KR20170078033A - Novel Statin intermediate, the preparation method of the same and the preparation method of Rosuvastatin using the same - Google Patents
Novel Statin intermediate, the preparation method of the same and the preparation method of Rosuvastatin using the same Download PDFInfo
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Abstract
The present invention provides novel statin intermediates and methods for their preparation. The present invention also provides novel rosuvastatin intermediates which can be prepared from the novel statin intermediates of the invention and processes for their preparation. The present invention also provides a process for preparing rosuvastatin hemicalcium salt using the novel intermediate of rosuvastatin of the present invention. The novel statin intermediates of the present invention can be produced in a high purity and a high yield under mild conditions, and thus the intermediates of rosuvastatin and rosuvastatin hemicalcium salt can be mass-produced easily and efficiently without complicated processes.
Description
The present invention relates to a novel statin intermediate, a process for preparing the same, and a process for preparing rosuvastatin using the same.
Statin inhibits cholesterol biosynthesis in the human body by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reducing agent. The HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is a rate-determining step in the biosynthesis of cholesterol. Therefore, decreasing the amount of cholesterol synthesis by statins increases the number of LDL receptors, thereby decreasing the concentration of LDL particles in the bloodstream, thereby reducing the risk of developing coronary artery disease. Statins have been used as therapeutic agents for hypercholesterolemia, hyperlipidemia and atherosclerosis by such pharmacological mechanisms. Examples thereof include lovastatin, simvastatin, atorvastain, pravastatin, fluvastatin, Cerivastatin, rosuvastatin, and pitavastatin. These structures are as follows, and they have a (3R, 5R) -dihydroxy carboxylic acid structure in common as indicated by "circle" in the following structural formula.
Therefore, if an intermediate having a moiety of (3R, 5R) -dihydroxy carboxylic acid, expressed as "circle" in the above scheme, is developed, it has an advantage that it can be used in all of the above-described statins.
On the other hand, studies on the above-exemplified methods for producing statins and their intermediates are actively under way. As an example, intermediates of rosuvastatin and their preparation are described in European Patent Publication EP 0,521,471 (Korean Patent Publication No. 1996-0005951); International Patent Publication No. WO 00/49014; International Patent Publication No. WO 06/067456; International Patent Publication No. WO 07/007119; International Patent Publication No. WO 06/091771; International Patent Publication No. WO 03/016317; International Patent Publication No. WO 06/106526; International Patent Publication No. WO 07/039287; International Patent Publication No. WO 08/053334; International Patent Publication No. WO 07/125547 and the like.
Specifically, European Patent Publication No. EP 0,521,471 discloses a process for preparing rosuvastatin hemicalcium salt using Compound A and Compound B as starting materials as shown in Reaction Scheme I below.
[Reaction Scheme I]
That is, the above-mentioned known method is a method in which after the coupling of the compound A and the compound B is preferentially performed, the resulting compound RO-1 is reacted with a deprotecting agent such as a fluorine ion source or an inorganic acid such as HF to obtain the compound RO-2 , And performing the step of reacting the compound RO-2 with sodium borohydride at -78 캜 to prepare the compound RO-3.
However, when the compound R0-1 is reacted with a strong acid as described above, the fluoro group of the phenyl group can be desfluorinated (see Organic Syntheses, 4, p 964 (1963), Organic Syntheses, 39, p 75 (1959), pitavastatine Fluorine-free material is present as a flexible substance). Furthermore, when the product is used in the subsequent reaction without purification after the deprotection reaction as in the above patent, the product can not be crystallized after that due to impurities, resulting in poor product yield (Korean Patent Publication No. 2007-0100970) The increase of the soft substances finally makes it difficult to produce rosuvastatin hemicalcium salt in high yield and high purity.
The condition for adding the diethylmethoxyborane solution at about -78 ° C to obtain the compound RO-3 is not only the ketone group in the α, β-unsaturated ketone form of the compound R0-2, but also the double bond (α, β-unsaturated ), There is a disadvantage in that a considerable amount of byproducts are generated, and these impurities are not well separated from the compound R0-3. Therefore, when the following reaction is carried out without purification, there is a disadvantage in that the final product, rosuvastatin hemiccium salt, can not be obtained in high yield and high purity.
As has been described above, the process for preparing rosuvastatin hemiccium salt, which has been known so far, is relatively difficult to produce on a commercially acceptable scale, and thus it is necessary to develop a simpler and less expensive process for preparing rosuvastatin hemiccium salt.
It is an object of the present invention to provide a novel statin intermediate and a process for its preparation.
It is another object of the present invention to provide novel rosuvastatin intermediates which can be prepared from the novel statin intermediates of the present invention and their preparation.
It is another object of the present invention to provide a process for preparing rosuvastatin hemicalcium salt using novel intermediates of rosuvastatin of the present invention.
The present invention provides novel statin intermediates and methods for their preparation. The present invention also provides novel rosuvastatin intermediates which can be prepared from the novel statin intermediates of the invention and processes for their preparation. The present invention also provides a process for preparing rosuvastatin hemicalcium salt using the novel intermediate of rosuvastatin of the present invention. Hereinafter, this will be described in detail.
New Statin Intermediates and methods for their preparation
According to one embodiment of the present invention, the present invention provides a compound represented by formula (I): < EMI ID =
(I)
In this formula,
R 1 is
The invention also provides a process for preparing the compounds of formula (I). Specifically, the production method of the present invention comprises: (A-1) hydrolyzing a compound of the formula (I-1) to prepare a compound of the formula (I-2); (A-2) introducing a group R < 1 > into the compound of formula (I-2) to prepare a compound of formula (I-3) And (A-3) oxidizing the compound of formula (I-3) to produce a compound of formula (I).
(I-1)
[Formula I-2]
[Formula I-3]
(I)
In this formula,
R 1 is
Hereinafter, steps (A-1) to (A-3) will be described.
The step (A-1) is a hydrolysis step and can be carried out under conventional ester hydrolysis conditions. Specifically, the reaction is carried out in the presence of a base, and an inorganic base selected from the group consisting of KOH, NaOH, Ca (OH) 2 and K 2 CO 3 can be used. The inorganic base may be used in an amount of 1.2 to 4 equivalents based on 1 equivalent of the compound of the formula (1-1), preferably about 3.5 equivalents. The reaction temperature may vary depending on the reaction solvent and the reaction base, but the reaction may be carried out at 25 to 70 ° C, preferably at about 40 ° C. The reaction time is preferably 1 to 48 hours and preferably 24 hours. However, it is not limited thereto.
The step (A-2) may be carried out under the conventional substitution reaction conditions as an introduction step of the R 1 group. Specifically, the reaction solvent may be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc) and acetone, preferably dimethylsulfoxide. In addition, the reaction can be carried out in the presence of a base, and an inorganic base selected from the group consisting of K 2 CO 3 , NaHCO 3 , NaOH and KOH can be used, and preferably K 2 CO 3 can be used. The inorganic base may be used in an amount of 1.1 to 3 equivalents based on 1 equivalent of the compound of the formula (1-1), preferably 1.3 equivalents. In addition, 1.1 to 3 equivalents may be used as the reactant introducing the R 1 group, and preferably 1.7 equivalents may be used. The reaction temperature may vary depending on the reaction solvent and the reaction base, but the reaction may be carried out at 25 to 70 ° C, preferably at 40 ° C. The reaction time is 1 to 72 hours, preferably 36 hours. However, it is not limited thereto.
The step (A-3) may be an oxidation step of alcohol, and an oxidizing agent may be chorochloric acid, and dichloromethane may be used as a solvent. However, it is not limited thereto.
The process for the preparation of the compounds of formula (I), the novel statin intermediate compounds of the present invention, is summarized in Scheme 1 below.
[Reaction Scheme 1]
Through the above production process, the novel statin intermediate compound (I) of the present invention can be easily produced at a high purity and a high yield under mild conditions. Therefore, the novel statin intermediate compounds of the present invention can be usefully used as intermediates for various statin compounds such as rosuvastatin.
Novel rosuvastatin statin intermediates and methods for their preparation
According to another embodiment of the present invention there is provided a compound represented by formula IV:
(IV)
In this formula,
R 1 is
The present invention also provides a process for preparing the compound of formula IV above. Specifically, the production method of the present invention comprises: (B-1) reacting a compound of the formula (I) and a compound of the formula (II) to prepare a compound of the formula (III); And (B-2) removing the diol protecting group of Formula III to produce a diol compound of Formula IV:
(I)
≪ RTI ID = 0.0 &
(III)
(IV)
R 1 is
The step (B-1) is carried out under the usual reaction conditions of the Wittig reaction. Specifically, the reaction can be carried out in the presence of a base, and a weak base selected from the group consisting of potassium carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydrogencarbonate and sodium carbonate can be used, and potassium carbonate is preferably used. The weak base may be a powder type or a granule type, and a powder type is preferable. The reaction temperature may vary depending on the reaction solvent and the reaction base, but the reaction may be carried out at 50 to 90 ° C, preferably at 60 ° C. The reaction time is preferably 1 to 5 hours. However, it is not limited thereto. The reaction solvent in step (B-1) may be a solvent selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile.
Further, the step (B-2) is carried out under the usual reaction conditions of the diol protecting group elimination reaction. Specifically, the reaction may be carried out in the presence of an acid, and the acid may be selected from the group consisting of hydrochloric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, and pyridium p-toluenesulfonate. These may be in the form of aqueous solutions dissolved in water. As the reaction solvent, a solvent selected from the group consisting of methanol, ethyl acetate and acetonitrile may be used. As the crystallization solvent, a solvent selected from the group consisting of methanol, ethanol, n-propyl alcohol and isopropyl alcohol can be used, and isopropyl alcohol can be preferably used.
The compound of formula (IV) of the present invention is a novel rosuvastatin intermediate having a rosuvastatin moiety. Conventional rosuvastatin intermediates (R 1 is methyl or t-butyl) are mostly prepared by a complicated process, but the compound of formula (IV) of the present invention can be prepared in a simple and efficient manner under mild conditions with high yield and high purity.
Process for preparing rosuvastatin hemicalcium salt using novel rosuvastatin intermediate
According to another embodiment of the present invention, there is provided a process for preparing rosuvastatin hemi-calcium salt using the novel rosuvastatin intermediate compound (IV) of the present invention. Specifically, the following steps are included.
(C-1) preparing a compound of the formula (IV): And (C-2) preparing a rosuvastatin hemi-calcium salt from the compound of formula IV.
(IV)
In this formula,
R 1 is
The step (C-1) is as described above.
The step (C-2) is a step for preparing a final product, rosuvastatin hemicalcium salt, by adding a calcium source in the presence of a base.
The base may be K 2 CO 3 , Ca (OH) 2 or NaH, preferably K 2 CO 3 .
Further, DMSO, IPA, THF, DME or DMSO may be used as the solvent.
The reaction temperature is preferably from 30 to 60 ° C and the reaction time is from 1 to 5 hours.
The process for preparing the rosuvastatin hemi-calcium salt from the novel statin intermediates of formula (I) of the present invention is summarized in the following reaction formula (2).
[Reaction Scheme 2]
Through the above-described production method, rosuvastatin hemicalcium salt can be produced under mild condition with high purity and high yield.
The novel statin intermediates of the present invention can be produced in a high purity and a high yield under mild conditions, and thus the intermediates of rosuvastatin and rosuvastatin hemicalcium salt can be mass-produced easily and efficiently without complicated processes.
Hereinafter, the present invention will be described in more detail by way of the following examples, but the present invention is not limited thereto.
Hereinafter, the reagents used in the examples were purchased from Aldrich, TCI, and Acros, unless otherwise noted, and 1 H-NMR was measured using Varian Inova 500 MHz FT-NMR (Varian, manufacturer) .
Example 1 Preparation of Statin Intermediate Compound of Formula I
Step 1: Preparation of compound II-2 ((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-
(30 g, 99.22 mmol) was added to a solution of tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2- , Jiangsu Alpha Pharmaceutical) and 300 ml MeOH were added to a 2 L 3-neck flask and stirred. NaOH (13.9 g, 347.27 mmol, 1.5 eq) was dissolved in 14 g of water, slowly added to the reaction solution, and the mixture was heated to 60 ° C and stirred for 20 hours. After cooling to room temperature, 33 ml of a 1: 1 solution of MeOH: concentrated hydrochloric acid was added to adjust the pH to 7, and the filtrate was concentrated under reduced pressure to obtain the title compound (wet 21.8 g, 100%).
1 H NMR (500 MHz, CDCl 3): δ 0.9 (q, 1H), 1.24 (s, 3H), 1.35 (s, 3H), 1.65 (d, 1H), 2.1 (dd, 1H), 2.4 (dd , 3.25 (dd, 1H), 3.3 (dd, 1H), 3.65-3.6 (m,
Step 2: Preparation of the compound of formula I-3 The preparation of cyclopentyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-
K 2 CO 3 (17.6 g, 127.31 mmol, 1.3 eq) was added to a 250 ml 3-neck flask and dissolved in 200 ml of DMSO, the compound of formula I-2 (20 g, 97.93 mmol) Lt; / RTI > Cyclopentyl bromide (20.43 g, 137.1 mmol, 1.4 eq) was added and stirred at 60 < 0 > C for 20 hours. The reaction mixture was cooled to room temperature and extracted with 200 ml of toluene and 200 ml of water. The aqueous layer was extracted again with 100 ml of toluene, and the toluene layer was collected and washed with 200 ml of H 2 O x 2 times. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil compound (20.0 g, 75%).
1 H NMR (500 MHz, CDCl 3): δ 1.35 (d, 1H), 1.38 (s, 3H), 1.5 (s, 3H), 1.62 ~ 1.55 (m, 2H), 1.78 ~ 1.65 (m, 4H) (Q, 1H), 3.65-3.5 (m, 1H), 4.15-4.0 (m, 2H) 1H), 4.4-4.3 (m, 1H)
Step 3: Preparation of cyclopentyl 2 - ((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate
0.48 g (4.03 mmol) of KBr, 9.3 g (110.65 mmol) of NaHCO 3 and 0.01 g (0.0356 mmol) of TEMPO were added to a 100 ml 3-neck flask and 100 ml of methylene chloride (MC) was added thereto and stirred. 4.4 g (16.21 mmol) of the compound of formula I-5 prepared in step 4 was dissolved in 20 ml of MC and added. The reaction vessel was cooled to -15 ° C and 14.3 g (23.05 mmol) of aqueous NaOCl solution (12%) was slowly added. The temperature was raised naturally and the mixture was stirred at room temperature for 1 hour. 100 ml of a 10% Na 2 S 2 O 3 aqueous solution was added to separate the layers. The organic layer was washed with 100 ml of 10% NaCl solution and 100 ml of water. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil compound (4.1 g, 92%).
1 H NMR (500 MHz, CDCl 3): δ 1.33 (d, 1H), 1.35 (s, 3H), 1.5 (s, 3H), 1.55 ~ 1.62 (m, 2H), 1.65 ~ 1.78 (m, 4H) 1H), 3.8-4 (m, 1H), 4.3-4.4 (m, 1H), 1.8-1.9 (m, 2H) 1H), 5.2 (s, IH), 5.4 (s, IH), 9.8 (s, IH)
Example 2 Preparation of Statin Intermediate Compound of Formula I
Step 1: Preparation of compound of formula I-3 The preparation of cyclohexyl 2 - ((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-
(10 g, 48.97 mmol) prepared in Step 1 of Example 1 was dissolved in 100 ml of DMSO, and K 2 CO 3 (8.8 g, 63.22 mmol, 1.3 eq) was added to a 250 ml 3-neck flask. And the mixture was stirred for 10 minutes. Cyclohexyl bromide (11.18 g, 68.55 mmol, 1.4 eq) was added and stirred at 60 < 0 > C for 20 hours. After cooling to room temperature, 100 ml of toluene and 100 ml of water were added and extracted. The aqueous layer was extracted again with 50 ml of toluene. The toluene layer was collected, washed with 100 ml of H 2 O x 2 times, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil compound (9.8 g, 70%).
1 H NMR (500 MHz, CDCl 3): δ 1.33 (d, 1H), 1.35 (s, 3H), 1.45 (s, 3H), 1.62 ~ 1.55 (m, 2H), 1.78 ~ 1.65 (m, 4H) (M, 2H), 2.35-2.3 (q, 1H), 2.4 (d, 1H), 2.52-2.48 1H), 4.15-4.0 (m, 1H), 4.4-4.3 (m, 1H)
Step 2: Preparation of the compound of formula (I) Cyclohexyl 2 - ((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-
0.48 g (4.03 mmol) of KBr, 9.3 g (110.65 mmol) of NaHCO 3 and 0.01 g (0.0356 mmol) of TEMPO were added to a 100 ml 3-neck flask and 100 ml of methylene chloride (MC) was added thereto and stirred. 4.6 g (16.21 mmol) of the compound of the formula I-3 prepared in the step 1 was dissolved in 20 ml of MC and added thereto. The reaction vessel was cooled to -15 ° C and 14.3 g (23.05 mmol) of aqueous NaOCl solution (12%) was slowly added. The temperature was raised naturally and the mixture was stirred at room temperature for 1 hour. 100 ml of a 10% Na 2 S 2 O 3 aqueous solution was added to separate the layers. The organic layer was washed with 100 ml of 10% NaCl solution and 100 ml of water. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil compound (4.1 g, 88%).
1 H NMR (500 MHz, CDCl 3): δ 1.33 (d, 1H), 1.35 (s, 3H), 1.45 (s, 3H), 1.55 ~ 1.62 (m, 2H), 1.65 ~ 1.78 (m, 4H) (Q, 1 H), 2.48-2.52 (q, 1H), 3.5-3.65 (m, 2H), 1.8-1.9 1H), 4.0-4.15 (m, 1H), 4.3-4.44 (m, 1H), 9.8 (s,
Example 3 Preparation of Statin Intermediate Compound of Formula I
Step 1: Preparation of compound of formula I-3 The preparation of adamantane 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-
The compound of formula I-2 (10 g, 48.97 mmol) prepared in step 1 of Example 1 was dissolved in 100 ml of DMSO and then K 2 CO 3 (8.8 g, 63.22 mmol, 1.3 eq ) Was added and stirred for 10 minutes. 1-Bromo adamantane (14.75 g, 68.55 mmol, 1.4 eq) was added and the mixture was stirred at 60 占 폚 for 20 hours. After cooling to room temperature, 100 ml of toluene and 100 ml of water were added and extracted. The aqueous layer was extracted again with 50 ml of toluene. The toluene layer was collected, washed with 100 ml of H 2 O x 2 times, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a brown oil compound (9.7 g, 59%).
1 H NMR (500 MHz, CDCl 3): δ 1.34 (d, 1H), 1.36 (q, 2H), 1.50 (s, 6H), 1.48 ~ 1.52 (t, 2H), 1.55 ~ 1.62 (m, 5H) 2H), 2.11-1.95 (m, 2H), 2.35-2.3 (q, 1H), 2.4 (d, 1H), 2.52-2.48 (q, 1H), 3.65-3.5 (m, 1H), 4.15-4.0 (m, 1H), 4.4-4.3 (m,
Step 2: Preparation of compound of formula I Preparation of adamantane 2 - ((4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-
0.48 g (4.03 mmol) of KBr, 9.3 g (110.65 mmol) of NaHCO 3 and 0.01 g (0.0356 mmol) of TEMPO were added to a 100 ml 3-neck flask and 100 ml of methylene chloride (MC) was added thereto and stirred. 5.5 g (16.21 mmol) of the compound of the formula I-3 prepared in the step 1 was dissolved in 20 ml of MC and added. The reaction vessel was cooled to -15 ° C and 14.3 g (23.05 mmol) of aqueous NaOCl solution (12%) was slowly added. The temperature was raised naturally and the mixture was stirred at room temperature for 1 hour. 100 ml of a 10% Na 2 S 2 O 3 aqueous solution was added to separate the layers. The organic layer was washed with 100 ml of 10% NaCl solution and 100 ml of water. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil compound (4.6 g, 85%).
1 H NMR (500 MHz, CDCl 3): δ 1.34 (d, 1H), 1.36 (q, 2H), 1.50 (s, 6H), 1.48 ~ 1.52 (t, 2H), 1.55 ~ 1.62 (m, 5H) 2H), 1.95-2.1 (m, 2H), 2.3-2.33 (q, 1H), 2.4 (d, 1H), 2.45-2.49 (q, 1H), 3.45-3.51 (m, 1H), 4.0-1.4 (m, 1H), 4.3-4.44 (m,
Example 4 Preparation of Rosuvastatin Intermediate Compound of Formula IV
Step 1: Compound of formula (III) Cyclohexyl 2 - ((4R, 6S) -6- (E) -2- (4- (4- fluorophenyl) -6- Sulfonamido) pyrimidin-5-yl) vinyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
(Methylsulfonyl) amino] -5-pyrimidinyl] methyl] triphenylphosphonium bromide < RTI ID = 0.0 > After dissolving 5 g (7.37 mmol) in 20 ml of DMSO, 3.1 g (22.11 mmol) of K 2 CO 3 was added at 18 ° C and stirred for 1 hour. 1.7 g (5.9 mmol) of the compound of Formula I prepared in Example 2 was added thereto and stirred at 60 ° C for 5 hours. After completion of the reaction, 20 ml of water was added dropwise, and the mixture was extracted twice with 20 ml of toluene. The organic layer was washed with 20 ml of 20% brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was recrystallized from 30 ml of methanol to obtain 3.2 g (yield 70%) of the compound of formula (III).
1 H NMR (500 MHz, CDCl 3 ):? 1.23 (s, 6H), 1.34 (s, 3H), 1.42 (s 3H), 1.52-1.6 (M, 2H), 2.42 (dd, 1H), 2.44-2.48 (q, 1H), 2.55 (dd, 1H), 3.4-3.44 1H), 5.42 (dd, 1H), 6.55 (dd, 1H), 3.75 (s, 3H) 1H), 7.14 (t, 2H), 7.67 (q, 2H)
Step 2: Compound of formula IV (3R, 5S, E) -cyclohexyl 7- (4- (4-fluorophenyl) -6-isopropyl- 2- (N-methylmethylsulfonamido) pyrimidin- -Yl) -3,5-dihydroxyhept-6-enoate < / RTI >
The compound of Formula III (12.8 g, 21.25 mmol) prepared in Step 1 was dissolved in THF (33 mL) at room temperature, followed by 2N-HCl (21.2 mL). The solution was stirred at room temperature for 1 hour, then a saturated aqueous solution of sodium hydrogencarbonate was added until the pH of the reaction solution became 8-9. The organic layer was washed with saturated sodium hydrogencarbonate (50 mL) and water (50 mL) successively, and then the organic layer was washed with ethyl acetate (20 mL) and ethyl acetate (20 mL) The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate (5 ml) was added to the concentrate, and the solution was dissolved in n-hexane (50 ml), followed by crystallization at room temperature for 3 to 5 hours. The solid was filtered off under reduced pressure, washed with a mixed solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v) and then washed with n-hexane (10 ml). Ethyl acetate (5 ml) was added to the obtained solid and dissolved by heating to 50 ° C. The reaction mixture was cooled to room temperature, and n-hexane (10 ml) was added thereto. When the solid was gradually formed, the temperature was cooled to 0 ° C. and slurry Respectively. The resulting solid was filtered off under reduced pressure, washed with a mixed solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v), washed with n-hexane (100 ml) and recrystallized. The resulting solid was dried under reduced pressure at room temperature to give 10.2 g (18.06 mmol) of the compound of formula IV (85% yield).
1 H NMR (500 MHz, CDCl 3 ):? 1.25 (s, 6H), 1.4-1.44 (m, 2H), 1.52-1.57 3H), 3.65 (s, 3H), 3.7 (m, 2H), 2.32 (dd, 2H), 7.68 (d, 1H), 6.84 (d, 1H), 6.74 (d, , 2H)
Example 5 Preparation of Rosuvastatin Intermediate Compound of Formula IV
Step 1: Compound of formula III adamantan 2 - ((4R, 6S) -6- (E) -2- (4- (4- fluorophenyl) -6- Methylsulfonamido) pyrimidin-5-yl) vinyl) -2,2-dimethyl-1,3-dioxan-4-yl) acetate
(Methylsulfonyl) amino] -5-pyrimidinyl] methyl] triphenylphosphonium bromide < RTI ID = 0.0 > After dissolving 5 g (7.37 mmol) in 20 ml of DMSO, 3.1 g (22.11 mmol) of K 2 CO 3 was added at 18 ° C and stirred for 1 hour. 2.0 g (5.9 mmol) of the compound of formula I prepared in Example 3 was added thereto and stirred at 60 DEG C for 5 hours. After completion of the reaction, 20 ml of water was added dropwise, and the mixture was extracted twice with 20 ml of toluene. The organic layer was washed with 20 ml of 20% brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was recrystallized from 30 ml of methanol to obtain 2.3 g of a compound of formula (III) (yield: 60%).
1 H NMR (500 MHz, CDCl 3): δ 1.13 (d, 1H), 1.22 (q, 2H), 1.23 (s, 6H), 1.34 (s, 3H), 1.45 (s, 6H), 1.48 ~ 1.52 (m, 2H), 1.55-1.62 (m, 5H), 1.65-1.78 (m, 4H), 1.8-1.9 (M, 1H), 2.4 (d, 1H), 2.45-2.49 (q, 1H), 3.45-3.51 , 7.12 (t, 2H), 7.68 (q, 2H)
Step 2: Compound of formula IV (3R, 5S, E) -Adamantane 7- (4- (4-Fluorophenyl) -6-isopropyl- 2- (N-methylmethylsulfonamido) pyrimidine- 5-yl) -3,5-dihydroxyhept-6-enoate
Compound (III) (13.9 g, 21.25 mmol) prepared in Step 1 was dissolved in THF (33 mL) at room temperature, followed by 2N-HCl (21.2 mL). The solution was stirred at room temperature for 1 hour, then a saturated aqueous solution of sodium hydrogencarbonate was added until the pH of the reaction solution became 8-9. The organic layer was washed with saturated sodium hydrogencarbonate (50 mL) and water (50 mL) successively, and then the organic layer was washed with ethyl acetate (20 mL) and ethyl acetate (20 mL) The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate (5 ml) was added to the concentrate, and the solution was dissolved in n-hexane (50 ml), followed by crystallization at room temperature for 3 to 5 hours. The solid was filtered off under reduced pressure, washed with a mixed solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v) and then washed with n-hexane (10 ml). Ethyl acetate (5 ml) was added to the obtained solid and dissolved by heating to 50 ° C. The reaction mixture was cooled to room temperature, and n-hexane (10 ml) was added thereto. When the solid was gradually formed, the temperature was cooled to 0 ° C. and slurry Respectively. The resulting solid was filtered off under reduced pressure, washed with a mixed solvent (10 ml) of cold n-hexane: ethyl acetate = 20: 1 (v / v), washed with n-hexane (100 ml) and recrystallized. The obtained solid was dried under reduced pressure at room temperature to obtain 11.5 g of a compound of the formula (IV) (yield: 88%).
1 H NMR (500 MHz, CDCl 3): δ 1.23 (d, 1H), 1.26 (q, 2H), 1.3 (s, 6H), 1.46 ~ 1.5 (t, 2H), 1.55 ~ 1.62 (m, 5H) (Q, 1 H), 2.4 (d, 1H), 2.45-2.49 (q, 2H), 1.67-1.71 (m, 2H), 7.72 (q, 2H), 6.70 (d, 2H), 7.30 (m,
Example 6 Preparation of rosuvastatin hemicalcium salt
The compound of formula IV (20 g, 35.6 mmol) prepared in example 4 was dissolved in ethanol (200 ml) and cooled to 0 ° C. 2N-NaOH aqueous solution (19.6 ml, 39.2 mmol) was added to the reaction solution, The temperature was raised to room temperature and stirred for 1 hour. The reaction solution was washed with diethyl ether (100 ml x 2), the aqueous layer was cooled to 0 ° C, and a solution of CaCl 2 (4.35 g, 39.2 mmol) in water (70 ml) was slowly added dropwise. The reaction solution was stirred at room temperature overnight, and the resulting white solid was filtered, washed with water (50 ml x 2) and hexane (50 ml x 2) and dried under reduced pressure to obtain a white solid, rosuvastatin hemi-calcium salt (14.9 g) was obtained (yield: 84%).
1 H NMR (500 MHz, CDCl 3): δ 1.15 ~ 1.22 (m, 6H), 1.26 ~ 1.32 (m, 1H), 1.45 ~ 1.50 (m, 1H), 2.28 ~ 2.53 (m, 1H), 3.40 ~ 1H), 6.49 (d, 1H), 6.49 (d, 2H), 3.74 (m, 2H) , 7.65-7.72 (m, 2H)
Example 7 Preparation of rosuvastatin hemicalcium salt
The compound of formula IV (22 g, 35.6 mmol) prepared in Example 5 was dissolved in ethanol (200 ml) and cooled to 0 ° C. 2N-NaOH aqueous solution (19.6 ml, 39.2 mmol) was added to the reaction solution, The temperature was raised to room temperature and stirred for 1 hour. The reaction solution was washed with diethyl ether (100 ml x 2), the aqueous layer was cooled to 0 ° C, and a solution of CaCl 2 (4.35 g, 39.2 mmol) in water (70 ml) was slowly added dropwise. The reaction solution was stirred at room temperature overnight, and the resulting white solid was filtered, washed with water (50 ml x 2) and hexane (50 ml x 2) and dried under reduced pressure to obtain a white solid, rosuvastatin hemi-calcium salt (14.9 g) was obtained (yield: 84%).
1 H NMR (500 MHz, CDCl 3): δ 1.15 ~ 1.22 (m, 6H), 1.26 ~ 1.32 (m, 1H), 1.45 ~ 1.50 (m, 1H), 2.28 ~ 2.53 (m, 1H), 3.40 ~ 1H), 6.49 (d, 1H), 6.49 (d, 2H), 3.74 (m, 2H) , 7.65-7.72 (m, 2H)
Claims (6)
(I)
In this formula,
R 1 is
(A-2) introducing a group R < 1 > into the compound of formula (I-2) to prepare a compound of formula (I-3) And
(A-3) oxidizing the compound of formula (I-3) to produce a compound of formula (I);
Lt; RTI ID = 0.0 > I < / RTI >
(I-1)
[Formula I-2]
[Formula I-3]
(I)
In this formula,
R 1 is
(IV)
In this formula,
R 1 is
(B-2) removing the diol protecting group of Formula III to prepare a diol compound of Formula IV;
Lt; RTI ID = 0.0 > (IV) < / RTI > comprising:
(I)
≪ RTI ID = 0.0 &
(III)
(IV)
In this formula,
R 1 is
(C-2) preparing a rosuvastatin hemicalcium salt from the compound of formula IV;
≪ RTI ID = 0.0 > rosuvastatin < / RTI >
(IV)
In this formula,
R 1 is
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019139919A1 (en) * | 2018-01-09 | 2019-07-18 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
| CN114280181A (en) * | 2021-12-23 | 2022-04-05 | 浙江海翔川南药业有限公司 | Detection method of rosuvastatin intermediate and related substances thereof |
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2015
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019139919A1 (en) * | 2018-01-09 | 2019-07-18 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
| US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
| CN114280181A (en) * | 2021-12-23 | 2022-04-05 | 浙江海翔川南药业有限公司 | Detection method of rosuvastatin intermediate and related substances thereof |
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