[go: up one dir, main page]

WO2013183800A1 - 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation - Google Patents

2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation Download PDF

Info

Publication number
WO2013183800A1
WO2013183800A1 PCT/KR2012/004518 KR2012004518W WO2013183800A1 WO 2013183800 A1 WO2013183800 A1 WO 2013183800A1 KR 2012004518 W KR2012004518 W KR 2012004518W WO 2013183800 A1 WO2013183800 A1 WO 2013183800A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl
butyl
acetate
crystalline
dioxan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2012/004518
Other languages
English (en)
Korean (ko)
Inventor
박장하
황성관
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MIRAE FINE CHEMICAL CO Ltd
Original Assignee
MIRAE FINE CHEMICAL CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MIRAE FINE CHEMICAL CO Ltd filed Critical MIRAE FINE CHEMICAL CO Ltd
Priority to PCT/KR2012/004518 priority Critical patent/WO2013183800A1/fr
Priority to JP2015515921A priority patent/JP6041985B2/ja
Priority to CN201280075132.XA priority patent/CN104520294B/zh
Publication of WO2013183800A1 publication Critical patent/WO2013183800A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate, which is a useful intermediate used to prepare statin-based hyperlipidemia therapeutics. It is about.
  • t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate is atorvastatin, fluvastatin, rosuvastatin (Rosuvastatin), Pitavastatin (Pitavastatin) is a useful intermediate used in the manufacture of statin-based hyperlipidemia therapeutics, and has a structure as shown in the following [Formula 1].
  • US 2006/0004200 A1 describes only the use of TEMPO as a catalyst, and does not describe the amount of sodium hypochlorite used.
  • the yield and purity of the product vary depending on the amount of sodium hypochlorite and the method / administration rate. It is not mentioned at all.
  • t-butyl 2-[(4R, 6S) -6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl] Acetate (in Scheme 1, compound A) was prepared by TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), potassium bromide (KBr), sodium bicarbonate (NaHCO 3 ) and sodium hypochlorite (NaOCl) ( Reacted with 0.78 molar equivalents to Compound A) to prepare t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate in syrup form.
  • Example 5 of WO 2010/023678 A1 describes a high yield, but the inventors have actually reproduced this method and analyzed the obtained product by GC (gas column chromatography). It was confirmed that the starting material Compound A contained about 30 w / w% or more.
  • t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate preparation method is a starting material (compound A)
  • t -Butyl 2-[(4R, 6S) -6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate is a process for preparing a mixture in which an excess is mixed.
  • High purity crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate has not been disclosed.
  • the present invention facilitates the handling of t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate, a useful intermediate of statin hyperlipidemia
  • the purpose is to provide a crystalline form with excellent storage stability.
  • the present invention provides crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane-4 which is used to obtain the product of the subsequent reaction in high purity and high yield. Its purpose is to provide generic acetate.
  • the present invention also provides a process for preparing crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate with high purity and high yield.
  • the purpose is to provide.
  • the present invention provides crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate.
  • Crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate of the present invention is an X-ray powder using Cu-K ⁇ radiation. Diffraction spectral peaks are shown at 9.0 ⁇ 0.2, 13.6 ⁇ 0.2, 14.5 ⁇ 0.2, 16.7 ⁇ 0.2 and 17.0 ⁇ 0.2 at 2 ⁇ .
  • the crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate of the present invention is X using Cu-K ⁇ radiation.
  • the -ray powder diffraction spectral peaks are shown at 9.0 ⁇ 0.1, 13.6 ⁇ 0.1, 14.5 ⁇ 0.1, 16.7 ⁇ 0.1 and 17.0 ⁇ 0.1 at 2 ⁇ .
  • the crystalline forms of the present invention have X-ray powder diffraction spectral peaks using Cu-K ⁇ radiation of 8.48 ⁇ 0.2, 9.0 ⁇ 0.2, 13.6 ⁇ 0.2, 14.5 ⁇ 0.2, 16.7 ⁇ 0.2 and 17.0 ⁇ 0.2, 18.5 ⁇ at 2 ⁇ . 0.2, 20.8 ⁇ 0.2, 21.8 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • Crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate of the present invention has a temperature increase rate of 1 ° C / min and purity of 98.9. %, It has a differential scanning calorimetry (DSC) endothermic transition at about 58.9 ° C.
  • the DSC endothermic transition value may vary depending on the purity of the crystalline form of the present invention, for example, may have a value within the range of 57.5 to 59.5 °C. This value may also depend on the rate of temperature rise of the instrument for measuring the DSC endothermic transition value.
  • the present invention also provides a process for preparing crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate comprising the following steps: :
  • the organic solvent is at least one solvent selected from methylene chloride or chloroform, and methylene chloride is more preferred.
  • the amount of tempo (TEMPO) is used in t-butyl 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxane 0.00yl to 0.020 molar equivalents relative to mole of -4-yl] acetate are preferred, and more preferably about 0.0034 molar equivalents.
  • the amount of potassium bromide or iodine bromide is t-butyl 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-di It is preferably 0.1 to 0.5 molar equivalents, and preferably about 0.21 molar equivalents, relative to moles of oxan-4-yl] acetate.
  • the amount of sodium bicarbonate or sodium hydrogen phosphate is t-butyl 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3 It is preferably 2 to 7 molar equivalents, and preferably 5.76 molar equivalents, relative to the moles of -dioxan-4-yl] acetate.
  • a mixed solution obtained by dissolving tempo, potassium bromide or iodine bromide, sodium hydrogen carbonate or sodium hydrogen phosphate in an organic solvent is first put into a reaction vessel and stirred, and then t-butyl dissolved in an organic solvent.
  • a solution of 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate can be added to the mixed solution, but in this order
  • the present invention is not limited thereto.
  • a mixed solution obtained by dissolving tempo, potassium bromide or iodine bromide, sodium hydrogen carbonate or sodium hydrogen phosphate in an organic solvent is first put into a reaction vessel and stirred, followed by t-butyl 2 in an organic solvent. It is preferable to add a solution of [[4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate to the mixed solution. Moreover, -10-5 degreeC is preferable and, as for mixing temperature, 0-5 degreeC is more preferable.
  • sodium hypochlorite may be added to an aqueous sodium hypochlorite solution.
  • the sodium hypochlorite aqueous solution may be prepared by a known method or commercially available, and the content of sodium hypochlorite is 9 w / w%, 10 w / w%, 11 w / w%, 12 w / w%, 13 w / w%, 14 w / w% and the like.
  • An aqueous sodium hypochlorite solution having a sodium hypochlorite content of 10 w / w% or more is preferred, the higher aqueous sodium hypochlorite solution is better, and the more preferable 14 w / w% sodium hypochlorite aqueous solution.
  • the temperature of adding sodium hypochlorite to the reaction solution is preferably -30 to -15 °C.
  • the stirring temperature is preferably -10 to 0 °C.
  • sodium hypochlorite is preferably added quickly at one time.
  • the reaction time is preferably 50 minutes to 1 hour 30 minutes to obtain high yield and high purity of the product.
  • GC gas column chromatography
  • sodium thiosulfate solution may be used in various concentrations of sodium thiosulfate solution, but 10 w / w% sodium thiosulfate solution thiosulfate solution).
  • a conventional work-up method may be added to the organic layer separated in the third step of the manufacturing method of the present invention.
  • a saturated sodium chloride solution is added to the organic layer separated in the third step, the organic layer is washed, the organic layer is separated, and the organic layer may be dried with a desiccant.
  • the desiccant is preferably anhydrous magnesium sulfate. More specifically, the organic layer separated in the third step (brine) after adding saturated sodium chloride solution to a separatory funnel, etc.
  • a work-up step may be used to remove moisture from the organic layer using a desiccant such as anhydrous magnesium sulfate.
  • the process of distilling the organic solvent under reduced pressure is carried out by a method commonly used in organic synthesis.
  • it can be distilled under reduced pressure using a machine such as a rotary evaporator.
  • vacuum vacuum drying may be dried at a reduced pressure of 3 to 6 cmHg for 5 minutes to 1 hour at 60 to 80 °C.
  • the drying time of the fifth step of the manufacturing method of the present invention is preferably 5 minutes to 1 hour, more preferably 10 minutes to 30 minutes.
  • the present invention also provides a method for purifying crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate comprising the following steps. :
  • the purification solvent is preferably selected from the group consisting of C1 to C10 alkane compounds or C3 to C10 cycloalkane compounds, more preferably using n-heptane.
  • the purification method of the present invention may further include the step of vacuum drying the crystal filtrate obtained in the seventh step.
  • the vacuum reduced-pressure drying is preferably reduced to 0 ⁇ 2 cmHg to dry for 10 minutes to 5 hours at 15 ⁇ 30 °C, but is not limited thereto.
  • crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate of the present invention is a crystal, it is easier to handle than an oil state, It has an excellent effect on storage stability.
  • the preparation method of the present invention provides crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate in high purity and high yield. And, there is an effect that does not require a separate purification process.
  • Example 1 is an X-ray powder diffraction of crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate produced in Example 1 The spectral graph is shown.
  • FIG. 2 is an X-ray powder diffraction of crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate produced in Example 1 Show spectral data.
  • FIG. 3 shows the DSC graph of the crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate produced in Example 1.
  • FIG. 3 shows the DSC graph of the crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate produced in Example 1.
  • Example 4 shows crystalline t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate and US 2006/0004200 A1 produced in Example 1; It is a photograph comparing the properties of t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate of Example 1.
  • Measurement method Ascending rate per minute after rising to 40 ° C: measured at 5 ° C / Min.
  • step A 100 ml was added and the organic layer was separated. 100 ml of saturated sodium chloride solution was added to the organic layer, and the organic layer was separated again. 150 ml of water was added to the organic layer, the mixture was stirred for 10 minutes, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the organic solvent methylene chloride was distilled under reduced pressure for 10 minutes at 3 cmHg at 40 ° C. 1 was obtained (step A).
  • step B The residue 1 was concentrated under reduced pressure in a vacuum dryer to 3 cmHg and dried at 80 ° C. for 30 minutes without additional humidity to obtain the title compound as light brown crystals (step B).
  • the X-RD graph of the product is shown in Figure 1, the value is shown in Figure 2.
  • the DSC value of the product is shown in Figure 3).
  • the reaction mixture was filtered under reduced pressure, and a solution of sodium thiosulfate solution 10 w / w% (10 w / w 100 ml of% sodium thiosulfate solution) was added and the organic layer was separated. 100 ml of saturated sodium chloride solution was added to the organic layer, and the organic layer was separated again. 150 ml of water was added to the organic layer, the mixture was stirred for 10 minutes, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the organic solvent methylene chloride was distilled under reduced pressure for 10 minutes at 3 cmHg at 40 ° C. 1 was obtained (step A).
  • Concentrated residue 1 was adjusted to 3 cmHg under reduced pressure in a vacuum dryer and dried at 80 ° C. for 30 minutes without additional humidity control to obtain concentrated residue 2.
  • the concentrated residue 2 was then vacuum dried under reduced pressure again at room temperature, that is, the pressure in the dryer was adjusted to 1 cmHg, and dried at room temperature for 3 hours without additional humidity control to obtain the title compound as light brown crystals (step B). ).
  • the X-RD graph of the product is shown in FIG. 1, and the value is shown in FIG. 2).
  • the reaction mixture was filtered under reduced pressure, and a solution of sodium thiosulfate 10 w / w% (10 w / 80% w% sodium thiosulfate solution) was added and the organic layer was separated.
  • 80 L of saturated sodium chloride solution was added to the organic layer, and the organic layer was separated again.
  • 100 L of water was added to the organic layer, the mixture was stirred for 20 minutes, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the organic solvent methylene chloride was distilled under reduced pressure at 40 ° C. and 3 cmHg for 3 hours to concentrate in an oily glass.
  • Object 1 was obtained (step A).
  • Concentrated residue 1 was adjusted to 3 cmHg under reduced pressure in a vacuum dryer and dried at 80 ° C. for 30 minutes without additional humidity control to obtain concentrated residue 2.
  • Concentrated residue 1 was adjusted to 3 cmHg under reduced pressure in a vacuum dryer and dried at 80 ° C. for 30 minutes without additional humidity control to obtain concentrated residue 2.
  • the crystal filtrate was then dried again under reduced pressure at room temperature under vacuum, that is, the pressure in the dryer was adjusted to 1 cmHg and dried at room temperature for 3 hours without additional humidity control to obtain the title compound as white crystals (X-RD of the product).
  • the graph is shown in FIG. 1, and the value is shown in FIG. 2.
  • Example 1 Except that the sodium hypochlorite solution used in Example 1 was used in molar equivalents as described in Table 1 below, only the concentration of Residue 1 was prepared by performing step A of the method described in Example 1 only. The results are shown in Table 1. However, the results of using 1.2 mol equivalents and 1.3 mol equivalents of NaOCl in the following [Table 1] refer to the yield and purity after obtaining the product in crystalline form by performing both Example 1 and Example 2 to step B, "Expected yield value" means "actual yield.”
  • Example 1 The yield is that in Example 1, the amount of the concentrated residue 1 is all t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate Is based on the molar equivalent of t-butyl 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan-4-yl] acetate Yield value,
  • the target compound is t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane-4 It can be seen that the purity of the -yl] acetate and the yield of the concentrated residue 1 vary greatly. In other words, as the excess amount of sodium hypochlorite solution was used, the yield of Concentrated Residue 1 containing the target compound was greatly decreased. When the sodium hypochlorite solution was used less, a large amount of starting material was difficult to be separated from the target compound. The purity of the desired compound was very low.
  • the amount of sodium hypochlorite solution used was t-butyl 2-[(4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxane-4- as a starting material.
  • T-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxane-4- which is the desired compound when the amount is from 1.2 to 1.3 molar equivalents relative to the mole of general acetate; It is confirmed that the purity of the general acetate is at least 95% and that the total yield can also be obtained at least 80%.
  • Example 1 the method of administering the aqueous sodium hypochlorite solution was not added at once as described in Example 1, but was divided into three portions and slowly added for 30 minutes. The same procedure was followed until step A to obtain concentrated residue 1.
  • the yield of the concentrated residue 1 was 84%, and as a result of confirming the concentrated residue 1 by GC, the target compound was t-butyl 2-[(4R, 6S) -6-formyl- relative to the total weight of the concentrated residue.
  • 2,2-dimethyl-1,3-dioxan-4-yl] acetate contained 92% by weight and the starting material contained 6% by weight.
  • Figure 4 is a photograph comparing the properties of the crystal form of Example 1 of the present invention and the material of Example 1 US 2006 / 0004200A1.
  • inventive example 1 was obtained with crystals, while in US 2006 / 0004200A1 example 1 no crystals were obtained and an oil phase was obtained.
  • Example 1 of the present invention t-Butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate has a highly reactive aldehyde functional group, so storage stability is a problem. Therefore, the storage stability of the crystal form of Example 1 of the present invention and the US 2006/0004200 A1 Example 1 was compared for about 12 months at room temperature, and the results are shown in the following [Table 2].
  • the aldehyde compound obtained by the preparation method of US 2006/0004200 A1 is always stored as an oil rather than a crystal due to the presence of a starting alcohol compound (about 30% as a result of GC verification), and thus the purity change is very large as described above. Therefore, it is difficult to handle at room temperature, and in particular, it is quite difficult to store and transport in hot summer.
  • t-butyl 2-[(4R, 6S) -6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate is an intermediate used in the preparation of a statin-based hyperlipidemia therapeutic agent Compare the crystalline form of Example 1 with the effect on subsequent reactions using US 2006/0004200 A1 Example 1 material as intermediate.
  • the final material pitavastatin hemicalcium salt (V compound)
  • V compound pitavastatin hemicalcium salt
  • the crystalline form of the present invention a material having a purity of 100% was obtained, but US 2006/0004200 When the oil phase of A1 was used, impurities exceeding 0.1% were detected and found to be unsuitable as products. In addition, it was confirmed that the present invention is superior in terms of yield than US 2006/0004200 A1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/KR2012/004518 2012-06-08 2012-06-08 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation Ceased WO2013183800A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/KR2012/004518 WO2013183800A1 (fr) 2012-06-08 2012-06-08 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation
JP2015515921A JP6041985B2 (ja) 2012-06-08 2012-06-08 結晶型ｔ−ブチル２−［（４Ｒ，６Ｓ）−６−ホルミル−２，２−ジメチル−１，３−ジオキサン−４−イル］アセテート及びその製造方法
CN201280075132.XA CN104520294B (zh) 2012-06-08 2012-06-08 结晶2‑[(4r,6s)‑6‑甲酰基‑2,2‑二甲基‑1,3‑二噁烷‑4‑基]乙酸叔丁酯及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2012/004518 WO2013183800A1 (fr) 2012-06-08 2012-06-08 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation

Publications (1)

Publication Number Publication Date
WO2013183800A1 true WO2013183800A1 (fr) 2013-12-12

Family

ID=49712179

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2012/004518 Ceased WO2013183800A1 (fr) 2012-06-08 2012-06-08 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation

Country Status (3)

Country Link
JP (1) JP6041985B2 (fr)
CN (1) CN104520294B (fr)
WO (1) WO2013183800A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503816B (zh) * 2016-02-17 2018-02-13 中节能万润股份有限公司 一种固体(4R‑cis)‑6‑甲酰基‑2,2‑二甲基‑1,3‑二氧己环‑4‑乙酸叔丁酯的制备方法
CN109456300B (zh) * 2018-08-21 2021-07-06 南京欧信医药技术有限公司 瑞舒伐他汀钙中间体的制备方法
CN111518073B (zh) * 2019-02-01 2022-09-16 鲁南制药集团股份有限公司 一种瑞舒伐他汀侧链中间体的制备方法
CN111471034A (zh) * 2020-03-18 2020-07-31 南京欧信医药技术有限公司 连续流微通道反应器中氧化制备瑞舒伐他汀侧链的方法
CN115611848A (zh) * 2022-09-27 2023-01-17 江苏阿尔法药业股份有限公司 一种瑞舒伐他汀钙中间体的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7161004B2 (en) * 2004-06-21 2007-01-09 Dr. Reddy's Laboratories Limited Processes to produce intermediates for rosuvastatin
KR20100052230A (ko) * 2008-11-10 2010-05-19 미래파인켐 주식회사 피타바스타틴 중간체의 제조방법 및 이를 이용한 피타바스타틴 헤미 칼슘염의 제조방법

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020028826A1 (en) * 2000-06-15 2002-03-07 Robl Jeffrey A. HMG-CoA reductase inhibitors and method
CN100429212C (zh) * 2006-06-30 2008-10-29 浙江东港药业有限公司 一种(4R-cis)-6-甲酰基-2,2-二甲基-1,3-二氧己环-4-乙酸叔丁酯的合成方法
WO2010023678A1 (fr) * 2008-08-27 2010-03-04 Biocon Limited Procédé de préparation d'intermédiaire de rosuvastatine
US8987444B2 (en) * 2010-01-18 2015-03-24 Msn Laboratories Private Limited Process for the preparation of amide intermediates and their use thereof
WO2012153950A2 (fr) * 2011-05-06 2012-11-15 웰이앤씨 주식회사 Procédé de préparation d'acétate de 2-((4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxan-4-yle) et de t-butyle
CN102617540A (zh) * 2012-04-19 2012-08-01 江苏施美康药业有限公司 (s)-3，6-二氧代-5，6-亚异丙基-5，6-二羟基己酸叔丁酯的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7161004B2 (en) * 2004-06-21 2007-01-09 Dr. Reddy's Laboratories Limited Processes to produce intermediates for rosuvastatin
KR20100052230A (ko) * 2008-11-10 2010-05-19 미래파인켐 주식회사 피타바스타틴 중간체의 제조방법 및 이를 이용한 피타바스타틴 헤미 칼슘염의 제조방법

Also Published As

Publication number Publication date
CN104520294B (zh) 2017-04-26
JP2015518881A (ja) 2015-07-06
JP6041985B2 (ja) 2016-12-14
CN104520294A (zh) 2015-04-15

Similar Documents

Publication Publication Date Title
JP6013326B2 (ja) キラルトリアゾロンの調製のための方法
JP6799037B2 (ja) 化学的方法
JPH01305076A (ja) タキソールを調製する方法
HUE026357T2 (en) Process for the preparation of a 1-triazole-2-butanol derivative
WO2013183800A1 (fr) 2-[(4r,6s)-6-formyl-2,2-diméthyl-1,3-dioxane-4-yl]acétate de t-butyle cristallin et son procédé de préparation
EP3386945A1 (fr) Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation
JP2012136544A (ja) ドセタキセルの製造方法及び医薬
EP3305769A1 (fr) Procédé de préparation de (7-phénoxy-4-hydroxy-1-méthyl-isoquinoléine-3-carbonyl)-glycine (roxadustat) et ses intermédiaires sur la base de l'ouverture simultanée du cycle oxazolique, de la fission d'éther et de la création d'imine
CA3030551A1 (fr) Procedes de preparation de 4-alcoxy-3-(acyl ou alkyl)oxypicolinamides
WO2011004980A2 (fr) Procédé de préparation de dérivés tricycliques
EP0473225A2 (fr) Procédé pour l'iodation ou la bromation de l'atome de carbone alpha méthylénique d'une amide secondaire
WO2022232949A1 (fr) Procédés de préparation des énantiomères de la 3,4-méthylènedioxyméthamphétamine (mdma) et de la n-méthyl-1,3-benzodioxolylbutanamine (mbdb)
JP5585822B2 (ja) 光学活性ニペコチン酸誘導体の製造方法
AU7445500A (en) Process for the preparation of a piperazine derivative
CZ2000804A3 (cs) Způsob výroby proteázového inhibitoru
EP3986400B1 (fr) Procédés et intermédiaires pour la production de composés de diazaspiro-lactame
EP2411392A2 (fr) Nouvelles formes cristallisées de l'adéfovir dipivoxil et leurs procédés de préparation
Paternotte et al. Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation
KR101175488B1 (ko) 결정형 ｔ-부틸 2-（（4Ｒ，6Ｓ）-6-포밀-2，2-디메틸-1，3-디옥산-4-일)아세테이트 및 이의 제조 방법
KR100995882B1 (ko) 피타바스타틴 또는 그의 염의 중간체의 제조방법
WO2011105649A1 (fr) Nouveau procédé de fabrication de la pitavastatine hémicalcium utilisant un nouvel intermédiaire
WO2017090991A1 (fr) Procédé de purification de dérivé de benzopyrane, forme cristalline correspondante et procédé de préparation de la forme cristalline
US4987231A (en) Optical resolution method for 3R-(3-carboxybenzyl)-6-(5-fluoro-2-benzothiazolyl)methoxy-4R-chromanol
HU186974B (en) Process for the preparation of 3a,7a-trans-4-bracket-7,7-ethylendioxy-3-oxo-octyl-bracket closed-7abeta-methyl-perhydro-indan-1,5-dione
HU228820B1 (en) Process for the preparation of distrontium ranelate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12878392

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2015515921

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12878392

Country of ref document: EP

Kind code of ref document: A1