of formula 4 - nitro substituted phenyl methylsulfonyl moiety number array coefficient after wetting ability, and hydrolysis method to bath comprises a number performed sequentially.

3><Reactive

In manufacturing method 3 of said compound, said compound of formula 3a from compounds of formula 2 - containing compounds of said formula 4 switching is carried out to a number molecular weight complex formation in the presence of alkali metal carbonate on my reacting method can be performed by the same process as. In addition, compounds of formula 2a from compounds of said formula 3a to compounds of formula 4 in the presence of alkali metal hydroxide to said switching is carried out by the same process as hydrolyzing method can be performed. In addition, molecular weight compounds of said formula 4 - containing alkali metal alkoxide in the presence of complex formation on my number when reaction, can be direct conversion into the compound of the formula 2a. The knit is capable of forming a complex number to my wetting ability, a transformer's wake up alkyl benzoate number encoded into blood k [syen benzo diary method wetting ability. In addition, compounds of formula 3 to compounds of said formula 2a alkali metal hydroxide or alkali metal carbonate from said switching is carried out, in the presence of oxidation number, the same process as a hydrolyzing method can be performed.

Thus, in one aspect, the present invention refers to a pharmaceutically acceptable salt or a manufacturing method including steps number substrate:

(A) a compound of formula 6 to a compound of formula 6 to obtain compounds of formula 5 by reacting compounds of formula 7 to fluoro zincates tartaric acid;

(B) compounds of formula 8 by reacting compounds of formula 4 to obtain a compound of said formula 5;

(C') - containing compounds of said formula 4 (i) molecular weight complex formation in the presence of alkali metal carbonate compounds of formula 3a reacting on my number is obtained, to give compounds of formula 2a hydrolyzing the compounds of said formula 3a (ii) alkali metal hydroxide or alkali metal alkoxide compounds of said formula 4 - containing complex formation in the presence of my number molecular weight on reacting to obtain compounds of formula 2a; and

Alkali metal hydroxide or alkali metal carbonate compounds of said formula 2a (d'), in the presence of oxidation number, obtaining hydrolyzing

<>Formula 2a

Formula 3a<>

<>Formula 4

<>Formula 5

<>Formula 6

<>Formula 7

<>Formula 8

The composition, and X is hydrogen or halogen,

Y is methane methylsulfonyl, 4 - toluene methylsulfonyl, or Br are disclosed.

In addition, the present invention refers to, a compound such as 4, a compound of formula 3 - nitro substituted phenyl methylsulfonyl moiety would number array after coefficient, hydrolysis process using the number comprises a bath method.

4><Reactive

In manufacturing method of said reactive 4, compounds of formula 2 - containing compounds of said formula 3 to compounds of formula 2said switching is carried out from a molecular complex formation on alkali metal carbonate or alkali metal alkoxide my number (thiol group a-containing agent for forming Meisenheimer complex) reacting in the presence of the same process as a method can be performed. In addition, compounds of formula 3 to compounds of said formula 2a alkali metal hydroxide or alkali metal carbonate from said switching is carried out, in the presence of oxidation number, the same process as a hydrolyzing method can be performed.

Thus, in another aspect, the present invention refers to a pharmaceutically acceptable salt or a manufacturing method including steps number substrate:

(A) a compound of formula 6 to a compound of formula 6 to obtain compounds of formula 5 by reacting compounds of formula 7 to fluoro zincates tartaric acid;

(B) compounds of formula 8 by reacting compounds of formula 4 to obtain a compound of said formula 5;

(C) hydrolyzing the compound of formula 3 to obtain the compounds of said formula 4 alkali metal hydroxide; and

(D ") - containing compounds of said formula 3 molecular weight alkali metal carbonate or alkali metal alkoxide in the presence of complex formation on my number reacting compounds of formula 2a to obtain; and

Compounds of said formula 2a (e ") alkali metal hydroxide or alkali metal carbonate, in the presence of oxidation number, obtaining hydrolyzing

<>Formula 2a

<>Formula 3

<>Formula 4

<>Formula 5

<>Formula 6

<>Formula 7

<>Formula 8

The composition, and X is hydrogen or halogen,

Y is methane methylsulfonyl, 4 - toluene methylsulfonyl, or Br are disclosed.

Hereinafter, the present invention through further in the embodiment detailed as follows. However, in the embodiment for the present invention is to exemplify the which, one of the present invention range will number are not disclosed.

In the embodiment 1. N - [(2R) - 1 - [1 - (3 -Benzoyl ) - 7 -Cyano - 5 - Yl] propane - 2 - yl] - 2 - knit (compounds of formula 5) number of bath

(R)- 1 - (3 - benzoyl ) - 5 - (2 - aminopropyl) indoline - 7 - carbonyl knight reel (1. 415 G, 3. 893 Mmol) after dissolving a 10 ml dichloro methane, triethylamine (0. 759 Ml, 5. 450 Mmol) in enemy about 10 °C-gate. 2 - Knit with neel benzene opinion gun chloride (0. 949G, 4. 282 Mmol) to the reaction mixture to a solution 10 ml dichloro methane melting said enemy-gate. Reaction mixture 4 time been rapidly at room temperature, be positive number (10 ml) applying a dichloro methane (10 ml X2) is extracted from the. By combining organic layer, anhydrous MgSO₄ It is 30 minutes stirring and applying his filtering. Decompressing concentrated within a vacuum drying the table in number to combine the compound 2. 134 G stingy. (Yield: 99. 95%, HPLC purity: 98. 71%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 2. 16 (M, 2H), 2. 60 (Dd, 2H), 2. 90 (T, 2H), 3. 59 (T, 2H), 3. 70 (M, 1H), 3. 73 (T, 2H), 4. 50 (T, 2H), 5. 21 (D, 1H), 6. 72 - 8. 10 (M, 11H)

In the embodiment 2. N - [(2R) - 1 - [1 - (3 -Benzoyl ) - 7 -Cyano - 5 - Yl] propane - 2 - yl] - 2 - knit (compounds of formula 5) number of bath

(R)- 1 - (3 - benzoyl ) - 5 - (2 - aminopropyl) indoline - 7 - carbonyl knight reel tartrate (32. 9 G, 64 mmol) be atrough-number (65 ml) and tetrahydrofuran mixable (20 ml) dissolving, triethylamine (28. 6 Ml, 205 mmol) was dissolved. The reaction mixture is cooled to 5 °C hereinafter and, 2 - knit with neel benzene opinion gun chloride (18 g, 81. 4 Mmol) was added. It agitated reaction mixture 10 hours at room temperature then, dichloro methane (100 ml X2) is extracted from the. Combined organic layer be a positive number, saturated saline solution washed and, very dry magnesium sulfate anhydride. Drying number and number contained in a stand-alone, after a concentrate filtrate, residues ethyl acetate (100 ml) is recrystallised table number compound to 34. 46 G stingy. (Yield: 98. 06%, HPLC purity: 98. 71%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 2. 16 (M, 2H), 2. 60 (Dd, 2H), 2. 90 (T, 2H), 3. 59 (T, 2H), 3. 70 (M, 1H), 3. 73 (T, 2H), 4. 50 (T, 2H), 5. 21 (D, 1H), 6. 72 - 8. 10 (M, 11H)

In the embodiment 3. N - [(2R) - 1 - [1 - (3 -Benzoyl ) - 7 -Cyano - 5 - Yl] propane - 2 - yl] - 4 - knit (compounds of formula 5) number of bath

(R)- 1 - (3 - benzoyl ) - 5 - (2 - aminopropyl) indoline - 7 - carbonyl knight reel tartrate (32. 9 G, 64 mmol) be atrough-number (65 ml) and tetrahydrofuran mixable (20 ml) dissolving, triethylamine (28. 6 Ml, 205 mmol) was dissolved. The reaction mixture is cooled to 5 °C hereinafter and, 4 - knit with neel benzene opinion gun chloride (18 g, 81. 4 Mmol) was added. It agitated reaction mixture 10 hours at room temperature then, dichloro methane (100 ml X2) is extracted from the. Combined organic layer be a positive number, saturated saline solution washed and, very dry magnesium sulfate anhydride. Number number contained in a stand-alone and drying, vacuum drying table 34 compounds form of cream to combine the number. 54 G stingy. (Yield: 98. 3%, HPLC purity: 98. 72%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 2. 16 (M, 2H), 2. 2 (Dd, 2H), 2. 87 (M, 2H), 3. 53 (M, 1H), 3. 58 (T, 2H), 3. 73 (M, 2H), 4. 46 (D, 1H), 4. 49 (T, 2H), 6. 74 - 8. 29 (M, 11H)

In the embodiment 4. N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - (compounds of formula 4) number of bath knit

In N - prepared by the number in the embodiment 1 [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - 2 - knit (compounds of formula 5) (0. 40G, 0. 729 Mmol) amide to dimethylformamide (4 ml) after dissolving, potassium carbonate (0. 302G, 2. 187Mmol) and sodium iodide (0. 033G, 0. 218Mmol) been applying. 2 - [2 - (2, 2, 2 - Trifluoroethoxy) phenoxy] ethyl methane sulfonate reaction mixture (0. 275G, 0. 875Mmol) after loading the, and heating to about 80 °C, stirring the same temperature in time-gate 10. A reaction mixture of dichloro methane (5 ml) and be positive number (10 ml) was then placed under organic layer pattern. Remaining dichloro methane (10 ml X2) is extracted from the. By combining organic layer, anhydrous MgSO₄ It is 30 minutes and applying an agitating his filtering. Compound number the table in vacuum drying concentrated filtrate of decompressing the 0. 532G stingy. (Yield: 95. 2%, HPLC purity: 98. 86%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 2. 18 (M, 2H), 2. 71 (Dd, 2H), 2. 93 (T, 2H), 3. 59 (T, 2H), 3. 73 - 3. 86 (M, 4H), 4. 06 (M, 1H), 4. 23 (T, 2H), 4. 41 (Dd, 2H), 4. 49 (T, 2H), 6. 80 - 8. 10 (M, 15H)

In the embodiment 5. N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - (compounds of formula 4) number of bath knit

In the embodiment 2 in number prepared by the N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - 2 - knit (compounds of formula 5) (32g, 58. 3 Mmol) amide to dimethylformamide (150 ml) after dissolving, potassium carbonate (9. 7 G, 1. 2 Equivalent) was applied. 2 - [2 - (2, 2, 2 - Trifluoroethoxy) phenoxy] ethyl methane sulfonate reaction mixture (22 g, 1. 2 Equivalent) after loading the, and heating to about 110 °C, stirring the same temperature in time-gate 10. After cooled down to room temperature, the reaction mixture to be positive number (300 ml) applying a dichloro methane (100 ml X2) is extracted from the. Water and saturated saline solution by combining organic layer washed and, anhydrous MgSO₄ 30 Minutes on drying, filtering out. The concentrated filtrate residue MeOH (100 ml) to compound 42 is recrystallised table number. 13 G stingy. (Yield: 94. 2%, HPLC purity: 98. 86%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 2. 18 (M, 2H), 2. 71 (Dd, 2H), 2. 93 (T, 2H), 3. 59 (T, 2H), 3. 73 - 3. 86 (M, 4H), 4. 06 (M, 1H), 4. 23 (T, 2H), 4. 41 (Dd, 2H), 4. 49 (T, 2H), 6. 80 - 8. 10 (M, 15H)

In the embodiment 6. N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 4 - (compounds of formula 4) number of bath knit

In the embodiment 3 in the form of prepared by the number N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - 2 - knit (compounds of formula 5) (32g, 58. 3 Mmol) amide to dimethylformamide (150 ml) after dissolving, potassium carbonate (9. 7 G, 1. 2 Equivalent) was applied. 2 - [2 - (2, 2, 2 - Trifluoroethoxy) phenoxy] ethyl methane sulfonate reaction mixture (22 g, 1. 2 Equivalent) after loading the, and heating to about 110 °C, stirring the same temperature in time-gate 10. After cooled down to room temperature, the reaction mixture to be positive number (300 ml) applying a dichloro methane (100 ml X2) is extracted from the. Water and saturated saline solution by combining organic layer washed and, anhydrous MgSO₄ 30 Minutes on drying, filtering out. Vacuum drying the filtrate cream form of table number compound 43. 53 G stingy. (Yield: 97. 3%, HPLC purity: 96. 71%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 18 (D, 3H), 2. 17 (M, 2H), 2. 71 (Dd, 2H), 2. 94 (T, 2H), 3. 60 (T, 2H), 3. 68 (T, 2H), 3. 75 (T, 2H), 4. 09 (M, 1H), 4. 24 (T, 2H), 4. 37 (Dd, 2H), 4. 49 (T, 2H), 6. 85 - 8. 23 (M, 15H)

In the embodiment 7. N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - knit (compounds of formula 3) number of bath

In the embodiment 5 in number prepared by the N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] (compounds of formula 4) - 2 - knit (40 g, 52. 16 Mmol) a, sodium hydroxide (2. 5 G, 1. 2 Equivalent) to methanol solution obtained by dissolving a 400 ml was applied to the solution. About 50 °C gradually warming and then to the reaction mixture, stirring the same temperature in 1 time-gate. Reaction mixture cooled down to room temperature and cream or telephone number to ethanol (100 ml) stirring time-gate 2 in applying 0 °C. The resulting yellow crystals by vacuum drying the table in number compound closing valve 29. 63 G by Congress. (Yield: 85. 73%, HPLC purity: 98. 93%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 1. 94 (M, 2H), 2. 75 (Dd, 2H), 2. 94 (T, 2H), 3. 59 (T, 2H), 3. 68 (T, 2H), 3. 72 - 3. 87 (M, 2H), 3. 86 (T, 2H), 4. 07 (M, 1H), 4. 23 (T, 2H), 4. 40 (Dd, 2H), 6. 70 - 8. 04 (M, 10H)

In the embodiment 8. N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 4 - knit (compounds of formula 3) number of bath

In the embodiment 6 in the form of prepared by the number N - [(2R) - 1 - [1 - (3 - benzoyl ) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] (compounds of formula 4) - 2 - knit (40 g, 52. 16 Mmol) a, sodium hydroxide (2. 5 G, 1. 2 Equivalent) to methanol solution obtained by dissolving a 400 ml was applied to the solution. About 50 °C gradually warming and then to the reaction mixture, stirring the same temperature in 1 time-gate. The reaction mixture is cooled down to room temperature pressure concentrated, dichloro methane (300 ml) with respect to the dissolved by the application. The reaction mixture and the saturated saline solution washed and MgSO positive number₄ By the application of very dry. Filtering the filtrate cream form of vacuum drying table number compound 32. 04 G stingy. (Yield: 92. 71%, HPLC purity: 96. 68%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 19 (D, 3H), 1. 94 (M, 2H), 2. 71 (Dd, 2H), 2. 92 (T, 2H), 3. 59 (T, 2H), 3. 68 (T, 2H), 3. 69 (T, 2H), 3. 83 (T, 2H), 4. 09 (M, 1H), 4. 24 (T, 2H), 4. 37 (Dd, 2H), 6. 85 - 8. 23 (M, 15H)

In the embodiment 9. N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - carbamoyl - indolin - 5 - yl] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - knit (compounds of formula 2) number of bath

In the embodiment 7 in number prepared by the N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - knit (compounds of formula 3) (0. 30 G, 0. 452Mmole) after dissolving a 3 ml of florfenicol, 5M aqueous sodium hydroxide (0. 21 Ml, 1. 05 Mmol) then a , 30% hydrogen peroxide (0. 126 Ml, 1. 233 Mmol) enemy evaporants-gate. Reaction mixture 4 time been rapidly at room temperature, sodium sulfite (0. 105 G, 0. 833 Mmol) is dissolved in water to a solution obtained by the enemy slowly-gate. Reaction mixture ethyl acetate (6 ml) extracted from the to 3 times. Drying the obtained extract was 30 minutes except magnesium sulfate on filtering. Of decompressing the concentrated filtrate, vacuum drying the table in number compound 0. 259 G stingy. (Yield: 84. 36%, HPLC purity: 97. 11%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 1. 84 (M, 2H), 2. 81 (Dd, 2H), 2. 93 (T, 2H), 3. 23 (T, 2H), 3. 43 (T, 2H), 3. 79 (T, 4H), 4. 15 (M, 1H), 4. 20 (T, 2H), 4. 40 (Dd, 2H), 6. 90 - 8. 00 (M, 10H)

In the embodiment 10. N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - carbamoyl - indolin - 5 - yl] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - knit (compounds of formula 2) number of bath

In the embodiment 7 in number prepared by the N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 2 - knit (compounds of formula 3) (23 g 34. 7Mmole) after dissolving a 50 ml of florfenicol, was cooled to 20 °C hereinafter. A reaction mixture of 30% hydrogen peroxide (12 ml, 2 equivalent) enemy evaporants-gate. The same temperature in cesium hydroxide (2 g, 0. 2 Equivalent) by applying a gradually to room temperature, stirring time-gate 2. 5% Sodium sulfite aqueous solution (100 ml) then placed dichloro methane (100 ml X2) is extracted from the. Water and saturated saline solution by combining organic layer washed and, anhydrous sodium sulfate is very dry. Vacuum drying the filtrate contained in compounds of table number 23 form of cream. 31 G stingy. (Yield: 98. 7% %, HPLC purity: 97. 11%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 24 (D, 3H), 1. 84 (M, 2H), 2. 81 (Dd, 2H), 2. 93 (T, 2H), 3. 23 (T, 2H), 3. 43 (T, 2H), 3. 79 (T, 4H), 4. 15 (M, 1H), 4. 20 (T, 2H), 4. 40 (Dd, 2H), 6. 90 - 8. 00 (M, 10H)

In the embodiment 11. N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - carbamoyl - indolin - 5 - yl] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 4 - (compounds of formula 2) number of bath knit

In the embodiment 8 in form of prepared by the number N - [(2R) - 1 - [1 - (3 - hydroxypropyl) - 7 - cyano - 5 - yl ] propane - 2 - yl] - N - [2 - [2 - [2, 2, 2 - trifluoroethoxy] ] - 4 - knit (compounds of formula 3) (23 g 34. 7Mmole) after dissolving a 50 ml of florfenicol, was cooled to 20 °C hereinafter. A reaction mixture of 30% hydrogen peroxide (12 ml, 2 equivalent) enemy evaporants-gate. The same temperature in cesium hydroxide (2 g, 0. 2 Equivalent) by applying a gradually to room temperature, stirring time-gate 2. 5% Sodium sulfite aqueous solution (100 ml) then placed dichloro methane (100 ml X2) is extracted from the. Water and saturated saline solution by combining organic layer washed and, anhydrous sodium sulfate is very dry. Vacuum drying the filtrate contained in compounds of table number 23 form of cream. 22 G stingy. (Yield: 98. 3% %, HPLC purity: 95. 11%)

¹ H non-NMR(400 MHz, CDCl₃ ) Δ 1. 21 (D, 3H), 1. 83 (M, 2H), 2. 75 (Dd, 2H), 2. 95 (T, 2H), 3. 23 (T, 2H), 3. 52 (T, 2H), 3. 63 (T, 2H), 3. 62 - 3. 72 (M, 1H), 4. 15 (M, 4H), 4. 34 (Dd, 2H), 6. 85 - 8. 22 (M, 15H)

In the embodiment 12. 1 - (3 - Hydroxypropyl) - 5 - [(2R) - 2 - [2 - [2 - (2, 2, 2 -Trifluoroethoxy) Phenoxy] ethyl] amino] propyl] indoline - 7 - carboxamide (compounds of formula 1, ) Number of bath