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2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method

A technology of alkylphenyl and alkylbenzene, which is applied in the field of preparation of intermediate products, can solve problems such as unsuitable for industrialized large-scale preparation, harsh reaction conditions, expensive raw materials, etc., and achieve improved atom utilization, convenient operation, and reduction of three wastes Effect

Inactive Publication Date: 2007-04-18
江苏吴中苏药医药开发有限责任公司 +1
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthesis of this compound was first seen in WO9408943 (priority date: October 21, 1992), the Journal of Medical Chemistry in 2000 (J.Med.Chem.43(15): 2946-61) and WO0053569 and Japanese Chemicals in 2005 Pharmacology Bulletin (Chem.Pharm.Bull.53(1):100-2) synthesized the compound through different approaches, although these methods have their own characteristics, but there are still deficiencies, such as some methods use The raw materials are relatively expensive, and some methods use harsh reaction conditions. Many intermediate products in some methods are liquid oils, which require column chromatography purification, which is not suitable for large-scale industrial production.

Method used

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  • 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method
  • 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method
  • 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Synthesis of p-octyl-3-bromopropiophenone

[0049] Add 121g (0.637mol) of octylbenzene and 124g (0.727mol) of 3-bromopropionyl chloride, 800ml of n-hexane into a 2l three-necked bottle equipped with a condensation drying tool, cool to 3°C with ice water externally, add 97g (0.73mol) Anhydrous AlCl 3Stir the reaction for half an hour, remove the ice-water bath and stir for 1 hour, then heat and reflux for half an hour to complete the reaction. Poured into 1500ml of ice water with stirring, solids precipitated, filtered, recrystallized from n-hexane, white flaky crystals, 159.5g (yield: 77%), mp: 53-4°C. 1 HNMR (CDCl 3 ): δ7.87(d, 2H, J=8.4Hz, ArH), 7.27(d, 2H, J=8.4Hz, ArH), 3.76(t, 2H, J=6.87Hz, CH 2 ), 3.55(t, 2H, J=6.87Hz, CH 2 ), 2.66(t, 2H, J=7.72Hz, CH 2 ), 1.65-1.56 (m, 2H), 1.30-1.26 (m, 10H), 0.88 (t, 3H, J=6.7Hz).

Embodiment 2

[0051] Synthesis of p-octyl-3-nitropropiophenone

[0052] Mix 70g (0.216mol) of p-octyl 3-bromopropiophenone and 340ml of DMF, cool it with ice water for external use to below 20°C, add 61g (0.884mol) of sodium nitrite, keep it at 20°C for 2 hours, pour it into 1200ml of water while stirring, Precipitate a yellowish solid, filter, wash with water, and dry by vacuum adsorption. The crude product is decolorized with 450ml of n-hexane and 1g of activated carbon under reflux for half an hour, filtered, crystallized by cooling, filtered, and vacuum-dried at room temperature to obtain 45.5g of a white solid. mp.60~2°C, yield 72.4%. 1 HNMR (CDCl 3 ): δ7.87(d, 2H, J=8.16Hz, ArH), 7.27(d, 2H, J=8.16Hz, ArH), 4.82(t, 2H, J=6.0Hz, CH 2 ), 3.65(t, 2H, J=6.0Hz, CH 2 ), 2.68(t, 2H, J=7.72Hz, CH 2 ), 1.66-1.61 (m, 2H), 1.30-1.26 (m, 10H), 0.88 (t, 3H, J=6.7Hz).

Embodiment 3

[0054] Synthesis of p-octyl-β-nitrophenylpropanol

[0055] Mix 13g (0.045mol) p-octyl 3-nitropropiophenone and 500ml ethanol, after dissolving, add 2.0g (0.053mol) sodium borohydride at room temperature, stir overnight, pour into 100ml ice water, adjust pH with dilute hydrochloric acid To 5, extract three times with ether, combine the extracts, wash twice with water, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain 13 g of oily liquid, which can be directly used for the next reaction. 1 HNMR (CDCl 3 ): δ7.26~7.13 (m, 4H, ArH), 4.78 (t, 1H, J=6.6Hz, CH), 4.63~4.40 (two groups of quintet, 2H, J=6.87Hz, CH 2 ), 2.60(t, 2H, J=7.7Hz, CH 2 ), 2.42~2.34(m, 2H), 2.15(s, br, 1H, OH), 1.60(t, 2H, J=6.87, CH 2 ), 1.30-1.19 (m, 10H), 0.88 (t, 3H, J=6.45Hz).

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Abstract

The invention provides a preparation method for (I) 2- amido -2-[2-(4- alkyl phenyl)ethyl]-1,3- propanediol, which comprises: using alkyl benzene (II) as initial material, with Lewis acid existing, to take Friedel-Crafts acylating reaction with 3- halogenated propionyl chloride and generate beta- halogenated alkylpropiophenone (IV); reducing IV by hydride to obtain 3- nitro -1-(4- alkyl phenyl) propanol (V); preparing 2- nitro -2- methylol -4-(4- alkyl phenyl)-1,4butanediol (VI) by hydroxymethylation; reducing nitro and removing benzalcoholhydroxy to VI and obtaining the objective product.

Description

technical field [0001] The present invention relates to the preparation method of 2-amino-2-[2-(4-alkylphenyl) ethyl]-1,3-propanediol of general formula (I), and the method for preparing intermediate product in preparation this product . [0002] [0003] In the formula: R is C 1-10 The alkyl group is preferably n-octyl. Background technique [0004] 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride, referred to as FTY-720, is prepared by modifying the structure of myriocin, the main component of Cordyceps sinensis Small molecular compound with good immunosuppressive activity, clinically used for organ transplantation to resist rejection and multiple sclerosis and other diseases. [0005] The synthesis of this compound was first seen in WO9408943 (priority date: October 21, 1992), the Journal of Medical Chemistry in 2000 (J.Med.Chem.43(15): 2946-61) and WO0053569 and Japanese Chemical in 2005 Pharmacology Bulletin (Chem.Pharm.Bull.53(1):100-2) synthesiz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C209/34C07C211/27
Inventor 朱崇泉高振云邓银来李锦玉沈成荣杨秋曹庆先
Owner 江苏吴中苏药医药开发有限责任公司
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