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Method for synthesizing vitamin d analogues

A compound and general formula technology, applied in the field of synthesis of vitamin D2 analogues by photolysis and Wittig chemistry, can solve problems such as poor double bond formation selectivity

Inactive Publication Date: 2011-11-30
CYCTOCHROMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preparation of vitamin D known in the prior art 2 The synthetic route to and its analogs has poor selectivity for double bond formation and requires multiple purifications to provide products of suitable purity

Method used

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  • Method for synthesizing vitamin d analogues
  • Method for synthesizing vitamin d analogues
  • Method for synthesizing vitamin d analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1-cis alcohol intermediate 2

[0041]

[0042] The starting material trans alcohol 1 (6 g; 10.434 mmol) was placed in 9-acetylanthracene (0.597 g; 2.710 mmol), freshly distilled triethylamine (0.015 mL; 0.103 mmol) and 300 mL of toluene. in the flask. The resulting mixture was cooled to between about -1.7°C and 6°C and stirred under argon. The mixture was then exposed to light from a UV lamp inserted into a uranium filter glass tube. Aliquots of 100 μL were taken at 30 min, 45 min and 60 min intervals and analyzed for completeness by HPLC. The results shown in Table 1 below indicated that the reaction was complete within 30 minutes.

[0043] Table 1

[0044] point in time

[0045] Subsequently, the reaction mixture was transferred to a flask and evaporated under vacuum at 35°C. The residue was dissolved in dichloromethane (CH 2 Cl 2 ), loaded into a silica gel cartridge (cartridge), and washed with 0-15% diethyl ether (...

Embodiment 2

[0046] Embodiment 2: the preparation of aldehyde 3

[0047]

[0048] The cis-alcohol 2 was oxidized to the aldehyde with a sulfur trioxide pyridine complex as described in the literature (see Tojo and Fernandez, Oxidation of Alcohols to Aldehydes and Ketones, Springer (2006)). In 10 mL of freshly distilled triethylamine, 34 mL of CH 2 Cl 2 In the presence of 68 mL of dimethyl sulfoxide (DMSO), the cis-alcohol 2 (6.8 g, 11.82 mmol) was mixed with SO 3 • Py (9.4 g; 59.12 mmol) reacted. This reaction provided a quantitative yield of aldehyde 3.

Embodiment 3

[0049] Example 3: Cis Vitamin D 2 Preparation of Intermediate 5

[0050]

[0051] Phosphine oxide 4 (5.8 g, 13.92 mmol) in 75 mL dry tetrahydrofuran (THF) was cooled to about -78 °C in a dry ice / acetone bath under argon. After cooling for 10 minutes, butyllithium (11.14 mL, 27.84 mmol, 2.5M in hexanes) was slowly added via syringe. The resulting mixture was stirred at about -78°C for 45 minutes. Aldehyde 3 dissolved in 40 mL of anhydrous THF was then added to this mixture via syringe. The resulting mixture was stirred at -78°C for 45 minutes, then allowed to warm to about 0°C over 45 minutes to 1.5 hours. The reaction was then stopped, and 200 mL of ethyl acetate was added to the mixture, which was then washed with brine and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The thick syrupy concentrate was dissolved in 200 mL of anhydrous THF and cooled to about -12°C in an ice-salt bath. To the cooled solution was added potassiu...

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Abstract

The present invention discloses methods for preparing vitamin D2 derivatives and intermediates of vitamin D2 derivatives. The present invention discloses an improved photolysis process for the preparation of cis intermediates (I) from trans starting materials (II). Also disclosed is an improved method for the formation of a trans double bond at C22-C23 of a vitamin D2 derivative, which has a negative effect on the desired cis double bond of compound (IIIA) relative to the undesired cis double bond of compound (IIIA). The trans double bond provides high selectivity.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority under 35 U.S.C. §119(e) of US Provisional Application 61 / 118,030, filed November 26, 2008, the disclosure of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention generally relates to methods for preparing vitamin D precursors and analogs. More specifically, the present invention relates to methods for the synthesis of vitamin D2 analogs using photolysis and Wittig chemistry. Background technique [0004] Vitamin D analogs are known to be pharmaceutically active and used in the treatment of various conditions such as psoriasis and neoplastic diseases. Preparation of vitamin D known in the prior art 2 The synthetic route to and its analogs has poor selectivity for double bond formation and requires multiple purifications to provide products of suitable purity. See, eg, Coutts et al., Org. Proc. Res. Dev., 6(3):246-255 ...

Claims

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Application Information

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IPC IPC(8): C07F9/53C07C401/00C07F7/18
CPCC07C401/00C07F7/188
Inventor 乌达·萨哈
Owner CYCTOCHROMA INC
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