Process for Preparing Paricalcitol and Intermediates Therefor

Abstract

The present invention provides a method for efficiently and economically producing paricalcitol and an intermediate used therein.

Description

Technology Field

[0001] The present invention relates to a method for producing paricalcitol and an intermediate therefor, and more specifically, to a method for producing paricalcitol efficiently and economically and an intermediate used therein. Background Technology

[0002] Paricalcitol ((1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((2R,5S,E)-6-hydroxy-5,6-dimethylhept-3-en-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol), a compound of Chemical Formula 1 below, is used in the treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure. ® Zemplar ® It is the active pharmaceutical ingredient (API) of ).

[0003] [Chemical Formula 1]

[0004]

[0006] U.S. Patent No. 8,013,176 discloses a method for purifying paricalcitol. The said patent describes a method for purifying paricalcitol by dissolving it in an isopropyl acetate solvent and then crystallizing it. However, the said purification method has the problem that it is difficult to remove more than 90% of the six isomers. Prior art literature

[0007] U.S. Patent No. 8,013,176 The problem to be solved

[0008] The objective of the present invention is to provide a method for economically producing high-purity paricalcitol with a high yield.

[0009] Another objective of the present invention is to provide an intermediate used in the above manufacturing method. means of solving the problem

[0010] One embodiment of the present invention relates to a method for producing paricalcitol of the following chemical formula 1, wherein the method of production of the present invention is

[0011] (i) a step of obtaining a compound of the following formula 4 by reacting the compound of the following formula 2 with the compound of the following formula 3 in a Julia Olefinization reaction;

[0012] (ii) a step of obtaining a compound of formula 6 by reacting the compound of formula 4 below with the compound of formula 5 below in a Horner-Wordsworth-Emmons reaction; and

[0013] (iii) includes the step of deprotecting the hydroxyl group of the compound of Chemical Formula 6 below.

[0014] [Chemical Formula 1]

[0015]

[0016] [Chemical Formula 2]

[0017]

[0018] [Chemical Formula 3]

[0019]

[0020] [Chemical Formula 4]

[0021]

[0022] [Chemical Formula 5]

[0023]

[0024] [Chemical Formula 6]

[0025]

[0026] In the above formula,

[0027] TES is triethylsilyl, and

[0028] TBS is t-butyldimethylsilyl, and

[0029] Ph is phenyl.

[0031] Hereinafter, the manufacturing method of the present invention will be explained in more detail with reference to the following reaction scheme 1. The method described in the following reaction scheme 1 is merely an example of a method used as a representative example, and the reaction reagents, reaction conditions, etc., can be changed as needed depending on the circumstances.

[0033] [Reaction Equation 1]

[0034]

[0036] Step 1: Synthesis of the compound of Chemical Formula 4

[0037] The compound of Chemical Formula 4 can be prepared by reacting the compound of Chemical Formula 2 with the compound of Chemical Formula 3 for olefinification.

[0038] The compound of Formula 3 above may be used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles, per 1 mole of the compound of Formula 2 above.

[0039] It is preferable to perform the above Julia olefinization reaction in the presence of a base.

[0040] The above base is not particularly limited, and any base capable of generating a carbon anion can be used. For example, LiHMDS, etc., can be used as the above base.

[0041] The reaction solvent is not particularly limited as long as the reaction proceeds, and preferably tetrahydrofuran, hexane, and diethyl ether may be used, and tetrahydrofuran is particularly preferred.

[0042] It is suitable to carry out the reaction at a temperature of -80 to 0°C, preferably -60 to -55°C, and the reaction time is suitable for 1 to 24 hours, preferably 2 to 4 hours.

[0044] Step 2: Synthesis of the compound of Chemical Formula 6

[0045] The compound of chemical formula 6 can be prepared by reacting the compound of chemical formula 4 with the compound of chemical formula 5 in a Horner-Wordsworth-Emmons reaction.

[0046] The compound of Formula 5 above may be used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles, per 1 mole of the compound of Formula 4 above.

[0047] The above Horner-Wordsworth-Emmons reaction can be performed in the presence of a base.

[0048] The above base is not particularly limited, and any base capable of producing an ylide may be used. For example, n-butyllithium, sodium hydride, methyl magnesium bromide, lithium bis(trimethylsilyl)amide, isopropyl magnesium bromide, sodium carbonate, etc. may be used as the base, and in particular, lithium bis(trimethylsilyl)amide is preferred.

[0049] The reaction solvent is not particularly limited as long as the reaction proceeds, and preferably tetrahydrofuran, hexane, and diethyl ether may be used, and tetrahydrofuran is particularly preferred.

[0050] It is suitable to carry out the reaction at a temperature of -80 to 0°C, preferably -60 to -55°C, and the reaction time is suitable for 1 to 24 hours, preferably 2 to 6 hours.

[0052] Step 3: Preparation of the compound of Chemical Formula 1

[0053] The compound of Chemical Formula 1 can be prepared by deprotecting the hydroxyl group of the compound of Chemical Formula 6.

[0054] The above deprotection reaction can be carried out using a deprotection reagent.

[0055] The above deprotection reagents may include tetra-n-butylammonium fluoride (TBAF), HF·pyridine, DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene), HCl, p-toluenesulfonic acid (pTSA), etc., and preferably pTSA is used.

[0056] The reaction solvent is not particularly limited as long as the reaction proceeds, and examples include THF, methanol, ethanol, isopropyl alcohol, dichloromethane, diethyl ether, acetonitrile, etc. Preferably, a mixed solvent of methanol and dichloromethane is used.

[0057] It is suitable to perform the reaction at a temperature of 0 to 100°C, preferably 10 to 30°C, and the reaction time is suitable for 1 to 24 hours, preferably 3 to 5 hours.

[0059] A manufacturing method according to one embodiment of the present invention may further include the step of dissolving the paricalcitol of Formula 1 produced in step (iii) in methanol, adding acetonitrile and stirring at room temperature, and then cooling and stirring to recrystallize.

[0060] The above cooling can be performed at 0°C or lower, and the above stirring can preferably be performed at -5 to 0°C.

[0061] Through the above recrystallization step, a high-purity crystalline form of paricalcitol of Formula 1 described later can be obtained.

[0063] In one embodiment of the present invention, the compound of Formula 2 can be prepared by a manufacturing method comprising the following steps.

[0064] (iv) A step of reducing the compound of Chemical Formula 7 below after ozone decomposition.

[0065] [Chemical Formula 7]

[0066]

[0068] Hereinafter, the method for preparing the compound of Chemical Formula 2 is explained in more detail with reference to Reaction Scheme 2 below. The method described in Reaction Scheme 2 below is merely an example of a method used as a representative example, and the reaction reagents, reaction conditions, etc., can be changed as needed depending on the circumstances.

[0070] [Reaction Equation 2]

[0071]

[0073] Step 4: Preparation of the compound of Chemical Formula 2

[0074] The compound of Chemical Formula 2 can be prepared by subjecting the compound of Chemical Formula 7 to an ozone decomposition reaction followed by a reduction reaction.

[0075] The above ozone decomposition reaction can be carried out using ozone, and it is preferable to use an industrial ozone generator.

[0076] In addition, it is preferable to carry out the ozone decomposition reaction in the presence of a base such as sodium bicarbonate.

[0077] Mixed solvents of polar and non-polar types are suitable as reaction solvents; for example, methanol, ethanol, isopropanol, dichloromethane, etc., may be used, and a mixed solvent of methanol and dichloromethane is particularly preferred.

[0078] It is suitable to carry out the reaction at a temperature of -80 to 0°C, preferably -80 to -55°C, and the reaction time is suitable for 1 to 24 hours, preferably 2 to 4 hours.

[0080] One embodiment of the present invention relates to a method for preparing a compound of Formula 3, wherein the method for preparing according to one embodiment of the present invention is

[0081] (v) a step of reacting the compound of Formula 8 below with the compound of Formula 9 below to form a sulfide bond to obtain the compound of Formula 10 below;

[0082] (vi) a step of obtaining a compound of the following formula 11 by alkylating a compound of the following formula 10;

[0083] (vii) a step of oxidizing a compound of the following formula 11 to obtain a compound of the following formula 12; and

[0084] (viii) includes the step of protecting the hydroxyl group of the compound of Chemical Formula 12 below.

[0085] [Chemical Formula 8]

[0086]

[0087] [Chemical Formula 9]

[0088]

[0089] [Chemical Formula 10]

[0090]

[0091] [Chemical Formula 11]

[0092]

[0093] [Chemical Formula 12]

[0094]

[0095] [Chemical Formula 3]

[0096]

[0097] In the above formula,

[0098] TES is triethylsilyl.

[0100] Hereinafter, the method for preparing the compound of Chemical Formula 3 is explained in more detail with reference to Reaction Scheme 3 below. The method described in Reaction Scheme 3 below is merely an example of a method used as a representative example, and the reaction reagents, reaction conditions, etc., can be changed as needed depending on the circumstances.

[0102] [Reaction Equation 3]

[0103]

[0105] Step 5: Synthesis of the compound of Chemical Formula 10

[0106] The compound of chemical formula 10 can be prepared by reacting the compound of chemical formula 8 with the compound of chemical formula 9 to form a sulfide bond.

[0107] The compound of the above formula 9 may be used in an amount of 0.5 to 2 moles, preferably 0.8 to 1.5 moles, per 1 mole of the compound of the above formula 8.

[0108] The above sulfide bond formation reaction can be carried out using triphenylphosphine (PPh3) and azodicarboxylate.

[0109] As the above azodicarboxylate, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), etc., may be used.

[0110] The reaction solvent is not particularly limited as long as the reaction proceeds, and examples include dichloromethane, toluene, benzene, hexane, cyclohexane, heptane, pentane, diethyl ether, etc. Preferably, dichloromethane is used.

[0111] It is suitable to carry out the reaction at a temperature of -20 to 40°C, preferably -10 to 25°C, and the reaction time is suitable for 1 to 24 hours, preferably 2 to 4 hours.

[0113] Step 6: Synthesis of the compound of Chemical Formula 11

[0114] The compound of chemical formula 11 can be prepared by alkylating the compound of chemical formula 10.

[0115] The above alkylation reaction can be carried out using methyl magnesium bromide.

[0116] In addition, the above alkylation reaction can be carried out with or without the presence of a base.

[0117] The reaction solvent is not limited as long as the reaction proceeds, and examples include THF, toluene, benzene, diethyl ether, etc., and preferably diethyl ether is used. Potassium iodine, sodium iodine, cesium iodine, etc. can be used as additives.

[0118] It is suitable to perform the reaction at a temperature of 0 to 100°C, preferably 0 to 30°C, and the reaction time is suitable for 1 to 48 hours, preferably 1 to 3 hours.

[0120] Step 7: Synthesis of the compound of Chemical Formula 12

[0121] The compound of chemical formula 12 can be prepared by oxidizing the compound of chemical formula 11.

[0122] The above oxidation reaction can be carried out in the presence of ammonium molybdate using an oxidizing agent such as hydrogen peroxide.

[0123] The reaction solvent is not limited as long as the reaction proceeds, and examples include THF, methanol, ethanol, isopropyl alcohol, etc., and preferably ethanol is used.

[0124] It is suitable to perform the reaction at a temperature of 0 to 100°C, preferably 0 to 30°C, and the reaction time is suitable at 1 to 80 hours, preferably 12 to 24 hours.

[0126] Step 8: Synthesis of the compound of Chemical Formula 3

[0127] The compound of chemical formula 3 can be prepared by protecting the hydroxyl group of the compound of chemical formula 12.

[0128] The above protective reaction can be carried out by reacting the compound of Formula 12 with triethylsilyl chloride.

[0129] The above triethylsilyl chloride can be used in an amount of 2 to 5 moles per 1 mole of the compound of Formula 12.

[0130] The above protective reaction can be performed with or without the presence of a base.

[0131] The above base may be an organic base or an inorganic base, and for example, pyridine, triethylamine, imidazole, etc. may be used, and imidazole is particularly suitable.

[0132] The above base can be used in an amount of 3 to 10 moles per 1 mole of the compound of Formula 12.

[0133] The reaction solvent is not limited as long as the reaction proceeds, and examples include DMF, acetonitrile, THF, etc., and preferably DMF is used.

[0134] It is suitable to carry out the reaction at a temperature of -10 to 80°C, preferably 15 to 35°C, and the reaction time is suitable for 1 to 48 hours, preferably 18 to 24 hours.

[0136] One embodiment of the present invention relates to a compound of the following chemical formula 4, which is an intermediate for the production of paricalcitol.

[0137] [Chemical Formula 4]

[0138]

[0139] In the above formula,

[0140] TES is triethylsilyl.

[0142] In one embodiment of the present invention, the compound of Formula 4 may have a purity of 90% or more, preferably 95% or more.

[0144] One embodiment of the present invention is I / I in X-ray powder diffraction analysis. o This relates to a crystalline form of paricalcitol with a diffraction angle (2θ) value of 15.30±0.2, 14.31±0.2, 18.00±0.2 and 10.88±0.2, where (I: peak intensity at each diffraction angle, I0: greatest peak intensity) is 10% or more.

[0146] One embodiment of the present invention relates to a pharmaceutical composition for the treatment or prevention of chronic renal failure comprising the crystalline form of paricalcitol together with a pharmaceutically acceptable carrier.

[0147] The pharmaceutical composition of the present invention may include another physiologically active substance in addition to the crystalline form of paricalcitol.

[0148] The pharmaceutical composition according to the present invention may be administered orally and may be formulated into various forms such as tablets, capsules, granules, powders, emulsions, suspensions, and syrups. The various forms of the pharmaceutical composition may be manufactured by known technology using pharmaceutically acceptable carriers commonly used in each formulation, such as excipients, fillers, volume expanders, binders, disintegrators, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solvents, bases, dispersants, wetting agents, suspenders, stabilizers, coloring agents, and flavoring agents.

[0149] In the manufacture of the above-mentioned drug, the content of the crystalline form of paricalcitol of the present invention varies depending on the form of the drug, but is preferably 10 to 90 weight%, more preferably 30 to 80 weight%.

[0150] The dosage of the pharmaceutical composition of the present invention varies widely depending on the type of mammal, including the person being treated, the route of administration, body weight, sex, age, the severity of the disease, and the judgment of the physician. Generally, for oral administration, based on a typical adult weighing about 60 kg, the dosage of the active ingredient may be administered in an amount of about 1 to 240 mg per day, preferably 5 to 180 mg, and more preferably 10 to 120 mg. The above-mentioned daily dosage may be used at once or in divided doses depending on the severity of the disease and the judgment of the physician.

[0152] One embodiment of the present invention relates to paricalcitol of the following chemical formula 1 having a purity of 95% or higher.

[0153] [Chemical Formula 1]

[0154]

[0156] In one embodiment of the present invention, the paricalcitol of Formula 1 may preferably have a purity of 97% or more, more preferably 99% or more, and even more preferably 99.5% or more. Effects of the invention

[0157] According to the manufacturing method of the present invention, the compound of Formula 4, which is a key intermediate required for the production of paricalcitol, can be manufactured efficiently and simply, and from this, paricalcitol can be manufactured efficiently and economically. Brief explanation of the drawing

[0158] Figure 1 is an X-ray powder diffraction pattern of the crystalline form of paricalcitol. Specific details for implementing the invention

[0159] The present invention will be explained more specifically below through examples. These examples are provided solely for the purpose of illustrating the invention, and it is obvious to those skilled in the art that the scope of the invention is not limited to these examples.

[0161] Example 1: Preparation of a compound of Formula 10

[0162] 0.91 equivalents of mercaptobenzothiazole, the compound of Formula 9, and 1.0 equivalent of triphenylphosphine were added to a nitrogen-filled reactor, and then 14.2 v / w of dichloromethane was added to dissolve them. (S)-Roche ester, the compound of Formula 8, was dissolved by adding 5.6 v / w of dichloromethane and then added to the reactor. After cooling the reaction mixture to -5 to 0 ℃, 1 equivalent of DIAD was added dropwise while maintaining the internal temperature below 0 ℃. Once the dropwise addition was complete, the reaction mixture was heated to room temperature and stirred for 2 hours. After confirming the completion of the reaction, the reaction mixture was concentrated, diluted with 20 v / w of EA, 22 equivalents of MgCl2 were added, and the mixture was stirred for 1 hour. The reaction mixture was filtered, the obtained organic layer was dehydrated and concentrated, and then purified using a column (6.3% ethyl acetate in hexane). The compound of chemical formula 10 was obtained with a yield of 81% (purity: 99.3%).

[0163] 1 H NMR (300 MHz, CDCl3) δ 7.92 - 7.82 (m, 1H), 7.75 (dd, J = 7.9, 0.6 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.32 - 7.23 (m, 1H), 3.72 (s, 3H), 3.66 - 3.41 (m, 2H), 3.12 - 2.92 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H).

[0165] Example 2: Preparation of the compound of Formula 11

[0166] The compound of Formula 10 was added to a nitrogen-filled reactor and dissolved in 20 v / w diethyl ether. After cooling the reaction mixture to -5 to 0 °C, 3.3 equivalents of 3.0 M methyl magnesium bromide dissolved in diethyl ether were added dropwise while maintaining the internal temperature below 0 °C. Once the dropwise addition was complete, the reaction mixture was heated to room temperature and stirred for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, neutralized with 1.5 equivalents of 1 N HCl, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, then purified using a column (10–30% ethyl acetate in hexane). The compound of Formula 11 was obtained with a yield of 90% (purity: 99.6%).

[0167] 1 H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 7.7 Hz, 1H), 7.73 (dd, J = 7.9, 0.6 Hz, 1H), 7.47 - 7.34 (m, 1H), 7.34 - 7.16 (m, 1H), 4.01 (dd, J = 13.5, 1.8 Hz, 1H), 3.23 (s, 1H), 2.76 (dd, J = 13.5, 9.5 Hz, 1H), 2.12 - 1.93 (m, 1H), 1.34 - 1.18 (m, 6H), 1.11 (d, J= 6.9 Hz, 3H).

[0169] Example 3: Preparation of the compound of Formula 12

[0170] The compound of Formula 11 was added to a reactor, 10 v / w ethanol was added, and the mixture was stirred. 0.124 equivalents of ammonium molybdate were added, and the mixture was stirred for 10 minutes. After cooling the reaction mixture to -5 to 0 ℃, 7.7 equivalents of 30% hydrogen peroxide were added dropwise while maintaining the internal temperature below 0 ℃. Once the dropwise addition was complete, the reaction mixture was heated to room temperature and stirred for 12 hours. After confirming the completion of the reaction, a 15% aqueous sodium thiosulfate solution was added dropwise while maintaining the internal temperature below 10 ℃. 15 v / w ethyl acetate was added to separate the organic layer, and the organic layer was washed twice with brine. The obtained organic layer was dehydrated and concentrated, then purified using a column (25% ethyl acetate in hexane). The compound of chemical formula 12 was obtained with a yield of 90% (purity: 99.5%).

[0171] 1 H NMR (300 MHz, CDCl3) δ 8.29 - 8.15 (m, 1H), 8.14 - 7.94 (m, 1H), 7.62 (pd, J = 7.2, 1.4 Hz, 2H), 4.18 - 3.94 (m, 1H), 3.26 (dd, J = 14.3, 9.5 Hz, 1H), 2.36 (dqd, J = 9.0, 6.9, 2.1 Hz, 1H), 1.36 - 1.01 (m, 9H).

[0173] Example 4: Preparation of the compound of Formula 3

[0174] The compound of Formula 12 and 3 equivalents of imidazole were added to a reactor, followed by the addition of 7 v / w of DMF and stirring. 2 equivalents of triethylsilyl chloride were added at an internal temperature of 25 °C or lower. The reaction mixture was heated to 35 °C and stirred for 24 hours. After confirming the completion of the reaction, 7 v / w of a 10% aqueous ammonium chloride solution and 15 v / w of ethyl acetate were added, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, then purified using a column (6.3% ethyl acetate in hexane). The compound of Formula 3 was obtained in the form of a white solid with a yield of 90% (purity: 99.5%, %ee: 99.1%).

[0175] 1 H NMR (300 MHz, CDCl3) δ 8.28 - 8.12 (m, 1H), 8.00 (ddd, J = 9.4, 5.0, 4.1 Hz, 1H), 7.60 (pd, J = 7.2, 1.4 Hz, 2H), 4.06 (dd, J = 14.3, 0.8 Hz, 1H), 3.18 (dd, J = 14.3, 10.3 Hz, 1H), 2.33 - 2.12 (m, 1H), 1.17 (dd, J = 23.6, 16.7 Hz, 9H), 0.90 - 0.79 (m, 9H), 0.55 - 0.41 (m, 6H).

[0177] Example 5: Preparation of the compound of Formula 2

[0178] Vitamin D2, the compound of Chemical Formula 7, and 0.07 equivalents of sodium bicarbonate were added to a nitrogen-substituted reactor. 10 v / w methanol and 30 v / w dichloromethane were added to the reactor. After cooling the reaction mixture to -75 to -65 °C, ozone was added while maintaining the reaction mixture temperature. When the reaction mixture turned a deep blue color, the ozone injection was stopped, and the inside of the reactor was purged with nitrogen. 5 equivalents of dimethyl sulfide were added, and the mixture was stirred at room temperature for 12 to 18 hours. After stirring, 10 v / w distilled water was added, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, and then [into] a column (10% methyl tert -butyl ether in hexane) was purified. A compound of Formula 2 was obtained in the form of a colorless to yellow viscous liquid with a yield of 50% (purity: 90.5%).

[0179] 1 H NMR (300 MHz, CDCl3) δ 9.61 (d, J = 2.9 Hz, 1H), 2.63 - 2.03 (m, 4H), 2.03 - 1.03 (m, 9H), 1.01 - 0.85 (m, 6H).

[0181] Example 6: Preparation of the compound of Formula 4

[0182] 1.2 equivalents of the compound of Formula 3 were added to a nitrogen-substituted reactor and diluted with 20 v / w THF. After cooling the reaction mixture to -65 to -55 °C, 1.32 equivalents of 1 M LiHMDS in THF were added while maintaining the reaction mixture temperature at -55 °C or lower. After the dropwise addition was completed, the mixture was stirred for 30 minutes. While maintaining the reaction mixture temperature at -55 °C or lower, the compound of Formula 2 diluted in 4 v / w THF was added. After the dropwise addition was completed, the mixture was stirred for 20 minutes, then heated to room temperature and stirred for 1 hour. After confirming the completion of the reaction, 15 v / w of 10% aqueous ammonium chloride and 24 v / w of ethyl acetate were added, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, and then [into] a column (5–8% methyl tert -butyl ether in hexane) was purified. A compound of Formula 4 was obtained in the form of a colorless to yellow viscous liquid with a yield of 85% (purity: 95.5%).

[0183] 1 H NMR (300 MHz, CDCl3) δ 5.34 (dd, J = 15.3, 8.1 Hz, 1H), 5.19 (dd, J = 15.4, 8.4 Hz, 1H), 2.55 - 2.37 (m, 2H), 2.23 - 0.88 (m, 33H), 0.69 - 0.65 (m, 3H), 0.65 - 0.50 (m, 6H).

[0185] Example 7: Preparation of the compound of Formula 6

[0186] 1.2 equivalents of the compound of Formula 5 were added to a nitrogen-substituted reactor and diluted with 10 v / w THF. After cooling the reaction mixture to -65 to -55 °C, 1.32 equivalents of 1 M LiHMDS in THF were added while maintaining the reaction mixture temperature at -55 °C or lower. After the dropwise addition was completed, the mixture was stirred for 30 minutes. While maintaining the reaction mixture temperature at -55 °C or lower, the compound of Formula 4 diluted in 2 v / w THF was added. After the dropwise addition was completed, the mixture was stirred for 120 minutes, then the temperature of the reaction mixture was raised to -35 °C and stirred for 1 hour. After confirming the completion of the reaction, 6 v / w of 10% aqueous ammonium chloride and 13 v / w of ethyl acetate were added, and the organic layer was separated. An additional 10 v / w of ethyl acetate was added to the aqueous layer, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, then purified using a column (0–5% ethyl acetate in hexane). A colorless to off-white viscous liquid compound of Formula 6 was obtained with a yield of 75% (purity: 95.5%).

[0187] 1 H NMR (300 MHz, CDCl3) δ 6.16 (d, J = 11.1 Hz, 1H), 5.81 (d,J = 11.2 Hz, 1H), 5.42 - 5.09 (m, 2H), 4.15 - 3.95 (m, 2H), 2.90 - 2.67 (m, 2H), 2.53 - 0.91 (m, 24H), 0.91 - 0.82 (m, 33H), 0.72 - 0.47 (m, 9H), 0.09 - 0.02 (m, 12H).

[0189] Example 8: Preparation of paricalcitol of Formula 1

[0190] The compound of Formula 6 was added to a nitrogen-substituted reactor, and 2 v / w methanol and 3 v / w dichloromethane were added and stirred. 0.6 equivalents of pTSA were added and stirred at room temperature for 3 hours. After confirming the completion of the reaction, 5 v / w of 5% aqueous sodium bicarbonate and 15 v / w ethyl acetate were added, and the organic layer was separated. An additional 10 v / w of ethyl acetate was added to the aqueous layer, and the organic layer was separated. The obtained organic layer was dehydrated and concentrated, then purified using a column (2–8% methanol in dichloromethane). Paricalcitol of Formula 1 was obtained in the form of a white solid with a yield of 85% (purity: 97.2%).

[0191] 1 H NMR (300 MHz, CDCl3) δ 6.31 (d, J = 11.2 Hz, 1H), 5.85 (d, J = 11.2 Hz, 1H), 5.48 - 5.22 (m, 2H), 4.20 - 3.93 (m, 2H), 2.94 - 2.63 (m, 2H), 2.59 - 2.36 (m, 3H), 2.28 - 0.86 (m, 29H), 0.66 - 0.39 (m, 3H).

[0192] 13C NMR (75 MHz, CDCl3) δ 142.92, 139.02, 131.20, 129.21, 123.82, 115.33, 72.37, 67.42, 67.22, 56.33, 56.23, 48.16, 45.73, 44.67, 42.20, 40.41, 40.33, 37.19, 28.92, 27.79, 27.01, 26.38, 23.46, 22.26, 20.98, 15.66, 12.34.

[0194] Example 9: Preparation of the crystalline form of paricalcitol of Formula 1

[0195] The paricalcitol of Formula 1 obtained in Example 8 above was vacuum dried for 12 hours in a nitrogen-substituted reactor, and then 15 v / w methanol was added and completely dissolved at 35 °C. While maintaining the temperature of the reaction mixture, 26 v / w acetonitrile was added. Once the dropwise addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to -5 to 0 °C and stirred for 1 hour. The solid was filtered and washed twice with 2 v / w acetonitrile. After repeating the recrystallization process once, the obtained solid was filtered under argon gas, and the obtained compound was vacuum dried at 40 °C for 24 hours. Paricalcitol of Formula 1, a white solid, was obtained with a yield of 73% (purity: 99.8%).

[0196] X-ray powder diffraction analysis was performed on paricalcitol of Chemical Formula 1, which is the white solid above, and the results are shown in Table 1 and Figure 1 below.

[0197] The characteristic peaks appearing in the X-ray powder diffraction pattern of Fig. 1 are shown in Table 1 below, where '2θ' represents the diffraction angle and 'I / I0' represents the relative intensity of the peak. The diffraction angle has a deviation range of ±0.2°.

[0198] Through the above X-ray powder diffraction analysis, it was confirmed that the paricalcitol of Formula 1 obtained above is in a crystalline form.

[0199] 2θ I / I0(%) 15.30 100% 14.31 60% 18.00 28% 10.88 12% 16.47 9% 24.06 8% 22.18 7% 9.02 6% 28.73 6% 20.52 5% 23.03 5% 30.79 4%

Claims

Claim 1 A method for preparing paricalcitol of the following formula 1, comprising the steps of: (i) a step of obtaining a compound of the following formula 4 by reacting the compound of the following formula 2 with the compound of the following formula 3 in a Julia olefinization reaction; (ii) a step of obtaining a compound of the following formula 6 by reacting the compound of the following formula 4 with the compound of the following formula 5 in a Horner-Wordsworth-Emmons reaction; and (iii) a step of deprotecting the hydroxyl group of the compound of the following formula 6: [Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 1] In the above formula, TES is triethylsilyl, TBS is t-butyldimethylsilyl, and Ph is phenyl. Claim 2 A method of preparation according to claim 1, wherein the olefinization reaction of the Julia in step (i) is performed in the presence of a base. Claim 3 A method of preparation according to claim 1, wherein in step (ii) above, the Horner-Wordsworth-Emmons reaction is performed in the presence of a base. Claim 4 A method of preparation according to claim 1, wherein the deprotection reaction in step (iii) is performed using p-toluenesulfonic acid (pTSA). Claim 5 A manufacturing method according to claim 1, further comprising the step of dissolving the paricalcitol of Formula 1 produced in step (iii) in methanol, adding acetonitrile and stirring at room temperature, and then cooling and stirring to recrystallize. Claim 6 In claim 1, the compound of Formula 2 is prepared by a method comprising the step of (iv) ozone decomposing and then reducing the compound of Formula 7 below: [Formula 7] Claim 7 In claim 6, the ozone decomposition reaction in step (iv) is performed using ozone in the presence of a base. Claim 8 (v) a step of reacting the compound of Formula 8 below with the compound of Formula 9 below to form a sulfide bond to obtain the compound of Formula 10 below; (vi) a step of alkylating the compound of Formula 10 below to obtain the compound of Formula 11 below; (vii) a step of oxidizing the compound of Formula 11 below to obtain the compound of Formula 12 below; and (viii) a step of protecting the hydroxyl group of the compound of Formula 12 below, comprising a method for preparing the compound of Formula 3 below: [Formula 8] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] [Chemical Formula 3] In the above formula, TES is triethylsilyl. Claim 9 A method of preparation according to claim 8, wherein the sulfide bond formation reaction in step (v) is performed in the presence of a base. Claim 10 A method of preparation according to claim 8, wherein the alkylation reaction in step (vi) is performed using methyl magnesium bromide. Claim 11 A manufacturing method according to claim 8, wherein the oxidation reaction in step (vii) is performed using hydrogen peroxide. Claim 12 A method of preparation according to claim 8, wherein the protective reaction in step (viii) is carried out by reacting a compound of formula 12 with triethylsilyl chloride in the presence of a base. Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete

Images