WO2020040614A1 - Procédé de préparation de sel hemicalcique de l'acide (3r,5r)-7-[2-(4-flurophényl)-5-isopropyl-3-phényl-4-[(4-hydroxyméthylphénylamino)carbonyl]-pyrrrol-1-yl]-3,5-dihydroxyheptanoïque, intermédiaire utilisé à cet effet, et procédé de préparation de l'intermédiaire - Google Patents

Procédé de préparation de sel hemicalcique de l'acide (3r,5r)-7-[2-(4-flurophényl)-5-isopropyl-3-phényl-4-[(4-hydroxyméthylphénylamino)carbonyl]-pyrrrol-1-yl]-3,5-dihydroxyheptanoïque, intermédiaire utilisé à cet effet, et procédé de préparation de l'intermédiaire Download PDF

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WO2020040614A1
WO2020040614A1 PCT/KR2019/010799 KR2019010799W WO2020040614A1 WO 2020040614 A1 WO2020040614 A1 WO 2020040614A1 KR 2019010799 W KR2019010799 W KR 2019010799W WO 2020040614 A1 WO2020040614 A1 WO 2020040614A1
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formula
compound
alkyl
aryl
independently
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Korean (ko)
Inventor
박은정
이원일
박상욱
김보정
정서희
김철우
신상윤
조민용
손세일
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DAE WON PHARMACEUTICAL Co Ltd
Daewoong Pharmaceutical Co Ltd
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DAE WON PHARMACEUTICAL Co Ltd
Daewoong Pharmaceutical Co Ltd
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Priority to CN201980055467.7A priority Critical patent/CN112616314A/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/19—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/76—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1-
  • the present invention relates to a method for preparing hemicalcium salt, and intermediates used therein and a method for preparing the same.
  • Korean Patent No. 10-1329113 discloses (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl ] -Pyrrole-1-yl] -3,5-dihydroxy-heptanoic hemicalcium salt is described as follows.
  • Korean Patent No. 10-1329113 discloses a method for preparing Compound 2, which is a starting material, in Example 1, and the method is described in J. Med. Chem., 41, 26, (1998), 5297-5309. And Tetrahedron Lett., 43, 30, (2002), 5353. The method is shown in the following scheme.
  • the present inventors effectively use the (3R, 5R) -7- [2- (4- by a convergence method in which the main structural parts of the compound are synthesized separately and then coupled, rather than the sequential synthesis method as described above.
  • the present invention was completed by devising a method that can not only synthesize the reaction intermediate as a solid using a protecting group but also easily control the main flexible material.
  • One object of the present invention is to provide a novel (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [which can effectively solve the disadvantages of the conventional sequencing process. It is to provide a method for producing (4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • Another object of the invention is (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole -1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salts and intermediates used in the preparation thereof.
  • the present invention is (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbo Nil] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt, an intermediate used for the preparation thereof, and a method for producing the same are provided.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a new method for preparing the general] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • the preparation method comprising the following steps (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[( 4-hydroxymethylphenylamino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be prepared.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R is C 1 -C 6 alkyl.
  • P is tetrahydropyranyl, methoxymethyl, methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl , Benzyl, para-methoxybenzyl, dimethoxybenzyl, benzoyl or tert-butoxycarbonyl.
  • it is not limited thereto.
  • C x -C y represents a functional group having the carbon number of less than x with y.
  • X in the formula of the present specification represents a halogen atom.
  • X can be F, Cl, Br, and the like.
  • the step (1a) is a step of alkylating the active methylene compound, it can be carried out under basic conditions.
  • alkylation may be a reaction for substituting an alkyl group for a hydrogen atom of an organic compound.
  • the alkyl group can be represented by C n H 2n + 1 .
  • Alkylation can be carried out in nucleophilic or electrophilic reactions.
  • Examples of the base include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), N, N- Diisopropylethylamine (DIPEA), triethanolamine (TEA), pyridine, sodium hydride or potassium tert-butoxide (K [OC (CH 3 ) 3 ]), and the like, each of which may be used alone or in combination of two or more. Can be used. However, it is not limited thereto.
  • the step (1a) may be carried out under a solvent that can be used for the alkylation reaction of the active methylene compound, examples of the solvent, toluene, xylene, benzene, methylene chloride, butanol, tetrahydrofuran, ethyl acetate, propanol, Cyclohexanone, diethyl ether, dioxane, ethanol, methanol, pyridine, acetone, acetonitrile, n, n-dimethylformamide, dimethyl sulfoxide or an aqueous solution thereof, and the like; It can mix and use. However, it is not limited thereto.
  • the step (1a) may be carried out at a temperature of 20 to 30 °C, or by heating or reflux at 50 to 60 °C depending on the solvent.
  • Step (1b) is to remove the hydroxy protecting group of the compound of Formula C, it can be carried out in acid conditions.
  • a "protecting group” may be a group protecting a functional group in a reaction step by selectively reacting with a specific functional group to modify the functional group.
  • the compound including the protecting group may be an intermediate.
  • the acid examples include formic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, chromic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid (TFA), and the like. It can be used individually or in mixture of 2 or more in aqueous solution. However, it is not limited thereto.
  • the step (1b) may be carried out under a solvent that can be used for the deprotection reaction of the hydroxy protecting group, specifically, may be carried out under conditions such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane or water. .
  • step (1b) may be carried out at a temperature condition of 20 to 40 °C.
  • deprotection may be a reaction in which the introduced protecting group is removed and the protected functional group is recovered.
  • hydroxy groups can be recovered through deprotection of hydroxy protecting groups.
  • Step (1c) is a step of coupling the compound of Formula D with the compound of Formula E to form a pyrrole ring.
  • coupling may be a reaction of forming a new covalent bond through a reaction between organic compounds.
  • the coupling is a condensation reaction between a 1,4-dicarbonyl compound and a primary amine to form an enamine, and the enamine formed subsequently recovers aromaticity by intramolecular condensation reaction with a carbonyl group to form a pyrrole ring.
  • the coupling is a condensation reaction between a 1,4-dicarbonyl compound and a primary amine to form an enamine, and the enamine formed subsequently recovers aromaticity by intramolecular condensation reaction with a carbonyl group to form a pyrrole ring.
  • the step (1c) may be carried out under a solvent that can be used for the pyrrole cyclization reaction, specifically, methanol, ether, ethyl acetate, tetrahydrofuran, toluene, heptane, cyclohexane or hexane and the like may be used alone. Or two or more can be mixed and used. However, it is not limited thereto.
  • the step (1c) may be performed by heating at 80 to 90 °C depending on the temperature conditions or solvent of 20 to 30 °C.
  • the reaction may proceed in acid conditions, and usable acids include pivalic acid or toluene-4-sulfonic acid. However, it is not limited thereto.
  • the step (1d) is to remove the acetal protecting group of the diol in the compound of Formula F-1, it can be carried out in acid conditions.
  • the step of removing the acetal protecting group, the acetal is converted to hemiacetal in the acid conditions, hemiacetal is removed can be restored to the hydroxyl group.
  • the acid may be hydrochloric acid, bromic acid, iodic acid, sulfuric acid, acetic acid or trifluoroacetic acid, and the like, and these may be used alone or in combination of two or more. However, it is not limited thereto.
  • step (1d) may be carried out under a solvent that can be used for the deprotection reaction of the diol protecting group, specifically methanol, tetrahydrofuran or a mixture thereof may be used. However, it is not limited thereto.
  • step (1d) may be performed at a temperature condition of 20 to 30 °C.
  • the compound of Formula G is hydrolyzed under basic conditions, and then a calcium ion source is added thereto to give the final product (3R, 5R) -7- [2- (4-fluorophenyl) -5- Isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • hydrolysis under base conditions may be a hydrolysis reaction carried out in the presence of a base.
  • the hydrolysis reaction may be a decomposition reaction caused by the action of water molecules during a natural chemical reaction.
  • the hydrolysis reaction may be carried out under basic conditions using sodium hydroxide, potassium hydroxide or an aqueous solution thereof. These may be used alone or in combination of two or more. However, it is not limited thereto.
  • the hydrolysis reaction may be carried out under a solvent that can be used for the basic hydrolysis reaction of the ester, specifically methanol, tetrahydrofuran or water may be used, these may be used alone or in combination of two or more Can be. However, it is not limited thereto.
  • the hydrolysis reaction may be carried out under a temperature condition of 0 to 30 °C.
  • the hemicalcium salt production reaction may use a calcium ion source.
  • the calcium ion source include calcium acetate, calcium chloride, calcium carbonate, tricalcium phosphate, calcium citrate, calcium citrate maleate, calcium lactate, calcium gluconate, calcium hydroxide, calcium oxalate, calcium fluoride And calcium sulfate or these aqueous solutions. These may be used alone or in combination of two or more. However, it is not limited thereto.
  • the hemicalcium salt production reaction may be carried out under a solvent that can be used for the salt production reaction, specifically methanol, tetrahydrofuran or water, etc., these may be used alone or in combination of two or more. have. However, it is not limited thereto.
  • the hydrolysis reaction may be carried out at a temperature of 20 to 30 °C.
  • the preparation method comprising the steps (1a) to (1e) can be summarized by the following scheme 1.
  • the manufacturing method comprising the steps (1a) to (1e) can be used when P is R 6 R 7 R 8 C-.
  • P is R 6 R 7 R 8 C-.
  • it is not limited thereto.
  • the preparation method comprising the following steps (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[( 4-hydroxymethylphenylamino) carbonyl] -pyrrole-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be prepared.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R is C 1 -C 6 alkyl.
  • P is tetrahydropyranyl, methoxymethyl, methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl , Benzyl, para-methoxybenzyl, dimethoxybenzyl, benzoyl or tert-butoxycarbonyl.
  • it is not limited thereto.
  • the step (2a) is substantially the same as the step (1a). Therefore, redundant descriptions are omitted.
  • Step (2b) is a step of forming a pyrrole ring by coupling with the compound of formula E while maintaining the hydroxy protecting group of the compound of formula (C).
  • the step (2b) may be carried out under a solvent that can be used for the pyrrole cyclization reaction, methanol, ether, ethyl acetate, tetrahydrofuran, toluene, heptane, cyclohexane or hexane and the like can be used each of them alone Or two or more can be mixed and used. However, it is not limited thereto.
  • the step (2b) may be performed by heating at 80 to 90 °C depending on the temperature conditions or solvent of 20 to 30 °C.
  • Step (2c) is a step of removing the hydroxy protecting group and the diol protecting group at the same time in the compound of Formula F-2, can be carried out in acid conditions.
  • the acid may be formic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, chromic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid, and the like, each of which is solely an aqueous solution. Or two or more can be mixed and used. However, it is not limited thereto.
  • step (2c) may be carried out under a solvent that can be used for the deprotection reaction of a hydroxy protecting group or a diol protecting group, specifically, methanol, tetrahydrofuran or water may be used, and these may be used alone or two or more, respectively. It can mix and use. However, it is not limited thereto.
  • step (2c) may be performed at 20 to 30 °C.
  • the step (2d) is substantially the same as the step (1e). Therefore, redundant descriptions are omitted.
  • the preparation method comprising the steps (2a) to (2d) can be summarized by the following scheme 2.
  • the manufacturing method comprising the steps (2a) to (2d) can be used when P is R 3 R 4 R 5 Si-.
  • P is R 3 R 4 R 5 Si-.
  • it is not limited thereto.
  • the preparation method comprising the following steps (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be prepared.
  • R is C 1 -C 6 alkyl.
  • Step (3a) is a step of alkylating the active methylene compound, it can be carried out under basic conditions. At this time, step (3a) may be performed substantially the same as described in step (1a). Therefore, redundant descriptions are omitted.
  • Step (3b) is a step of coupling the compound of Formula D with the compound of Formula E to form a pyrrole ring.
  • Step (3b) may be performed substantially the same as the pyrrole cyclization reaction described in step (1c). Therefore, redundant descriptions are omitted.
  • Step (3c) is to remove the acetal protecting group of the diol in the compound of Formula F-1, it can be carried out in acid conditions.
  • step (3c) may be performed substantially the same as step (1d), and thus, detailed descriptions thereof will be omitted.
  • step (3d) the compound of Formula G is hydrolyzed under basic conditions, and then a calcium ion source is added thereto to give a final product of (3R, 5R) -7- [2- (4-fluorophenyl) -5-. Isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt. Since step (3d) may be performed substantially the same as step (1e), detailed descriptions thereof will be omitted.
  • the preparation method comprising the steps (3a) to (3d) can be summarized by the following scheme 3.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a compound represented by the general formula (A-1), which can be used as an intermediate in the production of general] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl.
  • P is tetrahydropyranyl, methoxymethyl, methoxyethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl, benzyl, Para-methoxybenzyl, dimethoxybenzyl, benzoyl or tert-butoxycarbonyl.
  • it is not limited thereto.
  • the present invention also provides a method for preparing the compound represented by Chemical Formula A-1.
  • the compound represented by Chemical Formula A-1 may be prepared according to a preparation method including the following steps.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 10 is C 1 -C 6 alkyl
  • X is halo
  • cross coupling may be a coupling reaction occurring between different compounds.
  • the present invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole- It provides a compound represented by the formula (A-2), which can be used as an intermediate in the preparation of 1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • the present invention also provides a method for preparing the compound represented by Chemical Formula A-2.
  • the compound represented by Chemical Formula A-2 may be prepared according to a preparation method including the following steps.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 10 is C 1 -C 6 alkyl
  • X is halo
  • the compound of A-1 may be prepared by substantially the same steps as described in Scheme 4, and then the compound of A-2 may be prepared by deprotection of a hydroxyl group.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- I] -3,5-dihydroxy heptanoic acid
  • Compound ⁇ 2-bromo-1- (4-fluorophenyl) -2-phenyl Ethan-1-one ⁇ is provided.
  • the compound represented by Formula B may be prepared according to a preparation method including the following steps.
  • a compound of Formula b-3 was prepared by reacting fluorobenzene, a compound of Formula b-1, with Friedel-Craft acylation with a compound of Formula b-2 as a starting material, followed by a bromination reaction.
  • the compound of B can be prepared.
  • the "Friedel-Craft Acylation Reaction” is a reaction in which a carbonyl group is introduced through an electrophilic Aromatic Substitution (EAS) with an acyl chloride compound to an aromatic compound or an aromatic compound derivative under Lewis acid conditions. Can be.
  • EAS electrophilic Aromatic Substitution
  • the “bromination reaction” may be a reaction in which Br group is introduced into the alpha position of the ketone by a halogen compound (Br 2 ) to be introduced under acidic or basic conditions.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a compound represented by the formula (C), which can be used as an intermediate in the production of general] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl.
  • the present invention provides a method for preparing a compound represented by Chemical Formula C.
  • the compound represented by Chemical Formula C may be prepared according to a preparation method including the step of preparing a compound of Chemical Formula C by reacting a compound of Chemical Formula A-1 with a compound of Chemical Formula B.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl.
  • the compound of Formula C can be obtained by simply coupling the compound of Formula A-1 with the compound of Formula B under basic conditions.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a compound represented by the formula (D), which can be used as an intermediate in the production of the]]-3,5-dihydroxy heptanoic acid hemicalcium salt.
  • the present invention provides a method for preparing a compound represented by Formula (D).
  • the compound represented by Formula D may be prepared according to a preparation method comprising the step of preparing a compound of Formula D by reacting a compound of Formula A-2 with a compound of Formula B.
  • the compound of Formula D may be prepared by the same reaction as described in Scheme 7, except for using the compound of Formula A-2 instead of the compound of Formula A-1 in Scheme 7. have.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a compound represented by the formula (F-2), which can be used as an intermediate in the production of general] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R is C 1 -C 6 alkyl.
  • the present invention provides a method for preparing a compound represented by Chemical Formula F-2.
  • the compound represented by Formula F-2 may be prepared according to a preparation method including the step of preparing a compound of Formula F-2 by reacting a compound of Formula C with a compound of Formula E.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R is C 1 -C 6 alkyl.
  • the compound of Formula C and the chemical of Formula E may undergo an intermolecular condensation reaction through a coupling reaction, and a continuous intramolecular condensation reaction may occur to prepare a compound of Formula F-2 including a pyrrole ring.
  • a coupling reaction may undergo an intermolecular condensation reaction through a coupling reaction, and a continuous intramolecular condensation reaction may occur to prepare a compound of Formula F-2 including a pyrrole ring.
  • the present invention also provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole- Provided is a method for preparing a compound represented by the formula (F-1), which can be used as an intermediate in the preparation of 1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • R is C 1 -C 6 alkyl.
  • the compound represented by Formula F-1 may be prepared according to a preparation method comprising the step of preparing a compound of Formula F-1 by reacting a compound of Formula D with a compound of Formula E.
  • the step is a first solvent selected from the group consisting of ethyl acetate, methylene chloride, chloroform, tetrahydrofuran, acetone, methanol, ethanol and isopropanol, and the agent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether.
  • Compound of formula (F-1) in solid phase can be obtained by using a mixed solvent in which two solvents are mixed. However, it is not limited thereto.
  • R is C 1 -C 6 alkyl.
  • the mixed solvent is ethyl acetate / hexane; Ethyl acetate / pentane; Ethyl acetate / heptane; Methylene chloride / hexane; Methylene chloride / pentane; Methylene chloride / heptane; Chloroform / pentane; Chloroform / heptane; Tetrahydrofuran / hexane; Tetrahydrofuran / pentane; Tetrahydrofuran / heptane; Acetone / water; Acetone / hexane; Acetone / pentane; Acetone / heptane; Acetone / petroleum ether; Methanol / water; Ethanol / water; And isopropanol / water, and may preferably be tetrahydrofuran / heptane. However, it is not limited thereto.
  • the compound of Formula F-1 may be prepared through substantially the same steps as described in Scheme 9 except for using the compound of Formula D instead of the compound of Formula C in Scheme 9.
  • the invention provides (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- It provides a method for preparing a compound represented by the general formula (G), which can be used as an intermediate in the production of general] -3,5-dihydroxy heptanoic acid hemicalcium salt.
  • the method includes preparing a compound of formula G from a compound of formula F-1 or a compound of formula F-2.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or combine with each other to form a 5- to 7-membered ring,
  • R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R 6 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 6 -C 12 aryl and one or more H of said C 6 -C 12 aryl is C 1 May be substituted with -C 6 alkoxy ⁇ ,
  • R 9 is C 1 -C 6 alkyl or C 6 -C 12 aryl
  • R is C 1 -C 6 alkyl.
  • the method for preparing the compound of Formula G is prepared using the compound of Formula F-1 or the compound of Formula F-2, wherein ethyl acetate, methylene chloride, chloroform, tetrahydrofuran, acetone, methanol ,
  • a mixed solvent in which a first solvent selected from the group consisting of ethanol and isopropanol, and a second solvent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether are obtained, thereby obtaining the compound of Formula G as a solid phase. can do.
  • the mixed solvent may be ethyl acetate / hexane; Ethyl acetate / pentane; Ethyl acetate / heptane; Methylene chloride / hexane; Methylene chloride / pentane; Methylene chloride / heptane; Chloroform / pentane; Chloroform / heptane; Tetrahydrofuran / hexane; Tetrahydrofuran / pentane; Tetrahydrofuran / heptane; Acetone / water; Acetone / hexane; Acetone / pentane; Acetone / heptane; Acetone / petroleum ether; Methanol / water; Ethanol / water; And isopropanol / water can be used in any one combination selected from the group consisting of. However, it is not limited thereto.
  • the compound of Formula G may be prepared through a step in which the compound of Formula F-1 or F-2 undergoes a deprotection reaction under acidic conditions such that the hydroxy group and the diol are simultaneously deprotected.
  • the new intermediates used in the preparation of 1-yl] -3,5-dihydroxy heptanoic acid hemicalcium salt can be purified by solidification when using a protecting group such as trityl, and can be stably synthesized in a high yield.
  • Step 1 Preparation of (((4-nitrobenzyl) oxy) methanetriyl) tribenzene
  • step 1 (((4-nitrobenzyl) oxy) methanetriyl) tribenzene (203 g) and zinc powder (174.5 g) obtained in step 1 were added to methanol (2 L) and cooled at 0-5 ° C.
  • Ammonium formate (213.5 g) was added to the reaction solution, and the mixture was refluxed for 2 hours.
  • the reaction solution was cooled to 20-25 ° C., filtered through celite, washed with CH 2 Cl 2 (0.5 L) to remove zinc. The filtrate was concentrated under reduced pressure, CH 2 Cl 2 (0.8 L) was added thereto, and the mixture was stirred until it was completely dissolved.
  • Step 3 Preparation of 4-methyl-3-oxo-N- (4-((trityloxy) methyl) phenyl) pentanamide
  • Step 1 Preparation of (((4-nitrobenzyl) oxy) methanetriyl) tribenzene
  • step 1 (((4-nitrobenzyl) oxy) methanetriyl) tribenzene (40 g) and zinc powder (53.04 g) obtained in step 1 were added to methanol (0.2 L) and stirred at 20 to 25 ° C.
  • Ammonium chloride (27.04 g) was added to the reaction solution, and the mixture was refluxed for 5 hours.
  • the reaction solution was filtered and washed with CH 2 Cl 2 (0.1 L).
  • the filtrate was concentrated under reduced pressure, and isopropanol (0.1 L) was added thereto, dissolved at 55 to 60 ° C., stirred at 30 to 40 ° C. for 1 hour, cooled to 10 to 15 ° C., and filtered after stirring for 1 hour.
  • the solid obtained was washed with IPA (0.02 L) after filtration. Vacuum drying at 50-55 ° C. for 12 hours gave the title compound.
  • Step 3 Preparation of 4-methyl-3-oxo-N- (4-((trityloxy) methyl) phenyl) pentanamide
  • Step 1 Preparation of tert-butyldimethyl ((4-nitrobenzyl) oxy) silane
  • Step 2 Preparation of 4-(((tert-butyldimethylsilyl) oxy) methyl) aniline
  • Step 3 Preparation of N- (4-(((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • step 2 4-(((tert-butyldimethylsilyl) oxy) methyl) aniline (500 mg) obtained in step 2 was diluted with toluene (10.5 ml), stirred at room temperature, and then added to TEA (90 ul, 0.63 mmol) in the reaction solution. And methyl 4-methyl-3-oxopentanoate (0.34 ml, 2.32 mmol) were added and heated to 110 to 12 0 ° C. for 2.5 hours. Subsequently, the reaction solution was cooled, washed with saturated aqueous NaHCO 3 solution, brine and distilled water, and the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.
  • Step 1 Preparation of 4-(((tert-butyldimethylsilyl) oxy) methyl) aniline (in situ)
  • Step 2 Preparation of N- (4-(((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • step 1 4-(((tert-butyldimethylsilyl) oxy) methyl) aniline (500 mg) obtained in step 1 was diluted with toluene (10.5 ml) and stirred at room temperature, and TEA (90 ml, 0.63 mmol) was added to the reaction solution. And methyl 4-methyl-3-oxopentanoate (0.34 ml, 2.32 mmol) were added and heated to 110 to 120 ° C. for 2.5 hours. Subsequently, the reaction solution was cooled, washed with saturated aqueous NaHCO 3 solution, brine and distilled water, and the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.
  • TEA 90 ml, 0.63 mmol
  • Step 1 Preparation of 1-methoxy-4-(((4-nitrobenzyl) oxy) methyl) benzene
  • Step 3 Preparation of N- (4-(((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 1 Preparation of ((4-methoxyphenyl) ((4-nitrobenzyl) oxy) methylene) dibenzene
  • the title compound was prepared in the same manner except for using methoxyphenyl-diphenylmethane-1-yl chloride in place of tert-butyldimethylsilyl chloride in step 1 of Example 2 (room temperature, 20 hours).
  • Step 2 Preparation of 4-(((4-methoxyphenyl) diphenylmethoxy) methyl) aniline
  • Step 3 Preparation of N- (4-(((4-methoxyphenyl) diphenylmethoxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • Example 2 The title compound was prepared in the same manner as in Example 1, except that 4-(((4-methoxyphenyl) diphenylmethoxy) methyl) aniline was used instead of 4-((trityloxy) methyl) aniline in Step 3 of Example 1 Prepared.
  • Step 1 Preparation of 4,4 '-(((4-nitrobenzyl) oxy) (phenyl) methylene) bis (methoxybenzene)
  • the title compound was prepared in the same manner except in the step 1 of Example 2, using 4,4 ′-(chloro (phenyl) methylene) bis (methoxybenzene) instead of tert-butyldimethylsilyl chloride (room temperature, 15.5 time).
  • Step 2 Preparation of 4-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) aniline
  • Step 3 Preparation of N- (4-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 1 Preparation of tert-butyl ((4-nitrobenzyl) oxy) diphenylsilane
  • Step 2 Preparation of 4-(((tert-butyldiphenylsilyl) oxy) medyl) aniline
  • Step 3 Preparation of N- (4-(((tert-butyldiphenylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide
  • N- (4-(((tert-butyldiphenylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide was prepared in the same manner as in step 3 of Example 2.
  • Step 1 Preparation of 1- (4-fluorophenyl) -2-phenylethan-1-one
  • the organic layer was concentrated under reduced pressure, IPA (0.26 L) was added thereto, and the reaction mixture was stirred at 55 to 60 ° C for 1 hour, at 20 to 30 ° C for 1 hour, and at 0 to 5 ° C for 2 hours to produce a solid.
  • the resulting solid was filtered, washed with IPA (0.06 L) and vacuum dried at 50-55 ° C. for 12 hours to afford the title compound.
  • Step 2 Preparation of 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one
  • the CH 2 Cl 2 layer was separated and washed twice more with 5% Na 2 SO 3 (0.29 L). 5% NaHCO 3 (0.29 L) was added and stirred at 20 to 25 ° C. for 1 hour.
  • the CH 2 Cl 2 layer was separated and washed with 5% NaCl (0.29 L).
  • MgSO 4 (30 g) was added to the organic layer, and dried and filtered.
  • the filtrate was concentrated under reduced pressure, hexane (0.4 L) was added thereto, and stirred at 20 to 30 ° C. for 1 hour and 0 to 5 ° C. for 2 hours to form a solid.
  • the resulting solid was filtered, washed with hexane (0.2 L) and vacuum dried at 25-30 ° C. for 12 hours to afford the title compound.
  • Example 8 4-methyl-3-oxo-N- (4-((trityloxy) methyl) phenyl) pentanamide (52.6 g) obtained in Example 1 was diluted with acetone (0.5 L), followed by K 2 CO 3 (31.2). g, 2 eq) was added and stirred at 20 to 30 ° C. 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one (33.1 g, 1 eq) obtained in Example 8 was added to the reaction solution, and stirred at the same temperature for 18 hours. It was refluxed for 3 hours. After completion of the reaction, K 2 CO 3 was filtered and washed with CH 2 Cl 2 (0.1L).
  • reaction solution was washed with distilled water (0.1 L) and brine (0.1 L) and concentrated under reduced pressure.
  • MeOH (0.15 L) was added to the concentrate, and stirred at 55 to 60 ° C. for 1 hour and at 20 to 30 ° C. for 2 hours to produce a solid.
  • the resulting solid was filtered, washed with MeOH (20 ml) and vacuum dried at 50-55 ° C. for 12 hours to afford the title compound.
  • Example 9-1 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3-oxo-N- (4-((trityloxy) methyl) Preparation of Phenyl) pentanamide
  • Example 8 4-methyl-3-oxo-N- (4-((trityloxy) methyl) phenyl) pentanamide (43.0 g) obtained in Example 1 was diluted with 5% acetone (0.25 L), followed by 20 minutes at room temperature. It was stirred and dissolved. K 2 CO 3 (19.17 g, 1.56 eq) was added thereto and stirred for 10 minutes. 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one (29.98 g, 1.1 eq) obtained in Example 8 was added to the reaction solution, followed by stirring at 25 to 35 ° C. for 12 hours. It was.
  • N- (4-(((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide (605 mg, 1.73 mmol) obtained in Example 2 was diluted with acetone (6.5 ml). Then, K 2 CO 3 (620 mg, 4.50 mmol) was added thereto and stirred at room temperature. To the reaction solution was added 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one (530 mg, 1.78 mmol) obtained in Example 8 diluted with acetone (2 ml). After further stirring at the same temperature for 66 hours, the mixture was filtered under reduced pressure to remove K 2 CO 3 .
  • the filtrate was concentrated under reduced pressure, diluted with EA and washed several times with brine.
  • the extracted organic layer was dried with Na 2 SO 4 and filtered under reduced pressure.
  • the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.
  • N- (4-(((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide (620 mg, 1.74 mmol) obtained in Example 4 was diluted with acetone (5.8 ml). Then stirred at room temperature. After dissolving K 2 CO 3 (626 ml, 4.54 mmol) in the reaction solution, 2 -bromo-1- (4-fluorophenyl) -2-phenylethan-1-one (510 mg, 1.74 mmol) was added dropwise to acetone (2 ml) and stirred at room temperature for 31 hours. Subsequently, EA was added, diluted, and washed several times with brine. The extracted organic layer was dried with MgSO 4 and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the title compound.
  • Example 13 tert-butyl 2-((4R, 6R) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-4-((4-(((4-methoxy Benzyl) oxy) methyl) phenyl) carbamoyl) -3-phenyl-1H-pyrrol-1-yl) ethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
  • Step 1 tert-butyl (3R, 5R) -7- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl Preparation of -1H-pyrrol-1-yl) -3,5-dihydroxyheptanonate
  • Step 2 (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrole-1- Preparation of Japanese] -3,5-dihydroxy heptanoic acid hemicalcium salt
  • Step 1 Preparation of 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 2 tert-butyl 2-((4R, 6R) -6- (2- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5- Preparation of Isopropyl-3-phenyl-1H-pyrrol-1-yl) ethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
  • the reaction solution was refluxed overnight under a Dean-Stark trap to remove water.
  • the reaction solution was cooled to 20 ° C. and concentrated under reduced pressure.
  • CH 2 Cl 2 (1.4 L) was added to the concentrate, followed by stirring.
  • the CH 2 Cl 2 layer was washed twice with distilled water (0.7 L).
  • the CH 2 Cl 2 layer was concentrated under reduced pressure, IPA (1.86 L) was added thereto, and the mixture was stirred until it dissolved cleanly.
  • the reaction solution was further stirred at 60 to 65 ° C. for 1 hour.
  • Distilled water (0.56 L) was added thereto, cooled to 20 to 30 ° C., and stirred at 20 to 30 ° C. for 2 hours and 0 to 5 ° C. for 1 hour to form a solid.
  • the resulting solid was filtered, washed with IPA (0.14 L) and distilled water (0.14 L) and vacuum dried at 50-55 ° C. for 12 hours to afford the title compound.
  • Step 3 tert-Butyl (3R, 5R) -7- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl Preparation of -1H-pyrrol-1-yl) -3,5-dihydroxyheptanonate
  • reaction solution was concentrated under reduced pressure and distilled water (430 ml) was added until the solid dissolved cleanly.
  • Aqueous 1M Ca (OAc) 2 solution (3.6 ml) was slowly added dropwise and stirred at room temperature for 15.5 hours.
  • the resulting solid was filtered under reduced pressure, washed several times with distilled water, and the filtered solid was dried in an oven.
  • Step 1 Preparation of 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 2 tert-butyl 2-((4R, 6R) -6- (2- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5- Preparation of Isopropyl-3-phenyl-1H-pyrrol-1-yl) ethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
  • Step 3 tert-Butyl (3R, 5R) -7- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl Preparation of -1H-pyrrol-1-yl) -3,5-dihydroxyheptanonate
  • Step 1 Preparation of N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 2 Preparation of 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide
  • Step 3 tert-Butyl 2-((4R, 6R) -6- (2- (2- (4-fluoromethyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5- Preparation of Isopropyl-3-phenyl-1H-pyrrol-1-yl) ethyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
  • Step 4 tert-butyl (3R, 5R) -7- (2- (4-fluorophenyl) -4-((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl Preparation of -1H-pyrrol-1-yl) -3,5-dihydroxyheptanonate

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Abstract

La présente invention concerne : un procédé de préparation de sel hemicalcique de l'acide (3R,5R)-7-[2-(4-flurophényl)-5-isopropyl-3-phényl-4-[(4-hydroxyméthylphénylamino)carbonyl]-pyrrrol-1-yl]-3,5-dihydroxyheptanoïque ; un intermédiaire utilisé à cet effet ; et un procédé de préparation de l'intermédiaire Le procédé de préparation selon la présente invention est réalisé d'une manière à synthèse convergente, des parties de structure principale du sel hemicalcique de l'acide (3R,5R)-7-[2-(4-flurophényl)-5-isopropyl-3-phényl-4-[(4-hydroxyméthylphénylamino)carbonyl]-pyrrrol-1-yl]-3,5-dihydroxyheptanoïque étant synthétisés séparément, puis couplés. Par conséquent, des substances apparentées peuvent être facilement contrôlées et le temps de préparation peut être raccourci, conduisant à une amélioration de la productivité des composés ainsi qu'à une augmentation du rendement du composé final.
PCT/KR2019/010799 2018-08-24 2019-08-23 Procédé de préparation de sel hemicalcique de l'acide (3r,5r)-7-[2-(4-flurophényl)-5-isopropyl-3-phényl-4-[(4-hydroxyméthylphénylamino)carbonyl]-pyrrrol-1-yl]-3,5-dihydroxyheptanoïque, intermédiaire utilisé à cet effet, et procédé de préparation de l'intermédiaire Ceased WO2020040614A1 (fr)

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KR102218320B1 (ko) * 2019-07-12 2021-02-23 대원제약주식회사 (3r,5r)-7-(2-(4-플루오로페닐)-5-이소프로필-3-페닐-4-((4-히드록시메틸페닐아미노)카보닐)-피롤-1-일)-3,5-디히드록시 헵탄산 헤미칼슘염의 제조방법, 및 이에 사용되는 중간체의 제조방법

Citations (5)

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EP0247633A1 (fr) * 1986-05-30 1987-12-02 Warner-Lambert Company Inhibiteurs de la synthèse du cholestérol du type trans[(carboxamido-3 ou 4-pyrrolyl-1 substitué)-2 alkyl]-6 hydroxy-4 pyranone-2
EP0680963A1 (fr) * 1994-05-04 1995-11-08 Warner-Lambert Company (Hydroxyphénylamino)carbonyl-pyrroles
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KR20160117843A (ko) * 2015-03-31 2016-10-11 대원제약주식회사 결정형 및 이의 제조방법
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