Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester

A technology of n-octylphenyl and dioxane, applied in the field of pharmacy, can solve the problems of cumbersome steps, high price, difficult to obtain and the like, and achieves the effects of mild reaction conditions, low production cost and convenient post-processing

Inactive Publication Date: 2013-01-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Kim et al. (Synthesis, 2006, 5, 753-755) reported a preparation method of a compound of formula I, using 4-n-octyl iodide benzene as a raw material, which has a higher price and is not easy to obtain; the method also uses cost High azide, and dangerous; in addition, the production cost of the palladium-catalyzed cross-coupling reaction used is high, not suitable for large-scale production
(Synlett, 2007, 18, 2841-2846) reported the preparation method of formula I compound, its step is loaded down with trivial details, and adopts highly toxic carbon tetrachloride to make solvent, and total yield is not high, thus also not suitable for industrialization Production

Method used

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  • Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester
  • Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester
  • Preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Synthesis of methyl 4-n-octylbenzoate

[0042] Preparation of Grignard reagent: under nitrogen protection, add 1,2-dibromoethane (0.3mL, 3.6mmol) to a closed three-necked flask containing magnesium chips (1.728g, 72.0mmol) and tetrahydrofuran (20mL) to initiate. After the initiation started, a solution of 1-bromo-n-octane (11.58g, 60mmol) in tetrahydrofuran (100mL) was added dropwise to the reaction flask, and the dropping rate was controlled to maintain the slight boiling of the reaction solution. After stirring vigorously at room temperature for about 30 minutes, , the magnesium chips are greatly reduced, and cooled to room temperature for later use.

[0043] Cross-coupling reaction: while Grignard reagent was being prepared, methyl p-chlorobenzoate (8.5295 g, 50 mmol), iron acetylacetonate (950 mg, 2.69 mmol, 5.4%) were dissolved in tetrahydrofuran (300 mL) and N-methyl In a mixed solvent of pyrrolidone (16 mL), the mixture was stirred under ice-cooling. Under the...

Embodiment 2

[0045] Synthesis of 4-n-octylbenzyl alcohol

[0046]Add methyl 4-n-octylbenzoate (3.1 g, 12.5 mmol), anhydrous lithium chloride (2.1 g, 50 mmol), sodium borohydride (1.89 g, 50 mmol) to ethylene glycol dimethyl ether (80 mL) In, reflux reaction for 6 hours. The reaction solution was quenched with 1M hydrochloric acid, adjusted to near neutral pH, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution (25mL) and saturated brine (30mL×3), and dried over anhydrous sodium sulfate. , and concentrated under reduced pressure to obtain 2.62 g of a colorless oil, with a yield of 95%. 1 HNMR (300MHz, CDCl 3 ): δ0.87(t, J=6.7Hz, 3H), 1.19-1.42(br d, J=8.4Hz, 10H), 1.58(t, J=7.4Hz, 2H), 1.87(s, 1H), 2.59(t, J=7.7Hz, 2H), 4.61(s, 2H), 7.15(d, J=7.8Hz, 2H), 7.25(d, J=7.9Hz, 2H).

Embodiment 3

[0048] Synthesis of 4-n-octylbenzyl bromide

[0049] Dissolve 4-n-octylbenzyl alcohol (2.2g, 10mmol) in dichloromethane (40mL), add phosphorus tribromide (0.9g, 3.33mmol) dropwise, stir at room temperature for 30 minutes, then quench the reaction with ice water , and then extracted with dichloromethane, the organic layer was washed successively with saturated sodium bicarbonate solution (20mL×3) and saturated brine (30mL×3), dried over anhydrous sodium sulfate, and concentrated under pressure to obtain 2.60g of light yellow oil, Yield 92%. 1 H NMR (300MHz, CDCl 3 ): δ0.87(t, J=6.5Hz, 3H), 1.19-1.42(br d, J=9.5Hz, 10H), 1.59(t, J=7.4Hz, 2H), 2.59(t, J=7.7 Hz, 2H), 4.49(s, 2H), 7.14(d, J=8.0Hz, 2H), 7.29(d, J=8.1Hz, 2H).

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Abstract

The present invention relates to a preparation method of fingolimod intermediate, specifically relates to a preparation method of {5-[2-(4-n-octyl-phenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl} carbamic acid tert-butyl ester. The method includes performing cross-coupling reaction of a Grignard reagent prepared from n-octyl alkylogen with 4-halogen-benzoate, reducing the generated 4-n-octyl benzoate to 4-n-octyl benzyl alcohol, performing halogenation reaction to give 4-n-octyl benzyl halide, reacting the halide with triphenylphosphine to generate (4-n-octyl benzyl) triphenylphosphonium halide, performing Wittig reaction of the compound with (5-formyl-2,2-dimethyl-1,3-dioxane-5-yl) carbamic acid tert-butyl ester, generating {5-[2-(4-n-octyl-phenyl)-vinyl]-2,2-dimethyl-1,3-dioxane-5-yl}-carbamic acid tert-butyl ester, and preparing the compound by hydrogenation reduction.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamic acid Preparation method of tert-butyl ester. Background technique [0002] Fingolimod, whose trade name is Gilenya, has the structure of 2-amino-2-[2-(4-n-octylphenyl)ethyl]-1,3-propanediol. On September 22, 2010, the US FDA approved the use of fingolimod as a first-line drug for relapsing multiple sclerosis, becoming the first approved oral drug for the treatment of the disease. Currently, the drug has been approved for marketing in the United States, Canada, Europe, Russia, and Australia. [0003] {5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamic acid tert-butyl as shown in formula I Esters are important intermediates in the synthesis of fingolimod and its derivatives. At present, there are only 2 documents reporting the preparation method of the compound of formula I. Kim et al. (Synthesis, 200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/06
Inventor 孙宏斌甄乐
Owner CHINA PHARM UNIV
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