WO2014135096A1

WO2014135096A1 - Ivacaftor preparation method and intermediate thereof

Info

Publication number: WO2014135096A1
Application number: PCT/CN2014/072968
Authority: WO
Inventors: 李剑峰; 马文鹏; 蒋翔锐; 张容霞; 朱富强; 陈伟铭; 赵显国; 沈敬山
Original assignee: 上海特化医药科技有限公司; 中国科学院上海药物研究所; 山东特珐曼药业有限公司
Priority date: 2013-03-06
Filing date: 2014-03-06
Publication date: 2014-09-12
Also published as: CN104030981A

Abstract

An Ivacaftor preparation method and intermediate thereof, the method forms a quinoline ring by condensing the compound of formula III under an alkaline condition, or conducting reduction and cyclization reactions for the compound of formula VI under a reduction condition, thus avoiding the high-temperature condition required for forming the quinoline ring. The method has a high yield, low cost, and mild reaction condition, etc.

Description

Preparation method of I vacaftor and its intermediate

TECHNICAL FIELD The present invention relates to a process for the preparation of Ivacaftor and an intermediate thereof. Background technique

Ivacaftor is a drug developed by Vertex Corporation of the United States for the treatment of rare cystic fibrosis. It was approved by the US Food and Drug Administration (FDA) on January 31, 2012 under the trade name Kalyd _eC0 . This drug is used to treat a rare cystic fibrosis (CF) caused by a G551D mutation in the cystic fibrosis transmembrane transduction regulator (CFTR) gene, which is suitable for patients aged 6 years and older. The chemical name of Ivacaftor is: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroisoquinoline-3-carboxamide; English chemical name: N -(2,4-di-tert-butyl-5-hydroxyphenyl)-

4-0X0- 1 ,4-dihydroquinoline-3 -carboxamide, chemical structure is as follows:

IV3C3ftO"

The main synthetic routes reported by Ivacaftor are as follows (WO2006002421)

The synthesis of the quinolinone intermediate is the key, mainly through the following route:

Therefore, the key step in the synthesis of Ivacftor is the formation of the quinoline nucleus, whereas the quinoline nucleus in the prior art The synthesis is often used in high temperature conditions. See the reaction formula 1 (WO2011116397, WO2011050325A1, WO2011133953), the high temperature conditions used are relatively harsh, and the volatilization of high boiling solvents such as diphenyl ether at high temperatures inevitably adversely affects the working environment and the health of the operator. , polluting the environment.

Therefore, it is particularly urgent to find a new preparation method which is mild in conditions, high in yield, and which is less polluting to the environment and suitable for industrial production. Disclosure of the Invention In order to overcome the high temperature reaction in production, the inventors of the present invention have been striving to find a method for preparing Ivacaftor which is mild in condition, simple in operation, high in yield, low in cost, and safe and environmentally friendly.

In order to achieve the above object, in one aspect of the invention, there is provided a process for the preparation of a compound represented by the formula IV, which is carried out by the following reaction formula 1:

The compound represented by the formula III is subjected to a cyclization reaction to obtain a compound represented by the formula IV, wherein

X is a hydroxy, C^Cs linear or branched alkoxy group, benzyloxy group, phenoxy group or NH _{2 ;} preferably a linear or branched alkoxy group; more preferably a methoxy group, an ethoxy group or a benzene group Oxylate

Y is a hydroxy protecting group, preferably a linear or branched alkoxycarbonyl group or a benzyl group of C^Cs, more preferably methoxycarbonyl-C0 ₂ CH ₃ , ethoxycarbonyl-CO ₂ C ₂ H ₅ , butoxycarbonyl-C0 ₂ C ₄ H ₉ , tert-butoxycarbonyl or benzyl Base

The cyclization reaction is preferably carried out in an alkaline system by adding a base or an alkali metal to the reaction, the base being selected from the group consisting of an organic base and an inorganic base, preferably a 1,8-diazabicyclo ring. [5.4.0] -i ^monocarb-7-ene (DBU), alkali metal hydride, NaOH, KOH, sodium alkoxide, potassium alkoxide, potassium carbonate, pyridine or 4-dimethylaminopyridine (DMAP), but The alkali metal hydride includes NaH, KH, and CaH ₂ ; and more preferably sodium alkoxide, potassium alkoxide, NaOH, KOH, NaH, potassium carbonate; the alkali metal includes lithium, sodium, Potassium, cesium, etc., preferably sodium or potassium; wherein the sodium alkoxide is preferably sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, etc., potassium alkoxide is preferably potassium methoxide or potassium ethoxide , potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, etc.;

The reaction temperature is not limited, and is preferably a temperature ranging from room temperature to reflux;

The solvent is preferably methanol, ethanol, tert-butanol, acetonitrile, DMF, toluene or chlorobenzene, but is not limited to the above solvents.

Preferably, the compound represented by Formula III is prepared by the method shown in the following Reaction Scheme 2:

The compound represented by the formula I is reacted with the compound represented by the formula II to give a compound represented by the formula III,

Reaction formula 2

R is -0 or -NR ₂ R ₃ ,

Wherein, is an alkyl group of hydrogen or CH^, preferably -C3⁄4 or -C ₂ H _{5 ;}

R ₂ and R ₃ are each independently H or a d-C ₅ alkyl group, or R ₂ and R ₃ and a connate N atom form a 5-7-membered heterocyclic group or a substituted 5-7-membered heterocyclic group. The hetero atom in the 5- to 7-membered heterocyclic group includes 0, N or S; and R ₂ and R ₃ are each preferably independently methyl, ethyl or The N atom constitutes a morpholinyl group;

X and Y are as described above;

Preferably, the reaction conditions in the reaction formula 2 are acidic or neutral conditions, wherein the acidic conditions are preferably in the presence of acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, and the reaction temperature is not limited, generally -20 ° C to The temperature range of the reflux, the solvent is preferably acetic acid, ethanol, methanol, water, chloroform, toluene, chlorobenzene, acetonitrile or a mixed solvent thereof;

Preferably, the compound represented by the formula I in the reaction formula 2 is prepared by the method shown in the following reaction formula 3:

The compound represented by the formula A is reacted with a substituted acryloyl chloride compound to obtain a compound represented by the formula I,

Reaction formula

Where R and Y are as defined above ₍

The compound represented by the formula VI is reacted to obtain a compound represented by the formula IV,

among them,

The definition of Y is as described above;

Z is -OR ₄ or -NR ₅ R ₆ ;

R ₄ is an alkyl group of a Cr^Cu) group, a Cr(Cu) alkenyl group, an aryl group or an aryl group substituted C^do alkyl group, Preferred is a lower alkyl group of C^Cs, more preferably -CH ₃ or -C ₂ H ₅ ,

R ₅ and R ₆ are each independently an alkyl group of a Cr^Cu) group, a Cr(Cu) alkenyl group, an aryl group and an aryl group-substituted d Cu) alkyl group, preferably a d-C ₅ low-chain alkyl group, Preference is given to -CH ₃ .

In the reaction formula 4, the compound represented by the formula VI is reduced to a nitro group under acidic or neutral conditions, and then ring-closed to obtain a compound represented by the formula IV, and the reaction represented by the reaction formula 4 can be reduced and cyclized in the presence of a reducing agent. Once completed, there is no need to separate the intermediate, wherein the reducing conditions may be: in the presence of a hydrogenation catalyst, hydrogen is introduced to carry out the reaction, the hydrogenation catalyst is palladium carbon, active nickel or Pt0 ₂ , and the solvent used may be methanol, ethanol, DMF or Acetic acid, but not limited to the above solvent; or reducing conditions are: adding a reducing agent, such as iron powder, zinc powder or stannous chloride, adding calcium chloride or glacial acetic acid, the solvent used is alcohol or Alcohol-water mixed solvent; the reaction temperature is not limited, preferably from room temperature to reflux temperature range;

Preferably, the compound represented by the formula VI in the reaction formula 4 is produced by the following reaction formula 5:

Reaction formula 5

The compound represented by the formula V is subjected to a condensation reaction with an acetal or an orthoformate compound to obtain a compound represented by the formula VI.

among them,

The definitions of Y and Z are as described above.

The acetal or orthoformate compound has the following structure:

OR ₇

z people 〇 R ₈

1 ₇ and R ₈ are each independently substituted by Cr^Cu)alkyl, Cr^doalkenyl, aryl or aryl

C Guang CK)

Preferably, The acetal or orthoformate compound is hydrazine, hydrazine-dimethylformamide dimethyl acetal (DMF-DMA), trimethyl orthoformate, triethyl orthoformate, and the like;

The solvent used is acetonitrile, methanol, ethanol, DMSO, DMF, toluene, xylene, ethylene glycol dimethyl ether, but is not limited to the above solvents;

The reaction temperature is not limited and may range from room temperature to reflux;

Preferably, the compound represented by the formula V in the reaction formula 5 is prepared by the method shown in the reaction formula 6:

The compound represented by the formula B is subjected to an aminolysis reaction with the compound represented by the formula A to obtain a compound represented by the formula V,

Reaction formula 6 wherein

W is a halogen or a d-C ₅ alkoxy group, preferably chlorine, methoxy or ethoxy;

The definition of Y is as described above.

Another aspect of the present invention is to provide a method of preparing an Ivacaftor, which is implemented by the following route one or route two:

Wherein, R, X, Y, Ζ and W are as defined above, Step a: reacting a compound represented by Formula I with a compound represented by Formula II as shown in the above Reaction Scheme 2 to obtain a compound represented by Formula III;

Step b: The compound represented by Formula III is subjected to a cyclization reaction in an alkaline system as shown in the above Reaction Scheme 1 to obtain a compound represented by Formula IV;

The compound deprotection group represented by formula IV is obtained as the final target Ivacaftor;

Route 2, including the following steps:

Step c: reacting a compound represented by Formula V with an acetal or orthoformate compound as shown in the above Reaction Scheme 5 to obtain a compound represented by Formula VI;

Step d: The compound represented by the formula VI is reduced to a nitro group under acidic or neutral conditions as shown in the above Reaction Scheme 4, and then ring-closed to obtain a compound represented by the formula IV;

The compound deprotection group represented by formula IV gives the final target Ivacaftor;

More specifically, in the above method,

Step a: The reaction conditions are the same as those of the above reaction formula 2;

Step b: the reaction conditions are the same as those of the above reaction formula 1;

Step C: the reaction conditions are the same as those of the above reaction formula 5;

Step d: the reaction conditions are the same as those of the above reaction formula 4;

Step e: The protecting group of the compound represented by the formula IV is removed under acidic, basic or hydrogenation conditions to obtain the final target Ivacaftor.

The preferred route is as follows:

or

Among them, R and Z are as defined above.

In the above preparation method, the compound I is preferably prepared by the reaction shown in the reaction formula 3;

In the above production method, the compound V is preferably produced by the reaction shown in the reaction formula 6.

In addition, another aspect of the invention also provides novel intermediate compounds represented by III, IV and VI,

III IV VI

Wherein, in the compounds III and VI, X, Υ, Ζ are as defined above; in the compound IV, hydrazine is a hydroxy protecting group, preferably a linear or branched alkoxycarbonyl group or a benzyl group of c ₂ to c ₅ , more preferably ethoxylated. Carbonyl, butoxycarbonyl, tert-butoxycarbonyl or benzyl.

The invention provides two novel synthetic Ivacaftor preparation methods and provides an intermediate of Ivacaftor. The above method avoids various adverse effects caused by high temperature reaction, avoids using high boiling point solvent, is environmentally friendly and safe, and avoids the original The degradation of the target product under high temperature conditions and the corresponding impurities and low yield. Each reaction step is carried out under mild conditions, and the yield is high. No special condensing agent is used in the whole route, and the post-treatment is simple and convenient. The reagents and catalysts in the present method are commonly used industrial raw materials, avoiding the use of highly toxic solvents, the raw materials are cheap and easy to obtain, the reaction after the reaction is convenient, the operation is simple, the synthesis cost is low, and it is suitable for industrial production. Therefore, the method has the advantages of high yield, low cost, mild reaction conditions and the like. Detailed ways

The invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention. The temperatures and reagents employed in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objectives of the present invention.

In the following examples, nuclear magnetic resonance was measured by a Bruker AMX-400 nuclear magnetic resonance spectrometer, TMS was an internal standard, and chemical shifts were in ppm.

Preparation Example 1 Preparation of 3-methoxyacryloyl chloride

Methyl 3-methoxyacrylate (9 g, 77.6 mmol) was added to an aqueous solution of KOH (5.2 g), and reacted at 100 ° C for 1 hour. After TLC detection, the reaction was concentrated to a small volume to adjust the pH to acidity. Ethyl acetate was extracted, dried over anhydrous sodium sulfate and concentrated to give EtOAc (yield: 78.5%).

3-methoxyacrylic acid (6.2 g, 60.8 mmol) was dissolved in 20 ml of dichloromethane, and oxalyl chloride (7.5 ml, 1.2 eq) was added to the ice bath, and 1 drop of DMF was added thereto, and the mixture was reacted at room temperature for 1 hour to obtain 3-A. Oxyacryloyl chloride, evaporated to dryness for use.

Example 1 2,4-di-tert-butyl-5-(3-methoxyacrylamide:)phenylmethyl carbonate (compound)

1-1

Compound A-1 (Y=methoxycarbonyl) (8.5 g, 30.4 mmol) was added to dry pyridine, stirred under ice-cooling, and 3-methoxy acryloyl chloride was dissolved in anhydrous dichloromethane. To the pyridine solution of the compound A-1, and the reaction was carried out in an ice bath for about 1 hour. After the TLC reaction was completed, methylene chloride was added, and the mixture was washed with 1N hydrochloric acid. Column chromatography gave the title compound 2,4-di-tert-butyl-5-(3-methoxyacrylamide:)phenylmethyl carbonate (Il) 7 g (yield 70%).

iHNMRpOOMHz, CDC1 ₃ ): 51.34 (s, 9H), 1.40 (s, 9H), 3.68 (s, 3H), 3.89 (s, 3H), 5.30 (d, 1H, J=12), 7.07(s, 1H ), 7.39 (s, 1H), 7.67 (d, 1H, J = 12.3) o MS/ESI: 364.3 (M + H), 362.3 (MH)

Example 2 Preparation of Compound 1-2. (R is morpholinyl)

1-2

2,4-di-tert-butyl-5-(3-methoxyacrylamide:)phenylmethyl carbonate (Il) (200 mg, 0.55 mmol) prepared in Example 1 was dissolved in 2 ml of toluene, and morphine was added. Porphyrin (96mg, l.lmmol),

The reaction was completed by reflux at 120 ° C for 3 hours. Toluene was distilled off, and the residue was purified by column chromatography to yield 1-2 150 mg (yield: 65%).

iHNMRpOOMHz, CDC1 ₃ ): 51.34 (s, 9H), 1.40 (s, 9H), 3.21 (s, 4H) 3.69 (s, 3H), 3.89 (s, 4H), 4.80 (d, 1H, J=12.6) , 6.79(s, 1H), 7.36 (s, 1H), 7.48 (d, 1H, J = 12.3) o MS/ESI: 419.2 (M+H).

Example 3 Preparation of Compound 1-3 (R is anthracene, fluorenyldimethylamino)

I- 2,4-di-tert-butyl-5-(3-methoxyacrylamide:)phenylmethyl carbonate (Il) (200 mg, 0.55 mmol) prepared in Example 1 was dissolved in 2 ml of toluene. The hydrazine, hydrazine-dimethylamine hydrochloride (89 mg, 1.1 mmol) was added, and the reaction was refluxed at 120 ° C for 3 hours. Toluene was distilled off, and the residue was purified by column chromatography to yield Compound 1-3 158 mg (yield 68%).

iHNMRpOOMHz, CDC1 ₃ ): 51.34 (s, 9H), 1.40 (s, 9H), 3.21 (s, 6H) 3.69 ( s, 3H), 4.80 (d, 1H, J = 12.6), 6.79(s, 1H), 7.36 ( s, 1H), 7.48 (d, 1H, J = 12.3 ) o MS/ESI: 377 (M +H).

Example 4 Preparation of Compound III-1 (X is methoxy, Y is methoxycarbonyl)

III- l

Compound 1-2 (50 mg, 0.138 mmol) prepared in Example 2 was dissolved in 1 ml of acetic acid, and methyl anthranilate (Compound 11-1, X was methoxy) (25 mg, 0.166 mmol) was stirred at room temperature 1 The hour reaction ends. The mixture was neutralized with saturated sodium hydrogencarbonate, extracted with ethyl acetate, and the organic layer was washed with brine, and dried and concentrated to give compound III-l 60 mg (yield 91%).

iHNMRpOOMHz, CDC1 ₃ ): 51.34 ( s, 9H), 1.40 ( s, 9H), 3.68 ( s, 3H), 3.89 ( s, 3H), 5.30 (d, 1H, J=12), 7.07(s, 1H ), 7.39 ( s, 1H), 7.67 (d, 1H, J = 12.3) MS/ESI: 483.3 (M+H) 481.3 (MH).

Example 5 Preparation of Compound III-1 (X is methoxy, Y is methoxycarbonyl)

Compound 1-3 (100 mg, 0.266 mmol) prepared in Example 3 was dissolved in 1 ml of acetic acid, and methyl anthranilate (Compound 11-1, X was methoxy) (50 mg, 0.319 mmol) was stirred at room temperature 1 The hour reaction ends. The acetic acid was neutralized by the addition of saturated sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, and dried and concentrated to give Compound III-1, 115 mg (yield: 92%).

Preparation of Compound IV-1 (Y=methoxycarbonyl) of Example 6

IV-1

The title compound III-1 (50 mg, 0.1 mmol) of Example 4 was added to 2 ml of methanol, and sodium methoxide (7 mg, 0.12 mmol) was added and refluxed for 2 to 3 hours, and the reaction was completed. The solvent was evaporated to give Compound IV-1 (yield: 93%). iHNMRpOOMHz, CDC1 ₃ ): 51.35 (s, 9H), 1.45 (s, 9H), 3.80 (s, 3H), 6.95 (d, 1H, J=6.3), 7.37 (d, 1H, J=5.7), 7.40 (s, 1H), 7.46 (d, 1H, J=1.2), 7.50 (s, 1H), 8.41 (dd, 1H), 9.03 (s, 1H), 12.30 (s, 1H).

Example 7 Preparation of Compound IV-1 (Y=Methoxycarbonyl)

The title compound III-1 (100 mg, 0.2 mmol) of Example 4 was added to 2 ml of tert-butanol, and potassium t-butoxide (27 mg, 0.24 mmol) was added and refluxed for 2 to 3 hours, and the reaction was completed. The solvent was evaporated to give the compound IV-145 mg (yield: 93%).

Example 8 Preparation of Ivacaftor

Ivacaftor

The title compound IV-1 (50 mg, EtOAc) was evaporated. After reacting at room temperature for 2 to 3 hours, after the TLC detection reaction was completed, hydrochloric acid was added to adjust the pH to 5 to 6, and a solid was precipitated and filtered to obtain a compound Ivacaftor 44 mg (yield: 94%).

iHNMRpOOMHz, CDC1 ₃ ): 51.35 (s, 9H), 1.45 (s, 9H), 6.95 (d, 1H, J=6.3), 7.37 (d, 1H, J=5.7), 7.40 (s, 1H), 7.46 (d, 1H, J=1.2), 7.50 (s, 1H), 8.41 (dd, 1H), 9.03 (s, 1H), 12.30 (s, 1H).

Preparation of Compound B of Example 9 (W is ethoxy)

o-Nitrobenzoic acid (24 g, 144 mmol) was added to thionyl chloride (40 ml). After refluxing for 1 hour, the reaction was completed and the reaction mixture was clarified. The solvent was evaporated to dryness in dry THF (30 mL) to give o-nitrobenzoyl chloride, which was used directly in the next reaction.

Dissolve sodium metal (7.2 g, 313 mmol) in absolute ethanol (210 mL) at room temperature until sodium is dissolved. After refluxing for 10 minutes, the reaction solution was cooled to 50 ° C ~ 60 ° C, diethyl malonate (50 mL, 328 mmol) was added dropwise, and the reaction was refluxed for 30 minutes after the addition, the solution was clarified, and then cooled to - 20 °C. An o-nitrobenzoyl chloride in anhydrous THF (50 mL) was added dropwise to the reaction mixture, and the mixture was stirred for about 30 minutes, and the reaction temperature was kept below -10 ° C. Ice water (140 mL) was added dropwise to the reaction solution, the temperature of the reaction solution was kept below 0 ° C, and the pH of the reaction mixture was adjusted to 1-2 with dilute hydrochloric acid. Ethanol was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to give diethyl 2-(2-nitrobenzyl)malonate.

Diethyl 2-(2-nitrobenzyl)malonate (24 g, 77.7 mmol), added with 30 ml of water, refluxed at 110 ° C for 1 h, the reaction was cooled, and then extracted with ethyl acetate. The organic phase was concentrated to give an oily compound B-1 17 g (yield of the compound B-1 as 86.2% based on o-nitrobenzoic acid).

iHNMRpOOMHz, DMSO): 50.938 (t, 3H), 3.87 (q, 2H), 6.95 (d, 1H, J=6.3), 7.38 (m, 1H), 7.55 (m, 1H), 7.89 (m, 1H) .

Preparation of Compound V1 of Example 10 (Y is methoxycarbonyl)

V-l

The compound B-1 (2.79 g, 10 mmol) prepared in Example 9 and the compound Al (Y = methoxycarbonyl) (2.37 g, 10 mmol) were dissolved in 10 ml of DMF, heated to 120 ° C for 3 hours, and the reaction solution was placed. Ethyl acetate was added in cold, DMF was washed with water, and the organic phase was dried, concentrated, and then purified by column chromatography to give the compound Vl 2.1 g (yield: 44.7%).

iHNMRpOOMHz, CDC1 ₃ ): 51.35 ( s, 9H), 1.46 ( s, 9H), 3.90 ( s, 3H), 3.95 ( s, 2H) , 7.41 ( s, 1H), 7.49 (d, 2H) , 7.68 ( t, 1H), 7.80 (t, 1H), 8.21 (d, lH) o

Preparation of Compound VI-1 of Example 11 (Y is methoxycarbonyl, hydrazine is hydrazine, hydrazine-dimethylamino)

VI-1

The compound V-1 (200 mg, 0.427 mmol) prepared in Example 10 was dissolved in 5 ml of ethylene glycol dimethyl ether, and added to DMF-DMA (0.1 ml) and heated to reflux for 3 hours. The reaction was substantially complete by TLC, and the solvent was evaporated to give compound VI. -1210 mg (yield 90%).

iHNMRpOOMHz, CDC1 ₃ ): 51.35 (s 9H), 1.46 (s 9H), 3.11 (s 6H), 3.90 (s 3H), 7.41 (s 1H), 7.49 (d 2H), 7.68 (t 1H), 7.80 ( t 1H), 8.21 (d lH

Example 12 Preparation of Compound VI-2 (Y is methoxycarbonyl, hydrazine is methoxy)

VI-2

The compound V-1 (200 mg 0.427 mmol) prepared in Example 10 was dissolved in 5 ml of ethylene glycol dimethyl ether, and trimethyl orthoformate (0.1 ml) was added thereto, and the mixture was heated under reflux for 3 hours, and the reaction was substantially complete by TLC, and the solvent was evaporated. The compound VI-2195 mg (yield: 89.4%) was obtained.

iHNMRpOOMHz, CDC1 ₃ ): 51.35 (s 9H), 1.46 (s 9H), 3.82 (s 3H), 3.90 (s 3H), 7.41 (s 1H), 7.49 (d 2H), 7.68 (t 1H), 7.80 ( t 1H), 8.21 (d lH

Preparation of Compound IV-1 (Y=methoxycarbonyl) of Example 13

IV-1 The compound VI-1 (100 mg) prepared in Example 11 was dissolved in ethanol, 10 mg of Pd/C was added, hydrogen gas was introduced, and the reaction was carried out for 5 hours. After the TLC detection reaction was completed, Pd/C was filtered off, and the solvent was evaporated to give the compound IV- 185 mg (yield 90%).

iHNMRpOOMHz, CDC1 ₃ ): 51.35 (s, 9H), 1.45 (s, 9H), 3.90 (s, 3H), 6.95 (d, 1H, J=6.3), 7.37 (d, 1H, J=5.7), 7.40 (s, 1H), 7.46 (d, 1H, J=1.2),

7.50 (s, 1H), 8.41 (dd, 1H), 9.03 (s, 1H), 12.30 (s, 1H).

Example 14 Preparation of Compound IV-1 (Y=Methoxycarbonyl)

The compound VI-1 (500 mg) prepared in Example 11 was added to ethanol (2 ml), water (2 ml), acetic acid (1 ml), and zinc powder (300 mg) was added thereto, and refluxed at 90 ° C overnight, and the reaction was confirmed by TLC. The solid was removed by filtration, the pH was adjusted to 5-6, ethyl acetate was evaporated, the organic phase was dried and concentrated to give the title compound IV-1410 mg (yield: 89%).

Example 15 Preparation of Compound IV-1 (Y=Methoxycarbonyl)

The compound VI-2 (100 mg) prepared in Example 12 was dissolved in ethanol, Pd/C (10 mg) was added, hydrogen gas was introduced, and the reaction was carried out for 5-6 hours. After the TLC detection reaction was completed, the Pd/C was filtered off and concentrated. The solvent gave the title compound IV- 185 mg (yield: 90%).

Example 16 Preparation of Ivacaftor

Ivacaftor

With reference to the procedure of Example 8, the title compound IV-1 (50 mg, <RTI ID=0.0>>

Claims

Rights request

A method for producing a compound represented by the formula IV, which is carried out by the following reaction formula 1:

X is a hydroxy group, a linear or branched alkoxy group of C^Cs, a benzyloxy group, a phenoxy group or NH _{2 ;}

Y is a hydroxy protecting group.

2. A process for the preparation of a compound of the formula IV according to claim 1, wherein X is a linear or branched alkoxy group of C^C^; more preferably a methoxy group, an ethoxy group or a phenoxy group;

Y is a linear or branched alkoxycarbonyl group or a benzyl group of ₅ to ₅ ; more preferably a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, a t-butoxycarbonyl group or a benzyl group.

3. A process for producing a compound represented by the formula IV according to claim 1 or 2, wherein the compound represented by the formula III is subjected to a cyclization reaction in an alkaline system by adding a base or a base to the reaction. The metal is realized, the base is selected from the group consisting of an organic base and an inorganic base, preferably 1,8-diazabicyclo[5.4.0]^monocarb-7-ene, alkali metal hydride, NaOH, KOH, sodium alkoxide, alcohol Potassium, potassium carbonate, pyridine or 4-dimethylaminopyridine, but not limited to the above base, wherein the alkali metal hydride comprises NaH, KH and CaH ₂ ; and more preferably sodium alkoxide, potassium alkoxide, NaOH, KOH , NaH, potassium carbonate; the alkali metal includes lithium, sodium, potassium, rubidium, etc., preferably sodium, potassium; wherein the sodium alkoxide is preferably sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, n-butanol Sodium, sodium t-butoxide, potassium alkoxide is preferably potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide.

The process for producing a compound represented by the formula IV according to claim 1 or 2, wherein the compound represented by the formula III is produced by the method shown in the following reaction formula 2:

Reaction formula 2

R is ^! ^ or ^!^!^, wherein, is an alkyl group of hydrogen or CH^, R ₂ and R ₃ are each independently H or an alkyl group of d to C ₅ , or R ₂ and R ₃ are bonded to a bonded N atom a 5- to 7-membered heterocyclic group or a substituted 5 to 7-membered heterocyclic group, wherein the hetero atom in the 5- to 7-membered heterocyclic group includes 0, N or S;

X and Y are as claimed in claim 1 or 2.

The method for producing a compound represented by the formula IV according to claim 4, wherein in the reaction formula 2,

R is -0 or -NR ₂ R ₃ ;

Wherein ^ is an alkyl group of ^~^, preferably a methyl group or an ethyl group;

R ₂ and R ₃ each independently comprise a methyl group, an ethyl group or R ₂ and a morpholino group with a connate N atom.

The method for producing a compound represented by the formula IV according to claim 4, wherein the reaction condition in the reaction formula 2 is an acidic or neutral condition, wherein the acidic condition is preferably acetic acid, trifluoroacetic acid or p-toluene In the presence of a sulfonic acid, the solvent is preferably acetic acid, ethanol, methanol, water, chloroform, toluene, chlorobenzene, acetonitrile or a mixed solvent thereof.

7. The method for producing a compound represented by the formula IV according to claim 4, wherein the compound represented by the formula I in the reaction formula 2 is produced by the method shown in the following reaction formula 3: The compound represented by the formula A is reacted with a substituted acryloyl chloride compound to obtain a compound represented by the formula I,

A ¹ reaction formula 3

Wherein R is as claimed in claim 4; Y is as claimed in claim 1 or 2.

8. A process for the preparation of a compound represented by the formula IV, which is produced by the method of the following reaction formula 4:

among them,

Y as claimed in claim 1 or 2;

Z is -OR ₄ or -NR ₅ R ₆ , wherein

R ₄ is an alkyl group of a Cr^Cu) group, a Cr(Cu) alkenyl group, an aryl group or an aryl group substituted C^do alkyl group, and R ₅ and R ₆ are each independently an alkyl group of Cr^Cu), Cr ^Cu) Alkenyl, aryl and aryl substituted C^Cio.

9. A method of producing a compound represented by formula IV according to claim 8, wherein

Y as claimed in claim 1 or 2;

Z is -OR ₄ or -NR ₅ R ₆ , wherein

R ₄ is a lower alkyl group of C^Cs, more preferably -CH ₃ or -C ₂ H ₅ ,

R ₅ and R ₆ are each independently a lower alkyl group of d to C ₅ , more preferably -CH ₃ .

10. A process for producing a compound represented by the formula IV according to claim 8, wherein the compound represented by the formula VI in the reaction formula 4 is reduced under acidic or neutral conditions, and then the ring is closed to obtain a compound represented by the formula IV. The reaction shown in Formula 4 is carried out in the presence of a reducing agent, wherein the reducing conditions are: in the presence of a hydrogenation catalyst, hydrogen is introduced to carry out the reaction, the hydrogenation catalyst is palladium carbon, active nickel or Pt0 _{2 ;} or the reducing conditions are: A reducing agent is added, the reducing agent is iron powder, zinc powder or stannous chloride, and calcium chloride or glacial acetic acid is further added thereto, and the solvent used is an alcohol or an alcohol-water mixed solvent.

A method for producing a compound represented by Formula IV according to any one of claims 8 to 10, wherein

The compound represented by the formula VI in the reaction formula 4 is produced by the following reaction formula 5:

among them,

Y and Z are as defined in claim 8,

The acetal or orthoformate compound has the following structure:

OR ₇

z people 〇 R ₈

₁₇ and R ₈ are each independently a Cr ^ Cu) alkyl, Cr ^ do alkenyl group, an aryl group or an aryl group substituted with a C Cio hospital wide group.

The method for producing a compound represented by the formula IV according to claim 11, wherein the acetal or orthoformate compound is hydrazine, hydrazine-dimethylformamide dimethyl acetal, trimethyl orthoformate or the original Triethyl formate.

The method for producing a compound represented by the formula IV according to claim 11, wherein the compound represented by the formula V in the reaction formula 5 is produced by the method shown in the reaction formula 6: the compound represented by the formula B and the formula The compound represented by A undergoes an aminolysis reaction to produce a compound of formula V,

Reaction formula 6

Y is as claimed in claim 8.

14. A process for the preparation of an Ivacaftor which is carried out by protecting a compound of formula IV as follows:

Ivacaftor.

Y is a hydroxy protecting group, preferably a c ₂ ~ c ₅ linear or branched alkoxycarbonyl group or a benzyl group; more preferably an ethyl carbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group or a benzyl group.

15. A process for the preparation of an Ivacaftor according to claim 14 wherein the protecting group is removed under acidic-alkaline or hydrogenation conditions.

16. A method of preparing an Ivacaftor by the following route or route

Wherein X and Y are as claimed in claim 1 or 2; R is as claimed in claim 4; as claimed in claim 8 or 9;

Route 1, including the following steps:

Step a Reaction of the formula 2: The compound represented by the formula I is reacted with a compound represented by the formula II to obtain a compound represented by the formula III;

Step b: The reaction formula of the formula 1 is carried out by subjecting a compound represented by the formula III to a cyclization reaction in an alkaline system to obtain a compound represented by the formula IV;

The protective group of the compound represented by formula IV is removed under acidic, basic or hydrogenation conditions to obtain the final target Ivacaftor;

Route 2, including the following steps:

Step c: Reaction formula 5 according to claim 11 : reacting a compound represented by formula V with an acetal or orthoformate compound to obtain a compound represented by formula VI;

Step d: Reaction formula 4 according to claim 8: the compound represented by formula VI is reduced to a nitro group under acidic or neutral conditions, and then ring-closed to obtain a compound represented by formula IV;

The protecting group of the compound represented by formula IV is removed under acidic, basic or hydrogenation conditions to give the final target Ivacaftor.

17. The method of preparing an Ivacaftor according to claim 16, wherein

Step a: The reaction conditions are the same as those of the reaction formula 2 according to claim 4;

Step b: the reaction conditions are the same as those of the reaction formula 1 according to claim 3; Step c: the reaction conditions are the same as those of the reaction formula 5 according to claim 11;

Step d: the reaction conditions are the same as those of the reaction formula 4 according to claim 8;

Step e: The protecting group is removed under acidic, basic or hydrogenation conditions.

The method of preparing an Ivacaftor according to claim 16 or 17, wherein the method is implemented by the following route:

Wherein R and Z are as claimed in claim 16.

19. A compound represented by formula III,

III

Wherein X and Y are as claimed in claim 1 or 2.

20. A compound represented by the formula IV,

Wherein Y is a linear or branched chain of c ₂ ~c ₅

Carbonyl, tert-butoxycarbonyl or benzyl.

21. A compound represented by the formula VI,

VI

Wherein Y is as claimed in claim 1 or 2; Z is as claimed in claim 8 or 9.