KR20160126700A - New Statin intermediate, the preparation of the same and the preparation of Rosuvastatin using the same - Google Patents
New Statin intermediate, the preparation of the same and the preparation of Rosuvastatin using the same Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
Description
The present invention relates to a statin intermediate, a process for producing 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 Registered 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 R0-3.
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 the impurity due to impurities, resulting in poor yield of the product (see Korean Patent Publication No. 10-2007-0100970 The increase in the amount of the suppositories makes it difficult to produce rosuvastatin calcium 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.
Accordingly, it is an object of the present invention to provide a simple and efficient method for producing a core intermediate of rosuvastatin.
It is also an object of the present invention to provide novel intermediates used in the preparation of rosuvastatin core intermediates and methods for their preparation.
It is also an object of the present invention to provide rosuvastatin hemicalcium salt using novel intermediates of rosuvastatin.
The present invention provides a simple and efficient method for preparing core intermediates of rosuvastatin. The present invention also provides novel intermediates used in the preparation of rosuvastatin core intermediates and methods for their preparation. It is also an object of the present invention to provide rosuvastatin hemicalcium salt using novel intermediates of rosuvastatin. Hereinafter, this will be described in detail.
Process for the preparation of core intermediates of rosuvastatin
In the preparation of rosuvastatin hemicalcium salt, compounds of formula IV below are widely used as core intermediates.
(IV)
However, since the compound of formula (IV) is produced by a complicated process when it is produced by a conventional process, it needs to be produced easily and efficiently.
The present invention provides a method for preparing the compound of formula IV as a core intermediate of rosuvastatin.
In the present invention, the process for preparing the compound of formula (IV) comprises the following steps:
(A) reacting a compound of formula (I) and a compound of formula (II) to produce a compound of formula (III); And
(B) removing the diol protecting group A of formula (III) to prepare a diol compound of formula (IV).
(I)
≪ RTI ID = 0.0 &
(III)
In this formula,
A is
The above step (A) is carried out under the usual reaction conditions of the Wittig reaction, and the step (B) is carried out under the usual reaction conditions of the diol protecting group elimination reaction.
Novel intermediates and methods for their preparation
According to one embodiment of the present invention, the present invention provides an intermediate compound represented by the formula (I)
(I)
In this formula,
A is
In accordance with another embodiment of the present invention, there is provided a rosuvastatin intermediate compound represented by formula III:
(III)
Wherein A is as defined for formula (I).
The novel intermediates of the present invention can be readily prepared in high purity and high yield under mild conditions and can be usefully employed to prepare the compounds of formula IV, the core intermediates of rosuvastatin.
According to another embodiment of the present invention, the present invention provides a method for preparing the statin intermediate compound of formula (I). Specifically, the manufacturing method of the present invention includes the following steps:
(a) to to to introduce the R 1 group in the compound of formula I-1 to prepare a compound of formula I-2;
(b) removing the diol protecting group of the compound of formula (I-2) to produce a diol compound of formula (I-3);
(c) introducing a diol protecting group A into the compound of Formula I-3 to prepare a compound of Formula 4;
(d) removing the alcohol protecting group of the compound of formula (I-4) to prepare a compound of formula (5); And
(e) oxidizing the compound of formula (I-5) to produce a compound of formula (6).
(I-1)
[Formula I-2]
[Formula I-3]
[Formula I-4]
[Formula I-5]
(I)
In this formula,
A is as defined for formula I,
R 1 is a protecting group of a hydroxy group and may be selected from t-butyldimethylsilane, t-butyldiphenylsilane, acetyl, benzoyl, C 1-4 alkyl or C 3-10 cycloalkyl. Preferably, R < 1 > can be selected from t-butyldimethylsilane, t-butyldiphenylsilane, acetyl or benzoyl.
Hereinafter, steps (a) to (e) will be described.
The step (a) is preferably carried out in the presence of a base as a step of protecting the hydroxyl group (-OH).
Tert-butyl dimethyl chlorosilane, Tert-butyl diphenyl chlorosilane, acetyl chloride, or benzoyl chloride may be used as the hydroxyl group protecting reagent. Tert-butyl diphenyl chlorosilane is preferable.
Imidazole, pyridine or triethylamine may be used as the base, and imidazole is preferred.
The solvent may be dichloromethane or THF, preferably dichloromethane.
The compound of formula (I-1) as a reactant in step (a) and the protecting reagent may be reacted in a molar ratio of 1: 1 to 1: 2 equivalent, preferably 1: 1.2 equivalent.
Although the step (a) may vary depending on the type of base and solvent used, the reaction temperature is preferably 20 to 30 ° C, and the reaction time is preferably 30 minutes to 3 hours.
The step (b) is preferably a step of removing the diol protecting group, and is preferably carried out in the presence of an acid.
The acid may be selected from the group consisting of hydrochloric acid, acetic acid, p-toluenesulfonic acid and methanesulfonic acid. These may be in the form of aqueous solutions dissolved in water.
Further, THF may be used as the solvent.
The compound of formula (I-2) as the reactant in step (b) and hydrochloric acid or sulfonic acid may be reacted at a molar ratio of 1: 0.1 to 1: 1, preferably 1: 0.5, 1:36 is preferred.
Although the step (b) differs depending on the type of the acid and the solvent to be used, the reaction temperature is preferably 20 to 30 ° C, and the reaction time is preferably 8 to 15 hours.
The step (c) is a step of re-acetalizing the deprotonated diol in step (b), and is preferably carried out in the presence of an acid.
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.
Also, dichloromethane, acetone or THF may be used as the solvent.
In step (c), the compound of formula (I-3) as a reactant and the acetalizing reagent may be reacted at a molar ratio of 1: 1 to 1: 2, preferably 1: 1.2.
Although the step (c) differs depending on the kind of the acid and the solvent to be used, the reaction temperature is preferably 20 to 30 ° C and the reaction time is preferably 8 to 15 hours.
In the step (d), the step of removing the hydroxy protecting group which has been protected in step (a) is preferably carried out in the presence of a base.
The base may be selected from tetrabutylammonium fluoride or K 2 CO 3 .
The solvent may be THF, MeOH or dichloromethane.
In step (d), the compound of formula (I-4) as a reactant and the base may be reacted at a molar ratio of 1: 0.8 to 1: 1.5, preferably 1: 1.
Although the step (d) differs depending on the kind of the base and the solvent used, the reaction temperature is preferably 20 to 30 ° C and the reaction time is preferably 2 to 10 hours.
The step (e) is a step of oxidizing the hydroxyl group.
Dichloromethane can be used as the solvent.
In the step (e), the compound of Formula I-5 as the reactant and the oxidizing agent may be reacted at a molar ratio of 1: 0.8 to 1: 3 mol, preferably 1: 1.2.
Although the step (S-5) differs depending on the kind of the base and the solvent used, it is preferable that the reaction temperature is -15 ° C and the reaction time is 1 hour.
The process for the preparation of the compounds of formula (I), the novel intermediate compounds of the present invention, is summarized in the following reaction scheme (1).
[Reaction Scheme 1]
Through the above production process, the novel intermediate compound (I) of the present invention can be produced under mild conditions at high purity and high yield.
Process for the preparation of rosuvastatin hemicalcium salt using novel intermediates
According to another embodiment of the present invention, there is provided a process for preparing rosuvastatin hemicalcium salt using the novel intermediate compounds of the present invention (formula (I)). Specifically, the following steps are included.
(1) preparing a compound of formula (IV) by a process for preparing a compound of formula (IV) disclosed in the present invention; And (2) preparing rosuvastatin hemi-calcium salt from the compound of formula IV.
(IV)
The above step (1) is as described above.
The step (2) is a step of producing a rosuvastatin hemiccium salt as a final product, which is carried out 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 rosuvastatin hemicalcium salt from the novel statin intermediates 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 core intermediate of rosuvastatin can be produced easily and efficiently through the production method of the present invention.
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 Intermediate Compounds of Formula I
Step 1: Preparation of the compound of formula 2 {tert-butyl 2 - ((4R, 6S) -6 - ((tert-butyldimethylsilyloxy) methyl) -2,2-dimethyl-1,3-dioxan-4-
4-yl) acetate) (2.5 g, 9.6 mmol, 1 eq.) Was added to a solution of the compound of formula I-1 (tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- Jiangsu Alpha Pharmaceutical) was dissolved in 50 ml of methylene chloride (MC). Imidazole (2.28 g, 33.6 mmol) and DMAP (0.35 g, 2.88 mmol) were added at room temperature and stirred at room temperature for 30 minutes.
Tert-butyl dimethyl chlorosilane (1.74 g, 11.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 50 ml of water was added to the reaction mixture, stirred for 10 minutes, and then the organic layer was separated. 5 g of NaCl dissolved in 50 ml of water was added to the organic layer, layer separation was performed, and 50 ml of water was further added thereto. After stirring, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 3.4 g (yield: 96%) of the compound of the formula (I-2) in the form of a yellow oil.
1 H NMR (500 MHz, CDCl 3 ):? 0.043 (s, 6H), 0.82 (d, 9H), 1.39 (q, IH), 3.39-3.43 (q, IH), 3.61 (q, IH), 3.85-3.90
Step 2: Preparation of the compound of formula I-3 {(3R, 5S) -tert-butyl 6- (tert-butyldimethylsilyloxy) -3,5-dihydroxyhexanoate}
To a 100 ml 3-neck flask was added the compound of formula I-2 (tert-butyl-2 - ((4R, 6S) -6- (tert- butyldimethylsilyloxy) methyl) -2,2- , 3-dioxan-4-yl) acetate} (1 g, 2.67 mmol) was added, and 10 ml of THF was added and stirred. 7.3 ml (97.7 mmol) of 80% acetic acid was added slowly. The mixture was stirred at room temperature for 12 hours, and saturated NaHCO 3 aqueous solution was added to adjust the pH to 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to obtain 0.76 g (85%) of the compound of the formula I-3 as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.06 (s, 9H), 1.25 (t, 1H), 1.45 (s, 9H), 1.62 (t, 1H), 2.36-2.45 (m, 2H), 3.55 2H), 3.96-4.01 (m, 1H), 4.19-4.24 (m, 1H), 7.37-7.45 (m, 6H), 7.64 (d,
Step 3: To a solution of the compound of formula I-4 {tert-butyl 2 - ((4R, 6S) -6- (tert- butyldimethylsilyloxy) methyl) -2-phenyl-1,3-dioxan- Produce
((3R, 5S) -tert-butyl-6- (tert-butyldimethylsilyloxy) -3,5-dihydroxyhexanoate} (1 g, 2.99 mmol) prepared in Step 2 was dissolved in 10 ml of dichloromethane And 0.54 ml (3.59 mmol) of benzaldehyde dimethylacetal at room temperature. Then, 0.08 g (0.29 mmol) of pyridium p-toluenesulfonate was added at room temperature and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 0.95 g (2.25 mmol) of the compound of formula I-4 (yield: 75%).
1 H NMR (500 MHz, CDCl 3): δ 0.22 (s, 6H), 0.98 (s, 9H), 1.40 (s, 9H), 1.52-1.62 (m, 2H), 2.27-2.44 (m, 2H) , 3.78-4.04 (m, 3H), 4.32-4.42 (m, 1H), 5.98 (s, 1H), 7.32-7.46
Step 4: Preparation of the compound of formula I-5 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2-phenyl-1,3-dioxan-4-
Tert-butyl-2 - ((4R, 6S) -6- (tert-butyldimethylsilyloxy) methyl) -2-phenyl-1,3-dioxan-4-yl) acetate 2 g (4.73 mmol) was dissolved in 10 ml of tetrahydrofuran and 1.24 g (4.73 mmol) of tetrabutylammonium fluoride was added at room temperature and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, 10 ml of 10% sodium carbonate solution was added, and the organic layer was separated. The aqueous layer was extracted three times with 10 ml of dichloromethane. The combined organic layers washed with water 10 ml, and then, separate the organic layer was dried Na 2 SO 4, filtered and then concentrated in the organic solvent under reduced pressure to give compound 1.24 g (85%) of formula I-5.
1 H NMR (500 MHz, CDCl 3): δ 1.40 (s, 9H), 1.48-1.73 (m, 2H), 2.27-2.51 (m, 2H), 3.54-3.87 (m, 3H), 4.33-4.43 ( m, 1H), 5.88 (s, 1H), 7.42-7.56 (m, 5H)
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((4R, 6S) -6-formyl-2-phenyl-1,3-dioxan-4-
After adding 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 to a 100 ml 3-neck flask, 100 ml of methylene chloride (MC) was added and stirred.
5 g of the compound of formula I-5 (tert-butyl-2- (4R, 6S) -6- (hydroxymethyl) -2-phenyl-1,3-dioxan- 16.21 mmol) was dissolved in 20 ml of MC and added thereto.
After cooling the reaction vessel to -15 ° C, 14.3 g (23.05 mmol) of NaOCl aqueous solution (12%) is slowly added. 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 the compound of formula I (4.6 g, 92%) as a brown oil.
1 H NMR (500 MHz, CDCl 3): δ 1.39-1.49 (m, 10H), 1.81-1.85 (m, 1H), 2.32-2.49 (m, 2H), 4.30-4.34 (m, 2H), 5.88 ( s, 1H), 7.42-7.56 (m, 5H)
EXAMPLE 2 Preparation of Intermediate Compounds of Formula I
Step 1: Preparation of compound of formula I-2 {tert-butyl 2 - ((4R, 6S) -6 - ((tert-butyldiphenylsilyloxy) methyl) -2,2-dimethyl-1,3-dioxan- }
The compound of formula I-1 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- dimethyl- 1,3- dioxan- Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), imidazole (0.65 g, 9.6 mmol) and DMAP (0.3 g, 1.15 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
Tert-butyl diphenyl chlorosilane (1.27 g, 4.61 mmol) was added and the mixture was stirred at room temperature for 3 hours. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. To the organic layer was added a solution of 1 g of NaCl in 10 ml of water. The organic layer was separated by layer addition, and then 10 ml of water was added thereto. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 1.8 g (yield: 95%) of a compound of the formula I-2 in the form of a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.14 (s, 6H), 1.47 (d, 9H), 1.51 (d, 6H), 2.25-2.33 (m, 1H), 2.37 (q, 1H), 3.50 (m, 6H), 7.75-7.83 (m, 1H), 3.62 (q, (m, 4H)
Step 2: Preparation of the compound of formula I-3 {(3R, 5S) -tert-butyl 6- (tert-butyldiphenylsilyloxy) -3,5-dihydroxyhexanoate}
Butyl-2 - ((4R, 6S) -6- (tert-butyldiphenylsilyloxy) methyl) -2,2-dimethyl-1 , 3-dioxan-4-yl) acetate} (1 g, 2.00 mmol) was added, and 10 ml of THF was added and stirred. 5 ml of 80% acetic acid was added slowly. Stirred at room temperature for 2 hours and was added to a saturated NaHCO 3 aqueous solution adjusted to pH 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to obtain 0.80 g (87%) of a compound of the formula (I-3) as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 0.98 (s, 9H), 1.42 (s, 9H), 1.52-1.64 (m, 2H), 2.30-2.52 (m, 2H), 3.22-3.31 (m, 1H), 3.83-4.08 (m, 3H), 7.36-7.46 (m, 4H), 7.57-7.68 (m, 6H)
Step 3: To a solution of the compound of formula I-4 {tert-butyl 2 - ((4R, 6S) -6- (tert-butyldiphenylsilyloxy) methyl) -2-phenyl-1,3-dioxan- Produce
Tert-butyl-6- (tert-butyldiphenylsilyloxy) -3,5-dihydroxyhexanoate (1 g, 2.18 mmol) prepared in Step 2 was dissolved in 10 ml of dichloromethane And then 0.36 ml (2.4 mmol) of benzaldehyde dimethylacetal at room temperature. Then, 0.06 g (0.22 mmol) of pyridium p-toluenesulfonate was added at room temperature and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 1.12 g (2.05 mmol) of the compound of formula I-4. (Yield: 94%).
1 H NMR (500 MHz, CDCl 3): δ 0.98 (s, 9H), 1.40 (s, 9H), 1.48-1.60 (m, 2H), 2.30-2.54 (m, 2H), 3.79-4.05 (m, 3H), 4.32-4.42 (m, 1H), 5.98 (s, 1H), 7.26-7.42 (m, 9H), 7.59-7.68
Step 4: Preparation of the compound of formula I-5 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2-phenyl-1,3-dioxan-4-
(Tert-butyl-2 - ((4R, 6S) -6- (tert-butyldiphenylsilyloxy) methyl) -2-phenyl-1,3-dioxan- acetate} (2 g, 3.66 mmol) was dissolved in 10 ml of tetrahydrofuran, 0.96 g (3.66 mmol) of tetrabutylammonium fluoride was added at room temperature, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, 10 ml of 10% sodium carbonate solution was added, and the organic layer was separated. The water layer was extracted three times with 10 ml of dichloromethane. The combined organic layers washed with water 10 ml, and then, separate the organic layer was dried Na 2 SO 4, filtered and then concentrated in the organic solvent under reduced pressure the compound 1.08 g (yield: 96%) of formula I-5 was obtained.
1 H NMR (500 MHz, CDCl 3): δ 1.40 (s, 9H), 1.48-1.73 (m, 2H), 2.27-2.51 (m, 2H), 3.54-3.87 (m, 3H), 4.33-4.43 ( m, 1H), 5.88 (s, 1H), 7.42-7.56 (m, 5H)
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((4R, 6S) -6-formyl-2-phenyl-1,3-dioxan-4-
Step 5 of Example 1 was repeated.
1 H NMR (500 MHz, CDCl 3 ): Same as Step 5 of Example 1
≪ Example 3 > Preparation of intermediate compound of formula (I)
Step 1: Preparation of compound of formula I-2 {tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan-4-
The compound of formula I-1 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- dimethyl-1,3- dioxan- Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), pyridine (0.9 g, 11.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
Acetyl chloride (0.66 g, 8.45 mmol) was added and the mixture was stirred at room temperature for 1 hour. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. After 5 ml of methylene chloride was extracted 2 times, 10 ml of water was added and stirred, and then an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 0.98 g (yield: 86%) of the compound of the formula I-2 in the form of a pale pink crystal.
1 H NMR (500 MHz, CDCl 3): δ 1.26 (q, 1H), 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H), 1.55 (d, 1H), 2.089 (s 2H), 4.27-4.31 (m, IH), 2.32 (q, IH)
Step 2: Preparation of the compound of formula I-3 {(3R, 5S) -tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate}
To a 100 ml 3-neck flask was added tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan- (1 g, 3.31 mmol) was added, and 10 ml of THF was added and stirred. 5 ml of 80% acetic acid was added slowly. Stirred at room temperature for 2 hours and was added to a saturated NaHCO 3 aqueous solution adjusted to pH 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to give 0.90 g (90%) of the compound of formula I-3 as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.41 (s, 9H), 1.53-1.61 (m, 2H), 2.04 (s, 3H), 2.37 (d, 2H), 3.96-4.07 (m, 4H) , 4.19-4.21 (m, 1 H)
Step 3: Preparation of compound of formula I-4 {tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2-phenyl-1,3-dioxan-
(1 g, 3.81 mmol) prepared in Step 2 was dissolved in 10 ml of dichloromethane, and 0.69 ml (4.58 mmol) of (3R, 5S) -tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate mmol) of benzaldehyde dimethylacetal at room temperature, 0.1 g (0.38 mmol) of pyridium p-toluenesulfonate was added at room temperature, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 1.06 g (3.05 mmol) of the compound of formula I-4 (yield: 80%).
1 H NMR (500 MHz, CDCl 3 ):? 1.22-1.48 (m, 10H), 1.73-1.79 (m, 1H), 2.52-2.62 (m, 5H), 4.09-4.43 s, 1 H), 7.32-7.46 (m, 5 H)
Step 4: Preparation of the compound of formula I-5 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2-phenyl-1,3-dioxan-4-
4 g of the compound of formula I-4 (tert-butyl-2- (4R, 6S) -6- (acetoxymethyl) -2-phenyl-1,3-dioxan- 5.71 mmol) was dissolved in 10 ml of methanol, 0.4 g (2.85 mmol) of potassium carbonate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, the crystals are filtered off and the solvent is distilled off under reduced pressure. The organic layer was washed with 10 ml of water, dried over Na 2 SO 4 and filtered. The organic solvent was concentrated under reduced pressure to obtain 1.33 g (76%) of the compound of the formula I-5. .
1 H NMR (500 MHz, CDCl 3): δ 1.40 (s, 9H), 1.48-1.73 (m, 2H), 2.27-2.51 (m, 2H), 3.54-3.87 (m, 3H), 4.33-4.43 ( m, 1H), 5.88 (s, 1H), 7.42-7.56 (m, 5H)
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((4R, 6S) -6-formyl-2-phenyl-1,3-dioxan-4-
Step 5 of Example 1 was repeated.
1 H NMR (500 MHz, CDCl 3 ): Same as Step 5 of Example 1
Example 4 Preparation of Intermediate Compounds of Formula I
Step 1: Preparation of the compound of formula I-2 {((4S, 6R) -6- (2-tert-butoxy-2-oxoethyl) -2,2- dimethyl- 1,3- dioxan- Manufacturing
The compound of formula I-1 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- dimethyl-1,3- dioxan- Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), pyridine (0.9 g, 11.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
Benzoyl chloride (1.19 g, 8.45 mmol) was added and the mixture was stirred at room temperature for 1 hour. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. After 5 ml of methylene chloride was extracted 2 times, 10 ml of water was added and stirred, and then an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 1.23 g (yield: 88%) of the compound of the formula (I-2) in the form of a pale pink crystal.
1 H NMR (500 MHz, CDCl 3): δ 1.26 (q, 1H), 1.38 (s, 3H), 1.42 (s, 9H), 1.48 (s, 3H), 1.54 (d, 1H), 2.08 (s 2H), 4.27-4.31 (m, 1H), 7.38-7.47 (m, 3H), 2.34 (q, ), 7.75-7.83 (m, 2H)
Step 2: Preparation of the compound of formula I-3 {((2S, 4R) -6-tert-butoxy-2,4-dihydroxy-6-oxohexyl benzoate}
To a 100 ml 3-neck flask was added the compound of formula I-2 {((4S, 6R) -6- (2-tert-butoxy-2-oxoethyl) -2,2-dimethyl-1,3-dioxan- ) methyl benzoate} (1 g, 2.74 mmol) was added, and 10 ml of THF was added and stirred. 5 ml of 80% acetic acid was added slowly. Stirred at room temperature for 2 hours and was added to a saturated NaHCO 3 aqueous solution adjusted to pH 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to obtain 0.83 g (93.3%) of the compound of the formula I-3 as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.40 (s, 9H), 1.53-1.63 (m, 2H), 2.30-2.54 (m, 2H), 3.81-3.88 (m, 2H), 4.28-4.53 ( m, 2H), 7.52-7.68 (m, 3H), 7.99-8.06 (m, 2H)
Step 3: Preparation of the compound of formula I-4 {((4S, 6R) -6- (2-tert-butoxy-2-oxoethyl) -2-phenyl-1,3-dioxan-4-yl) methyl benzoate}
1 g (3.08 mmol) of the compound of formula I-3 ({(2S, 4R) -6-tert-butoxy-2,4-dihydroxy-6-oxohexyl benzoate) prepared in step 2 was dissolved in 10 ml of dichloromethane, ml (3.70 mmol) of benzaldehyde dimethylacetal at room temperature, and then 0.08 g (0.30 mmol) of pyridium p-toluenesulfonate was added at room temperature and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 1.08 g (2.25 mmol) of the compound of formula I-4 (yield: 85%).
1 H NMR (500 MHz, CDCl 3 ):? 1.23-1.49 (m, 10H), 1.74-1.78 (m, 1H), 2.53-2.62 (m, 5H), 4.09-4.43 s), 7.32-7.46 (m, 5H), 7.56-7.66 (m, 3H), 8.05 (d, 2H)
Step 4: Preparation of the compound of formula I-5 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2-phenyl-1,3-dioxan-4-
2-oxoethyl) -2-phenyl-1,3-dioxan-4-yl) methyl benzoate}, prepared in step 3, 2 g (4.85 mmol) was dissolved in 10 ml of methanol, 0.34 g (2.42 mmol) of potassium carbonate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, the crystals are filtered off and the solvent is distilled off under reduced pressure. The organic layer was washed with 10 ml of water, dried over Na 2 SO 4 and filtered. The organic solvent was concentrated under reduced pressure to obtain 1.12 g (75%) of the compound of the formula I-5, ≪ / RTI >
1 H NMR (500 MHz, CDCl 3): δ 1.40 (s, 9H), 1.48-1.73 (m, 2H), 2.27-2.51 (m, 2H), 3.54-3.87 (m, 3H), 4.33-4.43 ( m, 1H), 5.88 (s, 1H), 7.42-7.56 (m, 5H)
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((4R, 6S) -6-formyl-2-phenyl-1,3-dioxan-4-
Step 5 of Example 1 was repeated.
1 H NMR (500 MHz, CDCl 3 ): Same as Step 5 of Example 1
EXAMPLE 5 Preparation of Intermediate Compounds of Formula IV
Step 1: Preparation of compound of formula III {tert-butyl 2 - ((4R, 6S) -6- (E) -2- (4- (4-fluorophenyl) -6-isopropyl- 2- (N-methylmethylsulfonamido) pyrimidine -5-yl) vinyl) -2-phenyl-1,3-dioxan-4-yl) acetate}
5 g (7.37 mmol) of [[4- (4-Fluorophenyl) -6- (methylsulfonyl) amino] -5-pyrimidinyl] methyl] triphenylphosphonium bromide in 20 ml of DMSO 3.1 g (22.11 mmol) of K 2 CO 3 was added thereto at 18 ° C, and the mixture was stirred for 1 hour. 1.8 g (5.9 mmol) of the compound of formula I prepared in Example 1 {tert-butyl 2 - ((4R, 6S) -6-formyl- And stirred at 60 < 0 > 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 brine 20 ml, dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was recrystallized from 30 ml of isopropyl alcohol (IPA) to obtain 3.2 g (yield 70%) of the compound of formula III .
1 H NMR (500 MHz, CDCl 3): δ 1.27 (s, 6H), 1.45 (s, 9H), 1.55 (m, 2H), 2.28-2.42 (dd, 2H), 3.38 (hept, 1H), 3.57 , 3.50 (m, 2H), 3.50 (2H, s), 3.50 (2H,
Step 2: To a solution of the compound of formula IV {(3R, 5S, E) -tert-butyl 7- (4- (4- fluorophenyl) -6-isopropyl- 2- (N- methylmethylsulfonamido) pyrimidin- 5-dihydroxyhept-6-enoate}
Compound (III) (13.3 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, and then saturated aqueous sodium hydrogencarbonate solution was added until the pH of the reaction solution became 8-9. The organic layer was separated, and the separated 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) 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) 5.1 g). 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 g (20.18 mmol) of the compound of formula IV (95% yield).
1 H NMR (500 MHz, CDCl 3): δ 1.28 (d, 6H), 1.48 (s, 9H), 1.63-1.72 (m, 2H), 2.02 (m, 2H), 2.28-2.44 (m, 2H) , 3.28 (s, IH), 3.30-3.36 (m, IH), 3.52 (s, 3H), 3.56 ), 5.48 (dd, 1 H), 6.68 (d, 1 H), 7.12
EXAMPLE 6 Preparation of Intermediate Compounds of Formula I
Step 1: Preparation of compound of formula I-2 {tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan-4-
The compound of formula I-1 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- dimethyl-1,3- dioxan- Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), pyridine (0.9 g, 11.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
Acetyl chloride (0.66 g, 8.45 mmol) was added and the mixture was stirred at room temperature for 1 hour. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. After 5 ml of methylene chloride was extracted 2 times, 10 ml of water was added and stirred, and then an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 0.98 g (yield: 86%) of the compound of the formula I-2 in the form of a pale pink crystal.
1 H NMR (500 MHz, CDCl 3): δ 1.26 (q, 1H), 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H), 1.55 (d, 1H), 2.089 (s 2H), 4.27-4.31 (m, IH), 2.32 (q, IH)
Step 2: Preparation of the compound of formula I-3 {(3R, 5S) -tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate}
To a 100 ml 3-neck flask was added tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan- (1 g, 3.31 mmol) was added, and 10 ml of THF was added and stirred. 5 ml of 80% acetic acid was added slowly. Stirred at room temperature for 2 hours and was added to a saturated NaHCO 3 aqueous solution adjusted to pH 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to give 0.90 g (90%) of the compound of formula I-3 as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.41 (s, 9H), 1.53-1.61 (m, 2H), 2.04 (s, 3H), 2.37 (d, 2H), 3.96-4.07 (m, 4H) , 4.19-4.21 (m, 1 H)
Step 3: Preparation of compound of formula I-4 {tert-butyl 2 - ((2R, 4S) -4- (acetoxymethyl) -1,5- dioxaspiro [5.5] undecan-2-yl)
(1 g, 3.81 mmol) prepared in Step 2 was dissolved in 10 ml of dichloromethane, and 0.7 ml (4.58 mmol) of (3R, 5S) -tert- butyl 6-acetoxy-3,5- dihydroxyhexanoate mmol) of 1,1-dimethoxycyclohexane at room temperature. Then, 0.1 g (0.38 mmol) of pyridium p-toluenesulfonate was added at room temperature and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 1.04 g (3.04 mmol) of the compound of formula I-4 (yield: 80%).
1 H NMR (500 MHz, CDCl 3 ):? 1.24 (s, 9H), 1.35-1.43 (m, 4H), 1.52-1.58 (m, 4H), 1.65-1.71 (m, 2H), 2.05 (s, 3H), 2.27-2.34 (m, 2H), 4.09-4.13
Step 4: Preparation of the compound of formula I-5 { tert - butyl 2 - ((2R, 4S) -4- ( hidroxymethyl ) -1,5-dioxaspiro [5.5] undecan-2-yl) acetate}
(Tert-butyl 2 - ((2R, 4S) -4- (acetoxymethyl) -1,5-dioxaspiro [5.5] undecan-2-yl) acetate} prepared in Step 3 mmol) were dissolved in 5 ml of methanol, 0.4 g (2.92 mmol) of potassium carbonate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, the crystals are filtered off and the solvent is distilled off under reduced pressure. The organic layer was washed with 10 ml of water, dried over Na 2 SO 4 and filtered. The organic solvent was concentrated under reduced pressure to obtain 1.42 g (81%) of a compound of the formula I-5, ≪ / RTI >
1 H NMR (500 MHz, CDCl 3 ):? 1.22 (s, 9H), 1.32-1.37 (m, 4H), 1.48-1.52 (m, 4H), 1.61-1.68 2H), 4.70 (m, 2H), 2.22-2.28 (m, 2H), 4.03-4.08
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((2R, 4S) -4-formyl-1,5-dioxaspiro [5.5] undecan-
0.42 g (3.49 mmol) of KBr, 8.06 g (95.9 mmol) of NaHCO 3 and 0.01 g (0.0549 mmol) of TEMPO were added to a 100 ml 3-neck flask and 100 ml of methylene chloride (MC) was added and stirred.
5 g of the compound of formula I-5 (tert-butyl 2 - ((2R, 4S) -4- (hydroxymethyl) -1,5-dioxaspiro [5.5] undecan- 16.65 mmol) was dissolved in 20 ml of MC and added thereto.
The reaction vessel is cooled to -15 ° C and then 12.39 g (19.98 mmol) of NaOCl aqueous solution (12%) is slowly added. 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 the compound of formula I in the form of a brown oil (4.57 g, 92%).
1 H NMR (500 MHz, CDCl 3 ):? 1.23 (s, 9H), 1.33-1.38 (m, 4H), 1.44-1.50 (m, 4H), 1.62-1.68 1H), 9.82 (s, 1H), < RTI ID = 0.0 >
Example 7 Preparation of Intermediate Compound of Formula IV
Step 1: Preparation of compound of formula III {tert-butyl 2 - ((2R, 4S) -4 - ((E) -2- (4- (4-fluorophenyl) -6-isopropyl- 2- (N-methylmethylsulfonamido) pyrimidine -5-yl) vinyl) -1,5-dioxaspiro [5.5] undecan-2-yl) acetate}
5 g (7.37 mmol) of [[4- (4-Fluorophenyl) -6- (methylsulfonyl) amino] -5-pyrimidinyl] methyl] triphenylphosphonium bromide in 20 ml of DMSO 3.1 g (22.11 mmol) of K 2 CO 3 was added thereto at 18 ° C, and the mixture was stirred for 1 hour. 1.76 g (5.9 mmol) of tert-butyl 2 - ((2R, 4S) -4-formyl-1,5-dioxaspiro [5.5] undecan-2-yl) acetate prepared in Example 7 Lt; 0 > 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 brine 20 ml, dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was recrystallized from 30 ml of isopropyl alcohol (IPA) to obtain 2.5 g (yield: 68% .
1 H NMR (500 MHz, CDCl 3): δ 1.27 (s, 6H), 1.45 (s, 9H), 1.58-1.72 (m, 12H), 2.30-2.44 (dd, 2H), 3.40 (hept, 1H) 2H), 7.64 (m, 2H), 7.30 (d, IH)
Step 2: To a solution of the compound of formula IV {(3R, 5S, E) -tert-butyl 7- (4- (4- fluorophenyl) -6-isopropyl- 2- (N- methylmethylsulfonamido) pyrimidin- 5-dihydroxyhept-6-enoate}
Compound (III) (13.1 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, and then saturated aqueous sodium hydrogencarbonate solution was added until the pH of the reaction solution became 8-9. The organic layer was separated, and the separated 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) 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) 5.1 g). 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 g (20.18 mmol) of the compound of formula (IV) (yield 95%).
1 H NMR (500 MHz, CDCl 3): δ 1.28 (d, 6H), 1.48 (s, 9H), 1.63-1.72 (m, 2H), 2.02 (m, 2H), 2.28-2.44 (m, 2H) , 3.28 (s, IH), 3.30-3.36 (m, IH), 3.52 (s, 3H), 3.56 ), 5.48 (dd, 1 H), 6.68 (d, 1 H), 7.12
EXAMPLE 8 Preparation of Intermediate Compounds of Formula I
Step 1: Preparation of compound of formula I-2 {tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan-4-
The compound of formula I-1 {tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2- dimethyl-1,3- dioxan- Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), pyridine (0.9 g, 11.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
Acetyl chloride (0.66 g, 8.45 mmol) was added and the mixture was stirred at room temperature for 1 hour. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. After 5 ml of methylene chloride was extracted 2 times, 10 ml of water was added and stirred, and then an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 0.98 g (yield: 86%) of the compound of the formula I-2 in the form of a pale pink crystal.
1 H NMR (500 MHz, CDCl 3): δ 1.26 (q, 1H), 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H), 1.55 (d, 1H), 2.089 (s 2H), 4.27-4.31 (m, IH), 2.32 (q, IH)
Step 2: Preparation of the compound of formula I-3 {(3R, 5S) -tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate}
To a 100 ml 3-neck flask was added tert-butyl 2 - ((4R, 6S) -6- (acetoxymethyl) -2,2-dimethyl-1,3-dioxan- (1 g, 3.31 mmol) was added, and 10 ml of THF was added and stirred. 5 ml of 80% acetic acid was added slowly. Stirred at room temperature for 2 hours and was added to a saturated NaHCO 3 aqueous solution adjusted to pH 7. After layer separation, the organic layer was washed with 10 ml of water and again with 10 ml of 10% NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered, and the organic solvent was concentrated under reduced pressure to give 0.90 g (90%) of the compound of formula I-3 as a yellow oil.
1 H NMR (500 MHz, CDCl 3): δ 1.41 (s, 9H), 1.53-1.61 (m, 2H), 2.04 (s, 3H), 2.37 (d, 2H), 3.96-4.07 (m, 4H) , 4.19-4.21 (m, 1 H),
Step 3: Preparation of compound of formula I-4 {tert-butyl 2 - ((7R, 9S) -9- (acetoxymethyl) -6,10-dioxaspiro [4.5] decan-
(1 g, 3.81 mmol) prepared in Step 2 was dissolved in 10 ml of dichloromethane, and 0.6 ml (4.58 mmol) of (3R, 5S) -tert-butyl 6-acetoxy-3,5-dihydroxyhexanoate mmol) of 1,1-dimethoxycyclohexane at room temperature. Then, 0.1 g (0.38 mmol) of pyridium p-toluenesulfonate was added at room temperature and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 10 ml of water was added, and the water layer and the organic layer were separated. The organic layer was separated and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 (v / v) To give 1.01 g (3.07 mmol) of the compound of formula I-4 (yield: 80%).
1 H NMR (500 MHz, CDCl 3): δ 1.22 (s, 9H), 1.32-1.36 (m, 4H), 1.48-1.52 (m, 4H), 1.75-1.81 (m, 2H), 2.03 (s, 1H), 4.17-4.21 (m, 2H), 4.75 (m, 2H), 2.24-2.28
Step 4: Preparation of the compound of formula I-5 {tert-butyl 2 - ((7R, 9S) -9- (hydroxymethyl) -6,10-dioxaspiro [4.5] decan-
(Tert-butyl 2 - ((7R, 9S) -9- (acetoxymethyl) -6,10-dioxaspiro [4.5] decan-7-yl) acetate} prepared in Step 3 mmol) were dissolved in 10 ml of methanol, 0.42 g (3.045 mmol) of potassium carbonate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, the crystals are filtered off and the solvent is distilled off under reduced pressure. The organic layer was washed with 10 ml of water, dried over Na 2 SO 4 and filtered. The organic solvent was concentrated under reduced pressure to obtain 1.33 g (76%) of the compound of the formula I-5. .
1 H NMR (500 MHz, CDCl 3 ):? 1.23 (s, 9H), 1.33-1.37 (m, 4H), 1.52-1.56 (m, 4H), 1.74-1.78 m, 2H), 4.01-4.05 (m, 1H), 4.17-4.21 (m, 2H), 4.73
Step 5: Preparation of compound of formula I {tert-butyl 2 - ((7R, 9S) -9-formyl-6,10-dioxaspiro [4.5] decan-
0.44 g (3.67 mmol) of KBr, 8.45 g (100.57 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 and stirred.
(Tert-butyl 2 - ((7R, 9S) -9- (hydroxymethyl) -6,10-dioxaspiro [4.5] decan-7-yl) acetate} prepared in Step 4 mmol) were dissolved in 20 ml of MC and added thereto.
After cooling the reaction vessel to -15 ° C, 13 g (20.95 mmol) of NaOCl aqueous solution (12%) is slowly added. 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 the compound of formula I in the form of a brown oil (4.57 g, 92%).
1 H NMR (500 MHz, CDCl 3 ):? 1.24 (s, 9H), 1.35-1.38 (m, 4H), 1.48-1.52 (m, 4H), 1.72-1.76 (m, 2H), 4.03-4.07 (m, 1H), 4.12-4.16 (m, 2H), 4.71
Example 9 Preparation of Intermediate Compound of Formula IV
Step 1: Preparation of the compound of formula III {tert-butyl 2 - ((7R, 9S) -9 - ((E) -2- (4- (4-fluorophenyl) -6-isopropyl- 2- (N-methylmethylsulfonamido) pyrimidine -5-yl) vinyl) -6,10-dioxaspiro [4.5] decan-7-yl) acetate}
5 g (7.37 mmol) of [[4- (4-Fluorophenyl) -6- (methylsulfonyl) amino] -5-pyrimidinyl] methyl] triphenylphosphonium bromide in 20 ml of DMSO 3.1 g (22.11 mmol) of K 2 CO 3 was added thereto at 18 ° C, and the mixture was stirred for 1 hour. 1.68 g (5.9 mmol) of tert-butyl 2 - ((7R, 9S) -9-formyl-6,10-dioxaspiro [4.5] decan- Lt; 0 > 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 isopropyl alcohol (IPA) (30 ml) to obtain 2.56 g (yield: 72% .
1 H NMR (500 MHz, CDCl 3): δ 1.27 (s, 6H), 1.45 (s, 9H), 1.65-1.92 (m, 10H), 2.32-2.45 (dd, 2H), 3.40 (hept, 1H) 2H), 7.63 (m, 2H), 6.70 (d, 2H), 3.50-3.57 (s, 6H)
Step 2: To a solution of the compound of formula IV {(3R, 5S, E) -tert-butyl 7- (4- (4- fluorophenyl) -6-isopropyl- 2- (N- methylmethylsulfonamido) pyrimidin- 5-dihydroxyhept-6-enoate}
Compound (7) (12.8 g, 21.25 mmol) prepared in Example 5 was dissolved in 33 mL of THF at room temperature, followed by addition of 2N-HCl (21.2 mL). The solution was stirred at room temperature for 1 hour, and then saturated aqueous sodium hydrogencarbonate solution was added until the pH of the reaction solution became 8-9. The organic layer was separated, and the separated 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) 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) 5.1 g). 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 g (20.18 mmol) of the compound of formula (IV) (yield 95%).
1 H NMR (500 MHz, CDCl 3): δ 1.28 (d, 6H), 1.48 (s, 9H), 1.63-1.72 (m, 2H), 2.02 (m, 2H), 2.28-2.44 (m, 2H) , 3.28 (s, IH), 3.30-3.36 (m, IH), 3.52 (s, 3H), 3.56 ), 5.48 (dd, 1 H), 6.68 (d, 1 H), 7.12
≪ Example 10 > Preparation of rosuvastatin hemicalcium salt
The compound of formula IV (17.64 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 off, washed with water (50 ml x 2) and hexane (50 ml x 2) and dried under reduced pressure. The dried solid was suspended in 20 ml of isopropyl alcohol, stirred for 10 hours, filtered, washed with isopropyl alcohol and n-hexane, and then dried under reduced pressure to obtain 14.8 g of rosuvastatin hemi-calcium salt as a white solid (Yield: 94%).
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- 2H), 7.27 (t, 2H), 3.43 (m, 4H), 3.53 (s, , 7.65-7.72 (m, 2H)
Claims (6)
(B) removing the diol protecting group A 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,
A is
(b) removing the diol protecting group of the compound of formula (I-2) to produce a diol compound of formula (I-3);
(c) introducing a diol protecting group A into the compound of Formula I-3 to prepare a compound of Formula 4;
(d) removing the alcohol protecting group of the compound of formula (I-4) to prepare a compound of formula (5); And
(e) oxidizing the compound of formula I-5 to prepare a compound of formula 6;
Lt; RTI ID = 0.0 > (I) < / RTI > comprising:
(I-1)
[Formula I-2]
[Formula I-3]
[Formula I-4]
[Formula I-5]
(I)
In this formula,
A is as defined in claim 1,
R 1 is an alcohol protecting group.
(2) preparing rosuvastatin hemicalcium salt from the compound of formula IV;
≪ RTI ID = 0.0 > rosuvastatin < / RTI >
(IV)
(I)
Wherein A is as defined in claim 1.
(III)
Wherein A is as defined in claim 1.
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Cited By (1)
| 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 |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521471A1 (en) | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
| WO2000049014A1 (en) | 1999-02-17 | 2000-08-24 | Astrazeneca Ab | Process for the production of tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate |
| WO2003016317A1 (en) | 2001-08-16 | 2003-02-27 | Teva Pharmaceutical Industries Ltd. | Processes for preparing calcium salt forms of statins |
| WO2006067456A2 (en) | 2004-12-24 | 2006-06-29 | Astrazeneca Uk Limited | Process for preparing rosuvastatin |
| WO2006091771A2 (en) | 2005-02-22 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Preparation of rosuvastatin |
| WO2006106526A1 (en) | 2005-04-04 | 2006-10-12 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| WO2007007119A1 (en) | 2005-07-08 | 2007-01-18 | Astrazeneca Uk Limited | Processes for the manufacture of rosuvastatin and intermediates |
| WO2007039287A1 (en) | 2005-10-05 | 2007-04-12 | Lek Pharmaceuticals D.D. | PROCESS FOR THE SYNTHESIS OF HMG-CoA REDUCTASE INHIBITORS |
| WO2007125547A2 (en) | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| WO2008053334A2 (en) | 2006-10-31 | 2008-05-08 | Aurobindo Pharma Limited | An improved process for preparing rosuvastatin calcium |
-
2015
- 2015-04-24 KR KR1020150058121A patent/KR20160126700A/en unknown
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521471A1 (en) | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
| WO2000049014A1 (en) | 1999-02-17 | 2000-08-24 | Astrazeneca Ab | Process for the production of tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate |
| WO2003016317A1 (en) | 2001-08-16 | 2003-02-27 | Teva Pharmaceutical Industries Ltd. | Processes for preparing calcium salt forms of statins |
| WO2006067456A2 (en) | 2004-12-24 | 2006-06-29 | Astrazeneca Uk Limited | Process for preparing rosuvastatin |
| WO2006091771A2 (en) | 2005-02-22 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Preparation of rosuvastatin |
| WO2006106526A1 (en) | 2005-04-04 | 2006-10-12 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| WO2007007119A1 (en) | 2005-07-08 | 2007-01-18 | Astrazeneca Uk Limited | Processes for the manufacture of rosuvastatin and intermediates |
| WO2007039287A1 (en) | 2005-10-05 | 2007-04-12 | Lek Pharmaceuticals D.D. | PROCESS FOR THE SYNTHESIS OF HMG-CoA REDUCTASE INHIBITORS |
| WO2007125547A2 (en) | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| WO2008053334A2 (en) | 2006-10-31 | 2008-05-08 | Aurobindo Pharma Limited | An improved process for preparing rosuvastatin calcium |
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 |
| US11970482B2 (en) | 2018-01-09 | 2024-04-30 | Ligand Pharmaceuticals Inc. | Acetal compounds and therapeutic uses thereof |
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