KR102218320B1 - Method of preparing(3r,5r)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxy-heptanoic acid hemi calcium salt, and method of preparing intermediates used therein - Google Patents

Abstract

The present invention is (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxy methyl phenyl amino)carbonyl)-pyrrole-1 -Yl)-3,5-dihydroxyheptanoic acid hemicalcium salt production method is provided. The production method of the present invention is (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrole -1-yl)-3,5-dihydroxyheptanoate hemicalcium salt is synthesized individually and then coupled to each of the major structural parts. Accordingly, the related material can be easily controlled and the manufacturing time can be shortened, thereby improving the productivity of the compound, and also increasing the yield of the final compound.

Description

(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)- Method for preparing 3,5-dihydroxy hemicalcium salt hemicalcium salt, and method for preparing intermediates used therein {METHOD OF PREPARING(3R,5R)-7-(2-(4-FLUOROPHENYL)-5-ISOPROPYL-3- PHENYL-4-((4-HYDROXYMETHYLPHENYLAMINO)CARBONYL)-PYRROL-1-YL)-3,5-DIHYDROXY-HEPTANOIC ACID HEMI CALCIUM SALT, AND METHOD OF PREPARING INTERMEDIATES USED THEREIN}

The present invention is (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1- It relates to a method for preparing the hemicalcium salt of day)-3,5-dihydroxyheptanoic acid and a method for preparing an intermediate used therein.

(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)- Hemicalcium salt of 3,5-dihydroxy heptanoate acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, inhibiting the synthesis of cholesterol in cells, and thus a lipid-lowering or cholesterol-lowering agent. It is useful as

Korean Patent Registration No. 10-1329112 discloses (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl ]-Pyrrole-1-yl]-3,5-dihydroxy-heptanoic acid hemicalcium salt is described in the following scheme.

(In the reaction formula of the above preparation method, R is alkyl, aryl or alkylaryl)

However, according to the above manufacturing method, related substances are generated due to the benzaldehyde used, and thus it is difficult to remove the generated related substances. In addition, when a problem occurs in an intermediate step by sequentially synthesizing the substituents one by one, it takes a lot of time to start again from the beginning. Therefore, the conventional manufacturing method has a problem that is not suitable for mass synthesis.

Accordingly, the present inventors effectively synthesize (3R,5R)-7-[2-(4-) by a convergent synthesis method in which the main structural parts of the compound are separately synthesized and then coupled, rather than the conventional sequential synthesis method. Synthesis of fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy heptanoic acid hemicalcium salt The present invention has been completed by devising a method that can easily control the main related substances as well as synthesize the reaction intermediate as a solid.

Korean Patent Registration No. 10-1329112

One object of the present invention is a novel (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[ which can effectively solve the shortcomings of the conventional sequential synthesis method. 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 present invention is (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrole It is to provide a method for preparing an intermediate used in the preparation of -1-yl]-3,5-dihydroxy hemicalcium hemicalcium salt.

In order to solve the above problems, (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbo of the present invention Neil]-pyrrol-1-yl]-3,5-dihydroxy heptanoic acid hemicalcium salt production method,

(S1) preparing a compound of the following formula C by reacting a compound of the following formula A with a compound of the following formula B;

(S2) reacting a compound of formula C with a compound of formula D to prepare a compound of formula E;

(S3) preparing a compound of the following formula F from the compound of formula E;

(S4) preparing a compound of formula G from the compound of formula F;

(S5) preparing a compound of formula H from the compound of formula G; And

(S6) preparing a compound of Formula 1 below from the compound of Formula H.

[Formula A]

[Formula B]

[Formula C]

[Formula D]

[Formula E]

[Formula F]

[Formula G]

[Formula H]

[Formula 1]

In the above formula, R ₁ and R ₂ each independently represent C ₁ -C ₆ alkyl,

X represents a leaving group.

The leaving group may be a halide such as Cl, Br or I, tosylate (OTs), triflate (OTf) or acetate (OAc).

The step (S1) is a step of alkylating the active methylene compound, and may be performed under basic conditions or neutral conditions. At this time, examples of the base used for the base condition include potassium carbonate, lithium carbonate, sodium 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 ter-butoxide (K[OC(CH ₃ ) ₃ ]), and the like, respectively. It can be used alone or in combination of two or more.

In addition, the step (S1) may be carried out under a solvent that can be used in the alkylation reaction of the active methylene compound, and examples of the solvent include 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 aqueous solutions thereof, and the like, and these may be used alone or in combination of two or more. It can be mixed and used.

The step (S2) is a step of forming a pyrrole ring by coupling the compound of formula C and the compound of formula D, and a solvent that can be used in the pyrrole cyclization reaction, for example, methanol, ether, ethyl acetate, tetrahydro Furan, toluene, heptane, cyclohexane, or hexane may be used, and these may be used alone or in combination of two or more. At this time, the pyrrole cyclization reaction may be performed under acid conditions, and pivalic acid or toluene-4-sulfonic acid may be used.

The step (S3) is a step of removing an alkyl group from the compound of Formula E, and may be performed under acid conditions. At this time, the acid conditions may be hydrochloric acid, bromic acid, iodic acid, sulfuric acid, acetic acid or trifluoroacetic acid, and these may be used alone or in combination of two or more.

The step (S4) is a step of selectively reducing the carboxyl group in Formula F, and may be performed in the presence of a boron-dimethylsulfide (DMS) complex or a boron-tetrahydrofuran complex as a reducing agent, and as a solvent, a hydrocarbon solvent (e.g., Hexane, n-heptane or toluene) or an ether solvent (eg, tetrahydrofuran, dioxane or diethyl ether) may be used, and these may be used alone or in combination of two or more.

The step (S5) is a step of causing the cleavage of the ketal group by an acid in the compound of formula G, a polar solvent (eg, methanol, ethanol or isopropyl alcohol), an ether solvent (eg, tetrahydrofuran, Dioxane or diethyl ether) and the like may be used, and these may be used alone or in combination of two or more.

In the step (S6), after hydrolyzing the compound of formula H under basic conditions, a calcium ion source is added thereto, and the final product is (3R,5R)-7-[2-(4-fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy heptanoic acid hemicalcium salt is prepared. At this time, the hydrolysis reaction and the salt preparation reaction may be performed in a solvent such as methanol, tetrahydrofuran, or water, and these may be used alone or in combination of two or more.

Examples of the calcium ion source used in the step (S6) include calcium acetate, calcium chloride, calcium carbonate, tricalcium phosphate, calcium citrate, calcium citrate maleate, calcium lactate, calcium gluconate, calcium hydroxide, calcium Oxalate, calcium fluoride, calcium sulfate, or aqueous solutions thereof. These may be used alone or in combination of two or more.

The method for preparing the compound of Formula 1 including steps (S1) to (S6) of the present invention can be represented by the following Scheme 1.

[Scheme 1]

The compound of formula C is (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl of the present invention. ]-Pyrrole-1-yl]-3,5-dihydroxyheptanoic acid hemicalcium salt is used as an intermediate used in the preparation, and is prepared by reacting a compound of formula A with a compound of formula B.

The preparation method of the compound of formula C can be represented by the following scheme 2.

[Scheme 2]

The compound of formula A can be prepared by reacting a compound of formula a-1 with a compound of formula a-2.

[Formula a-1]

(이때, R₁은 C₁-C₆알킬을 나타낸다)

(At this time, R ₁ represents C ₁ -C ₆ alkyl)

[Formula a-2]

(이때, R₃는 -O-(C₁-C₅알킬), Cl 또는 Br을 나타낸다)

(At this time, R ₃ represents -O-(C ₁ -C ₅ alkyl), Cl or Br)

The compound of Formula a-1 can be prepared using the compound of Formula a-3 below.

[Formula a-3]

The compound of formula a-1 can be prepared by esterifying the compound of formula a-3.

The preparation method of the compound of formula A can be represented by the following Scheme 3.

[Scheme 3]

The compound of formula B can be prepared by reacting a compound of formula b-1 with a compound of formula b-2 to prepare a compound of formula b-3, and halogenating the compound of formula b-3.

[Formula b-1]

[Formula b-2]

[Formula b-3]

The preparation method of the compound of Formula B can be represented by the following Scheme 4.

[Scheme 4]

According to Scheme 4, a compound of formula b-1 as a starting material is subjected to a Friedel-Craft acylation reaction with a compound of formula b-2 to prepare a compound of formula b-3, and then a compound of formula B is prepared through a halogenation reaction. can do.

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrole-1- of the present invention In accordance with the method for preparing the hemicalcium salt of general]-3,5-dihydroxy heptanoic acid, since each of the major structural parts of the compound is individually synthesized and then coupled, it is performed in a convergent synthesis method, so that the sequential synthesis method disclosed in the prior literature Compared to that, there is an advantage in that it is easy to control major related substances. In addition, the present invention can shorten the manufacturing time by reducing the risk factors inherent in the sequential synthesis pathway (such as having to return to the first route and repeat the synthesis when the synthesis fails in the middle of synthesis).

Hereinafter, the present invention will be described in detail through specific embodiments. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms as defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted as an ideal or excessively formal meaning unless explicitly defined in this application. Does not.

Example 1: Preparation of methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamido)benzoate

(Step 1-1): Preparation of methyl 4-aminobenzoate

After diluting 4-aminobenzoic acid (120 g, 1.0 eq) in methanol (1.2 L), it was dissolved by stirring at 0 to 5°C. SOCl ₂ (125 g, 1.2 eq) was slowly added thereto, and the temperature was gradually raised to reflux and stirred for 2 hours. After confirming the completion of the reaction, the mixture was cooled to 20 ~ 25°C and dried under reduced pressure, followed by adding water (1.2 L) and stirring. After adding an aqueous sodium hydrogen carbonate solution to a pH of 8 at 0 to 5°C to make a solid, water (1.2 L) was added and stirred for 30 minutes. The resulting solid was sufficiently washed with water, filtered, and dried under vacuum at 50° C. for 16 hours to obtain methyl 4-aminobenzoate.

Solid 128 g (yield 96.8%) moisture content 0.7% (< 1.0%)

(Step 1-2): Preparation of methyl 4-(4-methyl-3-oxopentanamido)benzoate

After diluting methyl 4-aminobenzoate (80 g, 1.003 eq) and methyl 4-methyl-3-oxopentanoate (76 g, 1.0 eq) obtained in step 1-1 in toluene (0.76 L), It was dissolved by stirring at room temperature. The reaction solution was refluxed for one day using a Dean-stark trap to remove moisture. After confirming the completion of the reaction, the mixture was cooled to 20 ~ 25°C, dried under reduced pressure, and dissolved in ethyl acetate (0.76 L), and the organic layer was washed twice with 20% aqueous hydrochloric acid solution. The extracted organic layer was washed with water (0.15 L), 10% aqueous sodium hydrogen carbonate solution (0.15 L) and saturated aqueous sodium chloride solution (0.06 L), dried with magnesium sulfate, and filtered. After drying the filtrate under reduced pressure, heptane (0.76 L) was added and stirred at room temperature for 10 hours to generate a solid. The resulting solid was thoroughly washed with heptane and filtered. Vacuum-dried at 50° C. for 16 hours to obtain methyl 4-(4-methyl-3-oxopentanamido)benzoate.

118.3 g of solid (85% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.40 (NH, br s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 2H), 2.75 (sep, J = 7.0 Hz, 1H), 1.05 (d, J = 7.0 Hz, 6H), MH+ 264.

(Step 1-3): Preparation of 2-bromo-1-(4-fluorophenyl)-2-phenylethan-1-one

Step a: Preparation of 1-(4-fluorophenyl)-2-phenylethan-1-one

After fluorobenzene (100 g) was placed in a reactor under nitrogen at 0° C., ammonium chloride (103 g) was added. After cooling to -10°C, phenylacetyl chloride (110.75 g) was added dropwise, followed by stirring for 2 hours. The reaction was terminated by adding ice water (600 g) and hydrochloric acid (0.03 L) to the reaction solution. Methylene chloride (1 L) was added to separate the organic layer, and the aqueous layer was washed once more with methylene chloride (0.5 L). The extracted organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (0.6 L) and 5% saturated aqueous sodium chloride solution (0.4 L), dried with magnesium sulfate, and then filtered through Celite. The filtrate was put in a reactor and dried to obtain 1-(4-fluorophenyl)-2-phenylethan-1-one.

150 g of solid (98% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 8.15-8.11 (m, 2H), 7.39-7.34 (m, 2H), 7.33-7.30 (m, 2H), 7.27-7.21 (m, 3H), 4.39 ( s, 2H), MH+ 215

Step b: Preparation of 2-bromo-1-(4-fluorophenyl)-2-phenylethan-1-one

Bromine (109 g) was diluted in methylene chloride (0.2 L), added dropwise to 1-(4-fluorophenyl)-2-phenylethan-1-one obtained in step a, and stirred for 10 minutes. After cooling to 15° C., 5% sodium sulfate (0.4 L) and methylene chloride were added to separate the organic layer. The extracted organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (0.4 L) and 5% saturated aqueous sodium chloride solution, and then concentrated under reduced pressure. The concentrate was diluted in hexane (2 L) to make a slurry, and then left to stand for one day. The resulting solid was filtered and dried under vacuum at 50° C. for 4 hours to obtain 2-bromo-1-(4-fluorophenyl)-2-phenylethan-1-one.

171 g of solid (81.4% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ): 8.18-8.14 (m, 2H), 7.55-7.53 (m, 2H), 7.40-7.31 (m, 5H), 7.18 (s, 1H).

(Step 1-4): Preparation of methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamido)benzoate

After diluting the methyl 4-(4-methyl-3-oxopentanamido)benzoate (167 g) obtained in step 1-2 in acetone (600 g), potassium carbonate (131.5 g) was added at 20°C. Stirred. After cooling to 18° C., 2-bromo-1-(4-fluorophenyl)-2-phenylethan-1-one (BFPE, 186 g) obtained in step 1-3 diluted in acetone (0.2 L) ) Was added dropwise, and the reaction solution was stirred for 6 hours, filtered and dried. The concentrate was washed with ethyl acetate (1.6 L) and distilled water (0.8 L), and the aqueous layer was washed once more with ethyl acetate (0.3 L). The extracted organic layer was concentrated under reduced pressure, diluted in a methanol:distilled water = 9:1 solution (v:v 1.25 L) and refluxed until cleanly dissolved. The reaction solution was cooled to 0 ~ 5°C, stirred for 2 hours, washed with cold methanol:distilled water=9:1 solution (0.167 L) and ice water (0.167 L) and filtered. The filtrate was diluted with hexane (0.835 L) to make a slurry, and then dried in vacuo at 50° C. for one day to obtain methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)- 4-methyl-3-oxopentanamido)benzoate was obtained.

224 g of solid (74.3% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.52 (NH, br s, 1H), 8.15-8.11 (m, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 3H), 5.43 (d, J = 11.0 Hz, 1H), 4.91 (d , J = 11.0 Hz, 1H), 3.80 (s, 3H), 2.90 (sep, J = 7.0 Hz, 1H), 1.17 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H) ), MH+ 476.

Example 2: Preparation of methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamido)benzoate

(Step 2-1): Preparation of 2-chloro-1-(4-fluorophenyl)-2-phenylethan-1-one

Sulfuryl chloride (100 g) was added under a calcium chloride guard tube. 1-(4-fluorophenyl)-2-phenylethan-1-one (150 g) obtained through substantially the same process as step a in step 1-3 was diluted with methylene chloride (0.23 L) to 10 ~ It was added dropwise at 15° C. for 4 minutes. Then, after stirring at room temperature for 2.5 hours, ice water (900 g) was added to the reaction solution to terminate the reaction. After diluting in methylene chloride (0.6 L), the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (0.3 L) and 5% saturated aqueous sodium chloride solution (0.3 L), dried with magnesium sulfate, and filtered through celite. The filtrate was dried under reduced pressure and then vacuum dried to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethan-1-one.

156 g solid (90% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 8.15-8.11 (m, 2H), 7.50-7.47 (m, 2H), 7.40-7.31 (m, 5H), 7.13 (s, 1H).

(Step 2-2): Preparation of methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamido)benzoate

After diluting the methyl 4-(4-methyl-3-oxopentanamido)benzoate (110 g) obtained in step 1-2 in acetone (0.66 L), potassium carbonate (86.6 g) at 20 to 25°C And stirred. Dilute 2-chloro-1-(4-fluorophenyl)-2-phenylethan-1-one (CFPE, 104 g) was added dropwise to acetone (0.22 L) while maintaining the same temperature. The reaction solution was refluxed for 8 hours, cooled to 20 ~ 25°C, and filtered. The filtrate was concentrated, diluted with ethyl acetate (1.0 L) and distilled water (0.5 L), stirred for 10 minutes, and washed. The aqueous layer was washed once more with ethyl acetate (0.18 L). The extracted organic layer was concentrated under reduced pressure, diluted in methanol:distilled water = 4:1 solution (v:v, 0.55 L) and refluxed for 1 hour. The reaction solution was slowly cooled to 0 ~ 5°C, stirred for 2 hours, washed with methanol:distilled water=4:1 solution (0.11 L) and ice water (0.11 L) and filtered. The filtrate was diluted with hexane (0.55 L) to make a slurry, and then dried under vacuum at 50° C. for 8 hours, and methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl) )-4-methyl-3-oxopentanamido)benzoate was obtained.

157 g of solid (79% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.52 (NH, br s, 1H), 8.15-8.11 (m, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 3H), 5.43 (d, J = 11.0 Hz, 1H), 4.91 (d , J = 11.0 Hz, 1H), 3.80 (s, 3H), 2.90 (sep, J = 7.0 Hz, 1H), 1.17 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H) ), MH+ 476.

Example 3: (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxy methyl phenyl amino)carbonyl)-pyrrole- 1-yl)-3,5-dihydroxyheptanoic acid hemicalcium salt preparation

(Step 3-1) Methyl 4-(1-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3- Preparation of dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxyamido)benzoate

Methyl 4-(2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxopentanamido)benzoate (800 g) obtained according to Example 1 And tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (552.5 g) and pivalic acid (177.2 g ) Was diluted in heptane (6.72 L), toluene (2.4 L) and tetrahydrofuran (2.4 L). The reaction solution was refluxed for one day using a Dean-stark trap to remove moisture. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate (8.0 L), stirred, and washed twice with distilled water (4 L). After the extracted organic layer was concentrated under reduced pressure to obtain a solid, it was diluted with isopropyl alcohol (4 L) and slurried at 50° C. for 1 hour. Hexane (4 L) was added to the reaction product, and the mixture was slurried for an additional hour at the same temperature. The reaction was cooled to room temperature and stirred for an additional hour. After filtering the resulting solid, washed twice with hexane (4 L) and dried at 50° C. for one day, methyl 4-(1-(2-((4R,6R)-6-(2-( tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl -1H-pyrrole-3-carboxyamido)benzoate was obtained.

845.5 g of solid (70.5% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.17 (NH, br s, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.28-7.25 ( m, 2H), 7.20 (t, J = 9.0 Hz, 2H), 7.08-7.03 (m, 4H), 7.01-6.97 (m, 1H), 4.13-4.08 (m, 1H), 3.95-3.89 (m, 1H), 3.80 (s, 3H), 3.80-3.74 (m, 2H), 3.25-3.19 (m, 1H), 2.30 (dd, J = 15.0 Hz, 5.0 Hz, 1H), 2.17 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.64-1.50 (m, 2H), 1.38 (s, 9H), 1.36 (d, J = 7.0 Hz, 6H), 1.35-1.30 (m, 1H), 1.31 (s, 3H) ), 1.16 (s, 3H), 0.92 (q, J = 12.0 Hz, 1H), MH-711.

(Step 3-2): 4-(1-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3- Preparation of dioxane -4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxyamido) benzoic acid

Methyl 4-(1-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3 obtained in step 3-1 above -Dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxyamido)benzoate (700 g) was added to acetonitrile ( It was diluted in 7 L) and stirred. Sodium hydroxide (98.3 g) was diluted in distilled water (2.1 L) and added dropwise to the reaction solution, followed by stirring at 50° C. for 5 hours. The reaction solution was cooled to room temperature and distilled water (7 L) was added to terminate the reaction. A 20% aqueous acetic acid solution (0.263 L of acetic acid, 1.05 L of distilled water) was added dropwise to the reaction solution to adjust the pH to 5.5 to 6.0, followed by stirring at room temperature for 3 hours. The resulting solid was filtered, washed 4 times with distilled water (2.8 L), and further washed twice with acetonitrile (2.1 L). The resulting solid was diluted in 95% ethanol (3.5 L), refluxed for 1 hour, and the reaction solution was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at 50° C. for one day to obtain 4-(1-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2 -Dimethyl-1,3-dioxane -4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxyamido)benzoic acid was obtained.

790 g of solid (71.5% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.13 (NH, br s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.28-7.25 ( m, 2H), 7.22-7.18 (m, 2H), 7.08-7.04 (m, 4H), 7.01-6.98 (m, 1H), 4.13-4.08 (m, 1H), 3.96-3.89 (m, 1H), 3.81-3.75 (m, 2H), 3.22 (sep, J = 7.0 Hz, 1H), 2.30 (dd, J = 15.0 Hz, 5.0 Hz, 1H), 2.18 (dd, J = 15.0 Hz, 8.0 Hz, 1H) , 1.64-1.50(m, 2H), 1.38(s, 9H), 1.36(d, J = 7.0 Hz, 6H), 1.36-1.30(m, 1H), 1.31(s, 3H), 1.16(s, 3H) ), 0.93 (q, J = 12.0 Hz, 1H), MH-698.

(Step 3-3): tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl) )-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate

4-(1-(2-((4R,6R)-6-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-1,3- obtained in step 3-2 above Dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxyamido) benzoic acid (1000 g) in tetrahydrofuran (10 After diluted in L), it was cooled to 0°C. After heating to 40 ~ 45 ℃ borein dimethyl sulfide (tetrahydrofuran 2 M solution) (1.79 L) was added dropwise and stirred for a day. After cooling the reaction solution to 0 °C, methanol (2 L) was slowly added dropwise to terminate the reaction. The reaction solution was concentrated under reduced pressure, diluted with isopropyl alcohol: distilled water = 4:1 (v:v, 12 L) solution, and then acetic acid (0.087 L) was added dropwise. Calcium hydroxide (213 g) was added to the reaction solution and refluxed for 1 hour, followed by filtration at high temperature. The filtered solid was washed once more with isopropyl alcohol: distilled water = 1:1 (5 L) solution. The filtrate was diluted in distilled water (4 L) and stirred at room temperature for 3 hours, and the resulting solid was filtered and washed with cold isopropyl alcohol:distilled water = 1:1 (2 L). The resulting solid was vacuum-dried at 50° C. for one day to obtain tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)). )Phenyl)carbamoyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was obtained.

884 g solid (90% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 9.78 (NH, br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.27-7.24 (m, 2H), 7.21-7.15 (m, 4H) ), 7.09-7.05 (m, 4H), 7.02-6.99 (m, 1H), 5.05 (OH, t, J = 5.5 Hz, 1H), 4.39 (d, J = 5.5 Hz, 2H), 4.13-4.08 ( m, 1H), 3.95-3.89 (m, 1H), 3.80-3.74 (m, 2H), 3.21 (sep, J = 7.0 Hz, 1H), 2.30 (dd, J = 15.0 Hz, 5.0 Hz, 1H), 2.19-2.15 (m, 1H), 1.63-1.50 (m, 2H), 1.38 (s, 9H), 1.36 (d, J = 7.0 Hz, 6H), 1.35-1.30 (m, 1H), 1.31 (s, 3H), 1.16 (s, 3H), 0.96-0.89 (m, 1H).

(Step 3-4): tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl Preparation of -3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate

Tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl obtained in step 3-3 above )-5-isopropyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (605 g) in tetrahydrofuran (3 L), methanol (3 L) and distilled water (3 L) were diluted, 1 N diluted hydrochloric acid (0.442 L) was added dropwise, followed by stirring at 45° C. for 2 hours. The reaction was terminated by adding sodium hydrogen carbonate (48.3 g) to the reaction solution, and the mixture was cooled to room temperature and stirred. It was concentrated under reduced pressure until the volume of the solvent was reduced by about 1/2, and 10% ethyl acetate/hexane (6 L) was added. The reaction solution was stirred at 50° C. for 30 minutes, cooled to room temperature, and further stirred for 1 hour. The resulting solid was filtered and washed with distilled water (0.6 L), and the obtained solid was diluted in hexane (1.2 L) to make a slurry, stirred at 40° C. for 2 hours, and filtered again. The resulting solid was vacuum-dried at 50° C. for one day to obtain tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl) -5-isopropyl-3-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanonate was obtained.

516.5 g solid (90.6% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 9.76 (NH, br s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.20-7.15 (m, 4H) ), 7.09-7.05 (m, 4H), 7.01-6.98 (m, 1H), 5.05 (OH, t, J = 6.0 Hz, 1H), 4.68 (d, J = 5.0 Hz, 1H), 4.62 (d, J = 5.0 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.96-3.90 (m, 1H), 3.83-3.73 (m, 2H), 3.54-3.48 (m, 1H), 3.22 (sep) , J = 7.0 Hz, 1H), 2.26-2.17 (m, 2H), 1.65-1.58 (m, 1H), 1.56-1.48 (m, 1H), 1.45-1.39 (m, 1H), 1.39 (s, 9H) ), 1.37 (d, J = 7.0 Hz, 6H), 1.31-1.25 (m, 1H).

(Step 3-5): (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-((4-hydroxy methyl phenyl amino)carbonyl) Preparation of -pyrrol-1-yl)-3,5-dihydroxy heptanoic acid hemicalcium salt

Tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-4-((4-(hydroxymethyl)phenyl)carbamoyl)-5-isopropyl obtained in step 3-4 -3-Phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanonate (1040 g) was diluted in tetrahydrofuran (5 L) and distilled water (5 L) and stirred. Sodium hydroxide (77.5 g) was diluted in distilled water (1.632 L) at 25 to 30°C, added dropwise to the reaction solution, and stirred for 3 hours. After the reaction solution was concentrated under reduced pressure, distilled water (5 L) and ethyl acetate (5 L) were added and stirred for 10 minutes to terminate the reaction. The organic layer was separated, and the aqueous layer was washed twice with ethyl acetate (5 L). Calcium acetate (153 g) was dissolved in distilled water (5 L), and then slowly added dropwise to the aqueous layer. The reaction solution was made into a slurry at room temperature for one day, and the resulting solid was filtered and washed with a small amount of distilled water. The resulting solid was diluted with ethyl acetate (7 L), methanol (0.7 L) and distilled water (7 L), and then butylhydroxyanisole (1.5 g) was added to reflux. The reaction solution was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with a small amount of water, and dried in vacuo at 50° C. for one day, 3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-( (4-hydroxymethylphenylamino)carbonyl)-pyrrol-1-yl)-3,5-dihydroxy heptanoic acid hemicalcium salt was obtained.

852 g of solid (81.5% yield)

¹ H NMR (500 MHz, DMSO-d ₆ ) 9.82 (NH, br s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26-7.23 (m, 2H), 7.21-7.14 (m, 4H) ), 7.09-7.05 (m, 4H), 7.01-6.98 (m, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.39 (d, J = 5.5 Hz, 2H), 3.97-3.91 (m, 1H), 3.79-3.73 (m, 1H), 3.72-3.67 (m, 1H), 3.54-3.50 (m, 1H), 3.25-3.19 (m, 1H), 2.02 (dd, J = 15.0 Hz, 4.0 Hz , 1H), 1.87 (dd, J = 15.0 Hz, 8.0 Hz, 1H), 1.63-1.56 (m, 1H), 1.53-1.46 (m, 1H), 1.40-1.35 (m, 1H), 1.36 (d, J = 7.0 Hz, 6H), 1.22-1.16 (m, 1H), MH-587 (acid mass).

Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art will be able to variously modify and change the present invention within the scope not departing from the spirit and scope of the present invention described in the following claims. You will understand that you can.

Claims (9)

(S1) preparing a compound of the following formula C by reacting a compound of the following formula A with a compound of the following formula B;
(S2) reacting a compound of formula C with a compound of formula D to prepare a compound of formula E;
(S3) preparing a compound of the following formula F from the compound of formula E;
(S4) preparing a compound of formula G from the compound of formula F;
(S5) preparing a compound of formula H from the compound of formula G; And
(S6) comprising the step of preparing a compound of formula 1 from a compound of formula H,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]- A method for producing hemicalcium salt of 3,5-dihydroxy heptanoic acid;
[Formula A]

[Formula B]

[Formula C]

[Formula D]

[Formula E]

[Formula F]

[Formula G]

[Formula H]

[Formula 1]

In the above formula, R ₁ and R ₂ each independently represent C ₁ -C ₆ alkyl,
X represents a leaving group.
The method of claim 1,
In Formula B, X is Cl, Br, I, tosylate (OTs), triflate (OTf) or acetate (OAc),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]- Method for producing hemicalcium salt of 3,5-dihydroxy heptanoate.
The method of claim 1,
Comprising the step of preparing a compound of Formula A by reacting a compound of Formula a-1 with a compound of Formula a-2,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]- A method for preparing hemicalcium salt of 3,5-dihydroxy heptanoic acid;
[Formula a-1]

(At this time, R ₁ represents C ₁ -C ₆ alkyl)
[Formula a-2]

(At this time, R ₃ represents -O-(C ₁ -C ₅ alkyl), Cl or Br)
The method of claim 1,
Preparing a compound of formula b-3 by reacting a compound of formula b-1 with a compound of formula b-2; And
Comprising the step of preparing the formula B by halogenating the compound of formula b-3,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]- A method for preparing hemicalcium salt of 3,5-dihydroxy heptanoic acid;
[Formula b-1]

[Formula b-2]

[Formula b-3]

Comprising the step of preparing a compound of the following formula C by reacting a compound of the following formula A with a compound of the following formula B,
A method for preparing a compound represented by formula C;
[Formula A]

[Formula B]

[Formula C]

In the above formula, R ₁ and R ₂ each independently represent C ₁ -C ₆ alkyl,
X represents a leaving group.
The method of claim 5,
Comprising the step of preparing a compound of Formula A by reacting a compound of Formula a-1 with a compound of Formula a-2,
A method for preparing a compound represented by formula C;
[Formula a-1]

(At this time, R ₁ represents C ₁ -C ₆ alkyl)
[Formula a-2]

(At this time, R ₃ represents -O-(C ₁ -C ₅ alkyl), Cl or Br)
The method of claim 5,
Preparing a compound of formula b-3 by reacting a compound of formula b-1 with a compound of formula b-2; And
Comprising the step of preparing the formula B by halogenating the compound of formula b-3,
A method for preparing a compound represented by formula C;
[Formula b-1]

[Formula b-2]

[Formula b-3]

The method of claim 5,
The reaction of the compound of formula A with the compound of formula B is carried out under basic conditions or neutral conditions,
Method for producing a compound represented by formula C.
The method of claim 5,
The reaction of the compound of formula A and the compound of formula B is
Toluene, xylene, benzene, methylene chloride, butanol, tetrahydrofuran, ethyl acetate, propanol, cyclohexanone, diethyl ether, dioxane, ethanol, methanol, pyridine, acetone, acetonitrile, n,n-dimethylformamide , Under a solvent containing dimethyl sulfoxide or an aqueous solution thereof,
Potassium carbonate, lithium carbonate, sodium 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 ter-butoxide (K[OC(CH ₃ ) ₃ ]) carried out under basic conditions,
Method for producing a compound represented by formula C.